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New medicinal use of Chinese medicine nutmeg and its extract
CN1846775A
China
- Other languages
Chinese - Inventor
高小平 邹文俊 刘忠荣 李伯刚 - Current Assignee
- Chengdu Diao Pharmaceutical Group Co Ltd
Worldwide applications
2005
CN
Application CN 200510020708 events
2005-04-14
2006-10-18
2010-02-03
Application granted
2010-02-03
2025-04-14
Anticipated expiration
Status
Expired - Lifetime
Description
translated from
Technical field
The present invention relates to the myristic new purposes of Chinese medicine, specifically, is the application in preparation 5 inhibitor and preparation treatment prostatic hyperplasia medicine, belongs to the field of Chinese medicines.
Background technology
Benign prostate hyperplasia (BPH) is a prostate hyperplasia, it is the elderly men common disease, blocking with the firm static due to the prostatic hyperplasia that dynamic property due to increasing with prostate smooth muscle tension force blocks is feature, clinical manifestation is residual for the bladder urine flows out obstruction, urgent micturition, frequent micturition, urine, often cause urinary tract infection even bring out nephritis, its sickness rate increased progressively with the age, the number of falling ill in recent years also obviously increases, seriously influence patient's physical exertion and social competence, thereby influence its quality of life.BPH adopts surgical result good mostly, but operation is not to have no danger for elderly patients, the BPH operation is a kind of traumatic and destructive procedure, death risk is arranged, therefore to seek the risk of Drug therapy to avoid performing the operation, and constantly perfect along with what the hyperplasia of prostate pathogeny was familiar with, medicine has become the important means of BPH treatment.
Though at present BPH the cutter reason takes place does not really also illustrate fully, the 5-alpha-reductase is widely accepted with the relation of BHP generation.The effect of 5-alpha-reductase is to make testosterone (T) metabolism be dihydrotestosterone (DHT), and is relevant with the generation of BPH.Studies show that simultaneously: 5 is the key enzyme of skin male hormone metabolism, the discovered in recent years various skin is sick relevant unusually with male hormone metabolism, some 5 inhibitor have been used for androgenetic alopecia and other androgen dependency dermatosiss, as (Yin Xingping such as acne, hirsutisms, Xia Long celebrating .5a-reductase in male hormone metabolism effect and inhibitor in the application of department of dermatologry. foreign medical science skin cypridology fascicle, 2004,30 (6): 375～377).DHT is the activity form of prostate androgen, by prostate breaks up, growth promoter is essential.But in the geratic period, prostata tissue keeps very high 5-alpha-reductase activity, and DHT content is raise, and therefore thinks to cause the key factor of prostatic hyperplasia.This theory is confirmed by a kind of research of 5-alpha reductase inhibitor finasteride.Finasteride reduces testosterone with competitive combination of 5 and combines with 5, and the blocking-up testosterone transforms to DHT, and the interior DHT of plasma D HT and prostate is descended rapidly, prostate is dwindled, and increase the urine flow rate, and improve and block symptom, reduce the complication of BPH.In recent years, the medicine of plant origin shows the good prospect of treatment BPH, as saw palmetto berry extract and pollen extract (Prostat), all has the effect that suppresses 5.
Semen Myristicae is the mature seed kernel of the tall and big aiphyllium plant of Myristicaceae Semen Myristicae Myristica fragrans Houtt.Originate in Maluku, China Taiwan, Yunnan, Guangdong introducing and planting.Put down in writing according to " Bencao Jingshu ": " the hot flavor of Semen Myristicae can loose and can disappear, wet can and in unobstructed, its gas fragrance, fragrance is gone into spleen earlier, spleen master digestion, gentle and hot fragrant, so whet the appetite, stomach is liked and is warmed up also." Chinese materia medica " thought: Semen Myristicae suffering, temperature are returned spleen, stomach, large intestine channel, and relieving diarrhea with astringents is arranged, and the effect of warming middle-JIAO to promote flow of QI is mainly used in the Deficiency and coldness of spleen and stomach chronic diarrhea, cold syndrome of the stomach distending pain and lack of appetite vomiting.Modern study shows that Semen Myristicae contains the tannic acid composition of volatile oil, fatty oil, starch, protein and Galla Turcica (Galla Helepensis) acids.Contain myristicin, safrole, elemicine, methyl Turbo cornutus Solander phenol and multiple terpene compound etc. in the volatile oil.Its main pharmacological is: antimicrobial, antioxidation, anesthesia, calmness and cause unreal effect (" Chinese materia medica ", Zhang Tingmo chief editor, Beijing, Higher Education Publishing House, 2002,1).But do not see as yet that so far Semen Myristicae suppresses the report of 5, prevention or treatment benign prostatic hyperplasia and relevant disease.
