CN106511334B - Antifertility drug, pharmaceutical preparation and application - Google Patents
Antifertility drug, pharmaceutical preparation and application Download PDFInfo
- Publication number
- CN106511334B CN106511334B CN201510587196.3A CN201510587196A CN106511334B CN 106511334 B CN106511334 B CN 106511334B CN 201510587196 A CN201510587196 A CN 201510587196A CN 106511334 B CN106511334 B CN 106511334B
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- CN
- China
- Prior art keywords
- dysosma
- deoxypodophyllotoxin
- podophyllotoxin
- spermicidal
- antifertility drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention relates to the field of medicines and discloses an antifertility drug, wherein the antifertility drug contains podophyllotoxin compounds, and the antifertility drug is applied to spermicidal contraception of mammals. Also discloses a pharmaceutical preparation which contains an active ingredient, wherein the active ingredient is the antifertility drug provided by the invention. The invention also provides application of the podophyllotoxin compound in preparation of an antifertility drug, wherein the antifertility drug is applied to spermicidal contraception in the reproductive tract of a mammal. The podophyllotoxin compound provided by the invention can be directly used as a spermicidal contraceptive in the reproductive tract of female mammals, particularly a spermicidal contraceptive medicament in the reproductive tract of human females, and has high safety and low toxicity to human organs. Therefore, the antifertility drug provided by the invention has very important practical significance and application and popularization values for improving the reproductive health level.
Description
Technical Field
The invention relates to an antifertility drug, a pharmaceutical preparation and application.
Background
In recent years, the infection rate of the genital tract of China is on a steep rising trend due to the number of people who are not married and pre-pregnant/the artificial abortion rate. Among various contraceptive measures commonly used at present, no matter intrauterine devices, tubal ligation and vas deferens ligation, hormone oral contraceptives and the like, the problems of large side effect, poor patient compliance, possible interference with normal endocrine of human bodies and the like exist after long-term use. In addition, there are many potential risk factors, especially teratogenicity, carcinogenicity, transmission of Sexually Transmitted Diseases (STDs), and the like. Among the numerous methods of contraception, spermicidal contraceptives in the female reproductive tract are a class of contraceptive methods with increased safety. It has the advantages of small side effect on the whole body and no interference to the normal physiological process of human body. Nonoxinol (NP-9) is a spermicidal contraceptive drug which is only popularized by the world health organization in the world, is a nonionic surfactant and kills sperms by reducing the surface tension of sperm lipid membrane and changing the osmotic pressure of the sperms. Although it is potent in spermicidal action, NP-9 has an increased incidence of damaging female vaginal epithelial cells, thereby increasing the risk of STDs transmission. Furthermore, many studies have demonstrated that it has liver-intestine circulation in vivo, accumulation in vivo, and toxicity to both liver and kidney. Although many sperm-killing contraceptive medicines applied to reproductive tracts at home and abroad, such as phytohemagglutinin, achyranthes bidentata saponin, chlorhexidine and the like, are not applied to clinical research due to overlarge toxic and side effects. Therefore, the method finds safe and low-toxicity spermicidal contraceptive applied to the reproductive tract, and has very important practical significance and application and popularization value for improving the reproductive health level.
Disclosure of Invention
The invention aims to provide an antifertility drug with good spermicidal effect, a medicinal preparation and application.
In order to achieve the above object, the present invention provides an antifertility drug, wherein the antifertility drug contains podophyllotoxin type compounds, and the antifertility drug is applied to spermicidal contraception of mammals.
The invention also provides a pharmaceutical preparation which contains an active ingredient, wherein the active ingredient is the antifertility drug provided by the invention.
The invention also provides application of the podophyllotoxin compound in preparation of an antifertility drug, wherein the antifertility drug is applied to spermicidal contraception in the reproductive tract of a mammal.
The inventor finds that the podophyllotoxin compound can be directly used as a spermicidal contraceptive medicament in the reproductive tract of female mammals, particularly in the reproductive tract of human females, the antifertility medicament can be directly applied to the reproductive tract and/or uterus of females, and the podophyllotoxin compound in the antifertility medicament can act with sperms to change the cell permeability of the sperms so as to kill the sperms or make the sperms lose vigor, so that the sperms cannot reach the oviducts through the uterus and are combined with the ova to achieve the effect of contraception. Furthermore, it does not interfere with the normal physiological function and physiological cycle of women. In particular, the podophyllotoxin compounds derived from the plant extract of the present invention are more safe. Therefore, the antifertility drug provided by the invention has very important practical significance and application and popularization values for improving the reproductive health level.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
According to the invention, the antifertility drug contains podophyllotoxin compounds, and the antifertility drug is applied to spermicidal contraception of mammals.
The antifertility drug of the present invention is an external contraceptive or is called spermicide, and therefore, the antifertility drug is applied to spermicidal contraception in the reproductive tract of mammals, preferably in humans. The use of said antifertility drugs as contraceptive agents for external use is well known to the person skilled in the art, i.e. they can be applied directly to the genital tract and/or uterus of female mammals, in particular human females, to achieve a spermicidal contraceptive effect.
Preferably, the podophyllotoxin compound of the present invention is podophyllotoxin and/or deoxypodophyllotoxin.
The sources of the podophyllotoxin compounds are not particularly limited, and the podophyllotoxin compounds can be derived from natural plant extracts, and can also be obtained by chemical synthesis and biotechnology, such as plant organ culture, cell suspension culture and the like. Among the sources of the above natural plants, the natural podophyllotoxins may be derived from plants of the berberidaceae family, the podophyllum genus (Dysosma), the rhododendron genus (diphyllia), the Sinopodophyllum genus (Sinopodophyllum), the thuja genus (Sabina) and the umbelliferae family, and in the present invention, preferred are Sabina vulgaris (Sabina vulgaris Ant), Sinopodophyllum hexandrum (royle) Ying, southern mountain lotus leaf (diphyllia grayi), Dysosma yunnanensis (dysosmaaurantiacalis (hand-Mazz), Dysosma minitans (Dysosma longissima, Wils) t.h.wang yutex, Dysosma versicolor (Dysosma japonica) and Dysosma japonica (Dysosma japonica), Dysosma versicolor (Dysosma japonica), Dysosma japonica, and Dysosma japonica, and Dysosma japonica, Dysosma yuvey (e, Dysosma japonica, Dysosma of the like, particularly preferred is an extract of Sabinavelgaris Ant. The podophyllotoxin compound derived from the plant extract of the present invention is more safe as a botanical drug.
According to the present invention, various extraction methods known to those skilled in the art can be referred to for the podophyllotoxin-like compound, and in the present invention, when the podophyllotoxin-like compound is derived from an extract of Sabina vulgaris (Sabina vulgaris Ant), the podophyllotoxin and deoxypodophyllotoxin can be obtained by the high performance counter current chromatography method disclosed in CN 104277049A.
The specific method comprises the following steps: taking fruit (cone) of juniperus chinensis as a raw material, crushing the raw material into coarse powder, performing cold soaking and percolation extraction by adopting 95% ethanol, combining ethanol extract of the juniperus chinensis, concentrating under reduced pressure to recover the ethanol, completely evaporating residual ethanol, and performing freeze drying to obtain the juniperus chinensis ethanol extract. HPLC analysis and detection prove that the podophyllotoxin mass percentage content in the ethanol extract of the sabina vulgaris is 0.41%, and the deoxypodophyllotoxin mass percentage content is 1.54%.