Summary of the invention
Technical scheme of the present invention has provided the new purposes of Chinese medicine Semen Myristicae and extract thereof.The present invention also provides and has contained the Semen Myristicae crude drug in whole or extract is pharmaceutical composition of active component and its production and use.
The invention provides application and Chinese medicine Semen Myristicae the application in preparation treatment prostatic hyperplasia medicine of Chinese medicine Semen Myristicae in preparation 5 inhibitor medicaments.
Described Chinese medicine Semen Myristicae comes from the mature seed kernel of the tall and big aiphyllium plant of Myristicaceae Semen Myristicae Myristica fragransHoutt.
Described Semen Myristicae is Semen Myristicae protogenic medicinal powder or water/extractive with organic solvent.
The present invention also provides a kind of pharmaceutical composition that is used to prepare the 5 inhibitor medicaments, it is to be active component by described Semen Myristicae protogenic medicinal powder or its water/extractive with organic solvent, adds the preparation that acceptable accessories or complementary composition are prepared from.
Wherein, described Semen Myristicae extractive with organic solvent is the extract of the mixed solvent formed with arbitrary proportion of a kind of or any two kinds or more of solvent in the organic solvents such as methanol, ethanol, ethyl acetate, n-butyl alcohol, ether, petroleum ether.
With above-mentioned Chinese medicine Semen Myristicae or its extract, after pharmaceutically acceptable auxiliary additive composition mixes, by corresponding conventional medicine formulation method, can prepare the 5 inhibitor, prevent and/or treat the medicine of prostatic hyperplasia.For example, with can received disintegrating agent in oral formulations, after auxiliary adding ingredients commonly used such as excipient, lubricant, binding agent, filler mix, operational approach routinely and process can be made for the medicine of tablet, pill, capsule or solid orally ingestible forms such as multiple corresponding slow releasing agent, controlled release agent; After surfactant, diluent, antiseptic, stabilizing agent, correctives, the thickening agents etc. such as solubilizing agent, emulsifying agent, retouching agent, foaming or defoamer of routine mix, by corresponding conventional method, can prepare the oral drugs of liquid preparation forms such as becoming water preparation, syrup, oral liquid; With the reagent mix of suspending agent, stabilizing agent, dispersant or the regulator solution osmotic pressure of routine,, be configured to injection by corresponding conventional method.
Further, the invention provides this preparation of drug combination method, wherein the preparation of Semen Myristicae extract may further comprise the steps:
A) Semen Myristicae water or 30～95% alcohol reflux are 1～3 time, and the solvent amount is respectively 6～8 times, and extraction time is 1～3 hour, and merge extractive liquid,, concentrate drying get sample A;
B) A is water-soluble, and with petroleum ether, ether, ethyl acetate or n-butanol extraction, decompression and solvent recovery gets water extract and corresponding extractive with organic solvent.
The present invention also provides the application of this pharmaceutical composition in preparation 5 inhibitor medicaments.
The present invention also provides the application of this pharmaceutical composition in preparation treatment prostatic hyperplasia medicine.
According to the present invention, can be with above-mentioned Chinese medicine Semen Myristicae or its extract of containing, or Chinese medicine Semen Myristicae and extract thereof and other have the compound preparation that the Western medicine that prevents and/or treats the prostatic hyperplasia effect or active ingredient of Chinese herbs compatibility are formed, according to the preparation technique of routine, be prepared into oral formulations or injection.