The solvent system adopts carbon tetrachloride: ethyl acetate: methanol: water-17: 6:15:3.5 (volume ratio). Taking 3.4L of carbon tetrachloride, 1.2L of ethyl acetate, 3.0L of methanol and 0.7L of water, fully and uniformly mixing in a 10L mixing kettle, standing for layering, and separating an upper phase from a lower phase for later use. And (3) taking the upper phase as a fixed phase, pressing the upper phase in a pneumatic mode and filling the working drum of the countercurrent chromatography main machine. Weighing 20g of ethanol extract of sabina vulgaris, dissolving with 200mL of lower phase solution, and filtering to obtain dissolved ethanol extract solution of sabina vulgaris for later use. Starting a countercurrent chromatographic separation device, adjusting the rotating speed of a main machine to 400rpm, pumping the dissolved ethanol extract solution of the sabina vulgaris at the flow rate of 5mL/min, keeping the flow rate unchanged after sample injection, and pumping a lower phase (a lower phase is used as a mobile phase) to elute podophyllotoxin and deoxypodophyllotoxin components in a working drum of the main machine. Collecting podophyllotoxin and deoxypodophyllotoxin components in the eluted mobile phase respectively according to the detection spectrogram, and determining the flowing time period of the podophyllotoxin and the deoxypodophyllotoxin components. The podophyllotoxin and the deoxypodophyllotoxin components which are separated and collected are subjected to reduced pressure concentration and vacuum drying, and finally 52mg of podophyllotoxin and 196mg of deoxypodophyllotoxin are obtained, and the purity of the podophyllotoxin and the purity of the deoxypodophyllotoxin are respectively 98.6% and 98.2% through HPLC detection.
Wherein, the Sabina vulgaris (Chinese arborescence) has Latin name Sabina vulgaris Ant, also called Xinjiang juniper, Tianshan juniper (Chinese arborescence), Gerber, Sabina vulgaris (Chinese arborescence), climbing juniper (Gansu Zhang Ye) or fetid juniper (inner Mongolian black flag).
The sabina vulgaris is creeping shrub of sabina, class of coniferae, order of coniferae, family of Cupressaceae, genus of sabina, less than 1m high, thin shrub or small arbor; produced in the areas of Tianshan to Altai mountain in Xinjiang, Ningxia Helan mountain, inner Mongolia, northeast of Qinghai, Qilian mountain in Gansu, northern slope and ancient waves, Jingtai, Jingyuan and the like, and the northern elm of Shaanxi. It is grown in rocky hillside in the area with elevation of 1100-2800 m (the blue sea can reach 3300 m), or in the mixed forest of coniferous trees or coniferous trees and broad-leaved trees, or on sand dunes.
The sabina vulgaris cones are fruits of sabina vulgaris shrub plants.
Furthermore, the invention also provides the application of the podophyllotoxin compound in the preparation of an antifertility drug, wherein the antifertility drug is applied to spermicidal contraception in the reproductive tract of a female mammal. Preferably for spermicidal contraception in the human female reproductive tract. The podophyllotoxin compound is preferably podophyllotoxin and/or deoxypodophyllotoxin. Wherein, the sources of the podophyllotoxin compounds have been specifically described above, and are not repeated herein.
Furthermore, the invention also provides a pharmaceutical preparation which contains an active ingredient, wherein the active ingredient is the antifertility drug disclosed by the invention.
According to the invention, the dosage form of the pharmaceutical preparation can be various pharmaceutical preparation dosage forms known in the field, therefore, the pharmaceutical preparation provided by the invention can also be various known pharmaceutical preparation dosage forms, in particular dosage forms which can be applied to respective external contraceptives, and for facilitating administration, the pharmaceutical preparation dosage form can be one selected from gels, foaming agents, membranes and suppositories. The above-mentioned various dosage forms can be prepared by a known method in the field of medicine.
When the medicinal preparation provided by the invention is a gel or a foaming agent, the content of active ingredients in the gel or the foaming agent is 0.1-60 wt%, the content of water in the gel or the foaming agent is 1-99 wt%, and the content of auxiliary materials in the gel or the foaming agent is 0.9-98 wt%. The preparation methods of the gel and the foaming agent are respectively conventional preparation methods of the gel and the foaming agent in the field of medicine. The auxiliary materials in the gel or the foaming agent can be medicinal auxiliary materials which are conventionally used in the field of medicine.