The present invention extracts from the Chinese medicine Semen Myristicae and obtains Semen Myristicae extract, and it has the active effect of 5 that suppresses evidence, and the prostatic hyperplasia of male rat is had the obvious treatment effect.Can be used for the pharmaceutical preparation for preparing the 5 inhibitor, treat and/or prevent prostatic hyperplasia, as oral formulations or injection.Have characteristics evident in efficacy, cheap, taking convenience.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The capsular preparation of embodiment 1 Semen Myristicae protogenic medicinal powder
Get the dry mature kernal of Chinese medicine Semen Myristicae Myristica fragrans Houtt, pulverize according to a conventional method, sieve, making granularity is 60～80 purpose Semen Myristicae fine powders, and fine powder incapsulates, sterilization, packing.
The preparation of embodiment 2 Semen Myristicae extracts
Take by weighing Semen Myristicae 1000g, with 90% alcohol reflux three times, the solvent amount is respectively 8 times, 6 times, 6 times, and extraction time was respectively 2 hours, 1 hour, 1 hour.Merge extractive liquid,, being recycled to does not have the alcohol flavor.50 ℃ of drying under reduced pressure get sample A.Take by weighing sample A 50g, use the 150ml dissolved in distilled water.Aqueous solution is used petroleum ether, ether, ethyl acetate, the n-butanol extraction of 3 times of volumes respectively, and decompression and solvent recovery gets sample B (petroleum ether phase), C (ether phase), D (ethyl acetate phase), E (n-butyl alcohol phase), F (water).
The preparation of embodiment 3 tablets
The composition of tablet: Semen Myristicae extract A 0.5g
HPMC
LV100 30g
Lactose 69g
Magnesium stearate 0.5g
Be total to 100g
With Semen Myristicae extract A, HPMC
LV100, the lactose mixing, be binding agent system wet granular with 75% ethanol, cross 22 mesh sieves, 50 ℃ of dryings 3 hours, 22 mesh sieve granulate add magnesium stearate mixing tabletting, make 1000, every 0.1g.Oral, 3 times on the one, each 2.
The preparation of embodiment 4 capsules
Capsule is formed: Semen Myristicae extract B 0.5g
Starch 99g
Magnesium stearate 0.5g
Be total to 100g
With Semen Myristicae extract B, starch, magnesium stearate mixing, encapsulated, totally 1000, every 0.1g.Oral, 3 times on the one, each 2.
The preparation of embodiment 5 injections
Injection is formed: Semen Myristicae extract C 0.5g
Tween 80 10ml
Sodium chloride 8g
Semen Myristicae extract C adds 10% sodium carbonate and transfers pH value to 7.0～7.5, and cold preservation is filtered, and adds Tween 80, adds the injection water to 1000ml, filter, and packing, embedding, 100 ℃ of flowing steam sterilizations, 30min is promptly.
Embodiment 6 compound tablet or capsular preparation
Prepare compound preparation with Semen Myristicae extract, get Semen Myristicae extract D 0.5g, Rhizoma Curcumae Longae extract 200g according to a conventional method, adds adjuvant, makes tablet or capsule.Every or a 200mg are used for the patient, and be oral, and 3 times on the one, each 1 or 1, be a course of treatment January.
Below prove beneficial effect of the present invention by pharmacodynamics test.