When the medicinal preparation provided by the invention is a film agent or a suppository, the content of the active ingredient in the film agent or the suppository is 0.1-60 wt%, and the content of the auxiliary material in the film agent or the suppository is 40-99.9 wt%. The preparation methods of the film agent and the suppository are respectively the conventional preparation methods of the film agent and the suppository in the field of medicine. The auxiliary materials in the film agent or the suppository can be medicinal auxiliary materials which are conventionally used in the field of medicine.
Wherein, the pharmaceutical excipients conventionally used in the medical field include but are not limited to: one or more of high molecular polymer, surfactant, cosolvent, stabilizer, pH regulator, preservative, etc.
Specifically, the high molecular polymer includes, but is not limited to: alginate, gelatin, pectin, xanthan gum, cyclodextrin, starch and its derivatives, cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, acrylic polymers (e.g., different types of carbomers (980, 971, 974, etc.)), polyacrylic acid, acrylic resins, and the like.
Surfactants include, but are not limited to: phospholipid, sodium lauryl sulfate, sodium dodecyl sulfonate, cetyl trimethyl ammonium bromide, monoalkyl glycerol ether, polyoxyethylene polyoxypropylene copolyether, polyglycerol-polybutylene fatty alcohol ether, butyl stearate, isopropyl isostearate, sodium dodecyl dimethyl acetate, alkylamidopropyl betaine and alkyl imidazolium.
Co-solvents include, but are not limited to: glycerol, propylene glycol, ethanol, polyethylene glycol (such as polyethylene glycol 400 and polyethylene glycol 200), span, Tween 80, Tween 20, and vegetable oil (such as soybean oil and corn oil).
pH modifiers include, but are not limited to: one or more of lactic acid, citric acid, glacial acetic acid, sodium hydroxide and sodium bicarbonate.
Stabilizers include, but are not limited to stearic acid and the like.
Preservatives include, but are not limited to, mixtures of one or more of benzoic acid, sodium benzoate, parabens (four methyl, ethyl, propyl, butyl esters of the paraben type), sorbic acid, and the like.
The preferred embodiments of the present invention have been described above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
The present invention will be described in detail below by way of examples.
Podophyllotoxin and deoxypodophyllotoxin were extracted from sabina vulgaris according to the method described in the specification (method of example 1 of CN 104277049 a), and the separated effective components were measured by high performance liquid chromatography and nuclear magnetic resonance. Wherein:
podophyllotoxin (podophyllotoxin) is white crystal powder, and has hydrogen nuclear magnetic resonance spectrum1H-NMR(400MHz，CDCl3)：δ2.50(s,1H,-OH)，δ2.80(m,2H,H11,12)，δ3.75(s,6H,H27,29)，δ3.81(s,3H,H28)，δ4.05(t,1H,H16)，δ4.55(m,2H,H13,H16)，δ4.75(d,1H,H10)，δ5.95(d,2H,-OCH2O-)，δ6.35(s,2H,H18,22)，δ6.50(s,1H,H3)，δ7.12(s,1H,H6)。
The molecular structural formula of podophyllotoxin is:
deoxypodophyllotoxin (deoxypodophyllotoxin) is white amorphous powder, and has hydrogen nuclear magnetic resonance spectrum1H-NMR(400MHz，CDCl3)：δ2.73(m,2H,H13)，δ2.78(m,1H,H11)，δ3.07(m,1H,H12)，δ3.75(s,6H,H27,29)，δ3.80(s,3H,H28)，δ3.92(m,1H,H16)，δ4.45(m,1H,H16’)，δ4.60(m,1H,H10)，δ5.94(dd,2H,H8)，δ6.34(s,2H,H18,22)，δ6.52(s,1H,H3)，δ6.67(s,1H,H6)。
The molecular structural formula of deoxypodophyllotoxin is as follows:
in the following examples, the podophyllotoxin was extracted and isolated by the above method, and the source of deoxypodophyllotoxin was a standard product obtained from Toronto research chemicals inc.