Test example 1 Semen Myristicae extract is to the active inhibitory action of prostate gland cancer cell 5
Prostate gland cancer cell (DU145 expresses 5) is kept cultivation according to a conventional method and is being contained 10% calf serum, the 100ug/ml streptomycin, and in 1640 culture medium of 100U/ml penicillin, next day is with 2 * 10
4/ hole is inoculated in 24 orifice plates, 37 ℃ of 5%CO
2Cultivated 24 hours in the saturated humidity incubator, renew bright culture medium, every hole adds the 0.1mM testosterone and adds testing sample respectively, with saw palmetto berry (Sabalberry extract, Madaus AG) positive control drug, continue to cultivate 2 hours, the collecting cell culture supernatant, with EIA test kit detection by quantitative dihydrotestosterone, measure the light absorption value under the 450nm condition, calculate the dihydrotestosterone amount according to the standard test value, determine the conversion of testosterone and the inhibition that sample is changed testosterone, the results are shown in Table 1 with this:
Table 1 Semen Myristicae is to the inhibitory action (sample concentration: 100 μ g/ml) of testosterone conversion in the prostate gland cancer cell
| The sample title | DHT(pg/ml) | The sample title | DHT(pg/ml) |
| Cell control cells+testosterone saw palmetto berry A B | 71 987.38 276.03 431.93 383.27 | C D E F | 179.32 464.29 449.31 479.45 |
Table 1 result shows, cell+testosterone group DHT concentration significantly raises than the cell matched group, each medicine group DHT concentration all obviously reduces than cell+testosterone group, show that Semen Myristicae extract A, B, C, D, E, F all have the active effect of the prostate gland cancer cell 5 of inhibition, wherein Semen Myristicae extract C is the strongest to the 5 inhibitory action, and effect is better than the control drug saw palmetto berry.
Test example 2 Semen Myristicae extracts are organized the active inhibitory action of 5 to rat prostate
Get the rat prostate tissue, add homogenate buffer (1: 5 volume), the consisting of of homogenate buffer: 0.88M sucrose, 1.5mM CaCl
2, tissue homogenate is got supernatant and testing sample or positive drug (finasteride: Merck Sharp ﹠amp through high speed centrifugation (10000 * g, 15min, 4 ℃); Dohme (U.K) Ltd produces, specification: 5mg * 10/box, and lot number: 235820) reaction is 10 minutes, adds 0.05mM testosterone, 0.02mM NADPH, measures light absorption value under the 450nm condition, and calculates suppression ratio: suppression ratio (%)=(A
0-A
1)/A
0* 100, the results are shown in Table 2:
Table 2 Semen Myristicae is to the active inhibitory action of prostata tissue 5 (sample concentration: 100 μ g/ml)
| The sample title | Suppression ratio (%) | The sample title | Suppression ratio (%) |
| Cell contrast homogenate+testosterone finasteride A B | - - 100 67 80.75 | C D E F | 93.72 63.24 69.31 69.45 |
Table 2 result shows, each medicine group all shows inhibitory action to prostata tissue 5 activity, show that Semen Myristicae extract A, B, C, D, E, F all have the active effect of the prostata tissue 5 of inhibition, wherein Semen Myristicae extract C is the strongest to the 5 inhibitory action, suppression ratio reaches 93.72%, and effect slightly is weaker than control drug finasteride (100% suppresses).
The outgrowth effect of test example 3 Semen Myristicae extract C treatment rat prostate
Choose 56 of normal male SD rats, be divided into seven groups at random, every group 8, be normal group (irritate stomach and give the equal-volume normal saline), castration group (excision bilateral testes), castration+testosterone group (is extractd bilateral testes, injection testosterone propionate 2mg/kg), the Semen Myristicae height, in, low dose group (castration+testosterone and irritate stomach give Semen Myristicae C extract), the positive drug group (also irritate stomach and give (10 * 1 plate/box of Prostats by castration+testosterone, every contains water solublity pollen extract P5 70mg, fat-soluble pollen extract EA10 4mg, Meirui Pharmaceutical Co., Ltd, Nanjing produces)).45 days posterior orbit rear vein beards of administration are got blood, and separation of serum is measured DHT concentration, and detection method and calculating are carried out with reference to the explanation of EIA test kit; Get and take off neck behind the blood and put to death rat, peel off the prostate surrounding tissue, take out the prostate siphonal lobe, place low-temperature homogenate after taking by weighing weight in wet base, centrifugal collection supernatant detects DHT and T concentration in the tissue, and detection method and calculate with reference to the EIA test kit explanation and carry out the results are shown in Table 3.