Example 1
This example illustrates the in vitro spermicidal efficacy observation of the antifertility drugs provided by the present invention.
Preparing a test solution: the podophyllotoxin obtained by the above method was used as a test sample (content: 98%) (HPLC assay). The podophyllotoxin test samples are diluted to 2.0mg/ml, 1.0mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml and 0.0625mg/ml by using physiological saline for later use.
The method for collecting and counting rat sperms comprises the following steps: SD male rats (3 male, 250) with license number SCXK 2013. sup. 0016 provided by Seaprol-Bikai laboratory animals Co., Ltd.) were placed in a sterile small beaker and washed with physiological saline and added with sperm nutrient solution (Tyrode solution: NaCl 4.0g, KCl 0.10g, CaCl)20.10g，MgCl2·6H2O 0.05g，NaH2PO4·2H2O 0.025g，NaHCO30.50g of Glucose and deionized water are used for dissolving in several times, the volume is fixed to 1000ml)4ml, a cross-shaped incision is made on the epididymis tail by using a dissecting scissors, the epididymis tail is placed in a water bath box at 37 ℃ for incubation for 10 minutes, a drop is put on a glass slide, and the sperm motility is checked under a low power microscope (10 multiplied by 10), wherein the sperm motility is required to be more than or equal to 60 percent; sucking 0.1ml of semen when the activity rate is more than or equal to 60%, adding into a small test tube containing 1.9ml of semen diluent, mixing, standing for 3 min, adding one drop into a sperm counting plate, and counting under a high power lens (10 × 40) (method: 4 small lattices of semen number × 4 × dilution multiple (20 times) × 10 times)4) Diluting semen to 10 with Tyrode solution according to the density measured by counting7And/ml, placing in a water bath at 37 ℃ for later use.
Rat spermicidal experimental method: and (3) respectively subpackaging 1ml of prepared test sample diluents with different concentrations into Eppendorf tubes, and placing the Eppendorf tubes in a 37 ℃ water bath for heat preservation for later use. In vitro spermicidal tests were performed on 3 portions of rat semen, respectively. According to the Sander-Cramer method (WHO semen operating manual), 0.2ml of the selected semen is added into the different test sample diluents, a drop of the semen is uniformly mixed and placed on a glass slide, 10 high-power visual fields are observed, and the spermicidal effect of the test sample within 20 seconds to 3 minutes is measured by taking all sperm inactivation as an end point. The effective concentrations of podophyllotoxin at different concentrations for inhibiting sperm motility in rats and the corresponding time points are shown in table 1.
TABLE 1
Note: "+" indicates at least one sperm movement in the field of view; "-" indicates no motile sperm in the visual field.
The results show that: the effective concentration of podophyllotoxin for 20 seconds for completely inhibiting sperm motility is 0.5 mg/ml.
Example 2
This example illustrates the in vitro spermicidal efficacy observation of the antifertility drugs provided by the present invention.
Preparing a test solution: taking deoxypodophyllotoxin as a test sample. The deoxypodophyllotoxin test sample is diluted to 2.0mg/ml, 1.0mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml and 0.0625mg/ml by using physiological saline solution for standby.
The rat sperm collection and counting method and the rat spermicidal experimental method were the same as in example 1. Effective concentrations of deoxypodophyllotoxin at different concentrations for inhibiting sperm motility in rats and corresponding time points are shown in table 2.
TABLE 2
Note: "+" indicates at least one sperm movement in the field of view; "-" indicates no motile sperm in the visual field.
The results show that: the effective concentration of deoxypodophyllotoxin for 20 seconds for completely inhibiting sperm motility is 0.5 mg/ml.
Example 3
This example illustrates the in vitro spermicidal efficacy observation of the antifertility drugs provided by the present invention.
Preparing a test solution: the podophyllotoxin and deoxypodophyllotoxin obtained by the method are taken as test samples (the content is 98 percent) (HPLC detection). The podophyllotoxin test sample is diluted to 2.0mg/ml, 1.0mg/ml, 0.5mg/ml, 0.25mg/ml, 0.125mg/ml and 0.0625mg/ml by using physiological saline, and the deoxypodophyllotoxin test sample is diluted to 2.0mg/ml, 1.0mg/ml, 0.5mg/ml, 0.25mg/ml and 0.125mg/ml for standby.
The human semen sample processing and sperm counting method comprises the following steps: taking semen of healthy adult male (semen of male with fertility and desire inhibition more than 7 days is selected from semen of human semen specimen, sperm motility rate is more than or equal to 70%, forward movement sperm is more than or equal to 75%, malformation is less than or equal to 20%), and placing in a container without spermIn a small beaker, semen nutrient solution (Tyrode solution: NaCl 4.0g, KCl 0.10g, CaCl) is added20.10g，MgCl2·6H2O 0.05g，NaH2PO4·2H2O0.025g，NaHCO30.50g and 0.50g of Glucose, dissolving by deionized water in several times, fixing the volume to 1000ml)3ml, placing the mixture in a water bath box at 37 ℃ for incubation for 10 minutes, taking one drop on a glass slide, and checking the sperm motility under a low power lens (10 multiplied by 10), wherein the motility is required to be more than or equal to 60 percent; sucking 0.1ml of semen when the activity rate is more than or equal to 60%, adding into a small test tube containing 1.9ml of semen diluent, mixing, standing for 3 min, adding one drop into a sperm counting plate, and counting under a high power lens (10 × 40) (method: 4 small lattices of semen number × 4 × dilution multiple (20 times) × 10 times)4) Diluting semen to 10 with Tyrode solution according to the density measured by counting6And/ml, placing in a water bath at 37 ℃ for later use.
Spermicidal experimental method: and (3) respectively subpackaging 1ml of prepared test sample diluents with different concentrations into Eppendorf tubes, and placing the Eppendorf tubes in a 37 ℃ water bath for heat preservation for later use. In vitro spermicidal tests were performed on 3 human sperms, respectively. Referring to the Sander-Cramer method (WHO semen operating Manual), 0.2ml of the selected semen is added into the above different test sample dilutions, immediately placed on a shaker and mixed for 5 seconds, one drop is placed on a glass slide, 10 high power fields (10 × 40) are observed at room temperature and 22 ℃, and the spermicidal effect of the test sample within 20 seconds to 3 minutes is measured by taking all sperm inactivation as an end point. The effective concentrations of podophyllotoxin and deoxypodophyllotoxin at different concentrations for inhibiting human sperm activity and the corresponding time points are shown in table 3.
TABLE 3
Note: "+" indicates at least one sperm movement in the field of view; "-" indicates no motile sperm in the visual field.
The results show that: the podophyllotoxin and deoxypodophyllotoxin can effectively inhibit the activity of human sperm within 20 seconds, and the effective spermicidal concentration is 0.25 mg/ml.
Example 4
And detecting whether the deoxypodophyllotoxin has a mutagenic effect on the salmonella typhimurium.
The sample treatment method comprises the following steps: samples were diluted with dimethyl sulfoxide (DMSO).
Test strains: the experimental strains of Salmonella typhimurium TA97, TA98, TA100 and TA102 were selected. The test is carried out after the tests such as spontaneous reversion, deep rough type (rfa) identification (crystal violet bacteriostasis test), uvrB deletion identification (ultraviolet sensitivity test), R factor (ampicillin resistance test) and pAQ1 plasmid (tetracycline resistance test), histidine requirement test, reaction to positive mutagen and the like are carried out, and the test is carried out after the tests meet the requirements.