Table 3 Semen Myristicae extract C to the prostatic hyperplasia rat blood serum, organize influence (n=8, the X ± SD) of DHT level
| Group | Dosage mg/kg | Serum DHT (pg/ml) | Tissue T (ng/ml) | Organize DHT (pg/ml) | Prostate weight in wet base (mg) |
| Semen Myristicae is low in normal castration castration+high Semen Myristicae of testosterone Prostat Semen Myristicae | - - 2 100 400 200 100 | 1057.32±389.92 218.26±258.35* 1352.17±107.12 673.24±203.31* 632.21±149.34* 715.82±229.37 889.63±313.45 | 102.73±32.41 0.83±0.16* 26.56±15.32 33.65±22.04 26.76±6.84 37.93±11.88 38.24±13.08 | 1043.90±279.87 2.45±1.41*** 961.44±158.67 474.24±151.03** 432.76±132.58** 534.47±154.57* 632.75±191.77 | 587.43±151.39 18.23±8.91** 933.72±301.75 512.44±107.83* 477.35±124.87* 573.54±104.05* 759.00±228.79 |
Annotate: compare with castration+testosterone group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 3 result shows, with castration+testosterone group relatively, each dosage group of Semen Myristicae extract C all has the effect trend that reduces serum DHT, organizes DHT and prostate weight in wet base, and action intensity strengthens with the increase of concentration; Wherein high dose group has remarkable reduction serum DHT (P＜0.05), organizes DHT (P＜0.01) and prostate weight in wet base (P＜0.05) effect, and its action intensity and Prostat are close; Middle dosage group has significant reduction effect (P＜0.05) to organizing DHT and prostate weight in wet base.
Above-mentioned pharmacodynamics test, though be the test of pesticide effectiveness of the Semen Myristicae extract C of embodiment 2 preparations, but various dose group medicine-feeding test result has shown the dose-effect relationship of drug extract treatment prostatic hyperplasia of the present invention, illustrate that medicine of the present invention has the effect of obvious treatment prostatic hyperplasia, and its effect strengthens with the increase of dosage, can be used for preparing the pharmaceutical preparation that treats and/or prevents prostatic hyperplasia, and is evident in efficacy, and steady quality, controllability is strong.
Claims (10)
Hide Dependent
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Claims (10)
Hide Dependent
translated from
1, the purposes of Chinese medicine Semen Myristicae in preparation 5 inhibitor medicaments.
2, the purposes of Chinese medicine Semen Myristicae according to claim 1 in preparation 5 inhibitor medicaments, it is characterized in that: described 5 inhibitor medicaments is the medicine of treatment prostatic hyperplasia.
3, purposes according to claim 1 and 2, described Chinese medicine Semen Myristicae are the mature seed kernel of the tall and big aiphyllium plant of Myristicaceae Semen Myristicae Myristica fragrans Houtt..
4, purposes according to claim 1 and 2 is characterized in that, described Chinese medicine Semen Myristicae is Semen Myristicae protogenic medicinal powder or myristic water or extractive with organic solvent.
5, a kind of pharmaceutical composition that is used to prepare the 5 inhibitor, it is an active component by Semen Myristicae protogenic medicinal powder or its water/extractive with organic solvent, adds the preparation that acceptable accessories or complementary composition are prepared into.
6, the pharmaceutical composition that is used to prepare the 5 inhibitor according to claim 5 is characterized in that: described Semen Myristicae extractive with organic solvent is the extract of the mixed solvent of one or more solvent compositions in the organic solvents such as methanol, ethanol, ethyl acetate, n-butyl alcohol, ether, petroleum ether.
7, the pharmaceutical composition of preparation 5 inhibitor according to claim 5 is characterized in that: described preparation is oral formulations or injection.
8, a kind of method for preparing the described pharmaceutical composition of claim 5, wherein the preparation of Semen Myristicae extract may further comprise the steps:
A) Semen Myristicae water or 30～95% alcohol reflux, the solvent amount is 6～8 times, and extraction time is 1～3 hour, and merge extractive liquid,, concentrate drying get sample A;
B) A is water-soluble, with petroleum ether, ether, ethyl acetate or n-butanol extraction, decompression and solvent recovery gets water extract and corresponding extractive with organic solvent.
9, the purposes of each described pharmaceutical composition of claim 5～8 in preparation 5 inhibitor medicaments.
10, the purposes of each described pharmaceutical composition of claim 5～8 in preparation treatment prostatic hyperplasia medicine.