The test method comprises the following steps:
reference is made to the method of the Ames experiment in the health food inspection and evaluation specifications (2003 edition). The test subjects were tested by the plate incorporation method with or without the addition of an in vitro activation system (S9 cocktail), respectively. 5 dosage groups are arranged in total, and the dosage is respectively 5 mg/vessel; 1 mg/dish; 0.2 mg/dish; 0.04 mg/dish stock solution; 0.008 mg/dish. Negative controls (spontaneous reversion), test solvent controls (DMSO) and positive controls (specific positives were selected with or without the addition of in vitro activation system for different strains, and the specific names and doses of the positives are given in table 4 below) were also provided.
In the plate mixing test, one tube (2ml) of the top layer culture medium which is melted and insulated at 45 ℃ is taken, 0.1ml of the tested object (or the contrast object) and 0.1ml of the bacterial liquid (if S9 is added, 0.5ml of the S9 mixed liquid is added) are added, the mixture is quickly and fully mixed, and then the mixture is poured onto the lower layer culture medium to be paved and solidified. The top layer of the medium was coagulated, the plate was inverted, and the medium was incubated at 37 ℃ for 48 hours, and the results were observed. Three plates were made for each dose. The test was repeated once. If a positive result is found, the test is repeated twice.
TABLE 4 Deoxypodophyllotoxin Ames test incorporation results
Note:
the positive substances selected without S9 in TA97, TA98 and TA102 are dexon (25 ug/dish) and the solvent is dimethyl sulfoxide.
The positive substance selected without adding S9 in TA100TA1535 is sodium azide (2.5 ug/dish), and the solvent is distilled water.
The positive substance selected from TA97, TA98, TA100 and S9 is 2-aminoanthracene (2 ug/dish), the positive substance selected from TA102 and S9 is 1, 8-dihydroxyanthraquinone (50 ug/dish), and the solvent is dimethyl sulfoxide. The test solvent control was DMSO.
And (3) test results:
the results of the deoxypodophyllotoxin plate incorporation method are shown in Table 4.
As can be seen from Table 4, the subject deoxypodophyllotoxin showed no increase in the number of reversion colonies in the presence or absence of the metabolic activation system, whereas the positive control of each strain showed more than twice the number of reversion colonies in the presence or absence of the metabolic activation system.
The results of the experiments show that the test substance deoxypodophyllotoxin showed no mutagenic effect in Ames experiments on TA97, TA98, TA100, TA102 and TA1535 by the plate incorporation method in the absence of in vitro activation system S9. In the presence of in vitro activation system S9, no mutagenic effect was shown on TA97, TA98, TA100, TA102 and TA 1535. Thus, the tested deoxypodophyllotoxin has no mutagenic effect on the salmonella typhimurium.
Comparative example 1
This comparative example is for explaining the observation of spermicidal effect using physiological saline as a negative control group
Test solution: physiological saline, lot number: 13032331, supplied by Jiangsu tetracyclic biopharmaceuticals, Inc. The rat sperm collection and counting method and the rat spermicidal experimental method were the same as in example 1. The effective concentration of physiological saline for inhibiting sperm motility in rats and the corresponding time points are shown in table 5.
TABLE 5
Note: "+" indicates at least one sperm movement in the field of view; "-" indicates no motile sperm in the visual field.
The results show that: physiological saline does not have a spermicidal effect.
From the above results, it can be seen that the podophyllotoxin compounds provided by the present invention can be used for spermicidal contraception in mammals, particularly in humans. Is especially suitable for being used as a spermicidal contraceptive in the genital tract of human females, and has good spermicidal effect. In addition, the podophyllotoxin in the podophyllotoxin compound also has the dual functions of antivirus and spermicidal, and the deoxypodophyllotoxin has less genetic toxicity, less stimulation to mucous membrane and safer application.
Claims (4)
1. Use of deoxypodophyllotoxin in the manufacture of an antifertility drug, characterized in that said antifertility drug is applied in spermicidal contraception in the human female reproductive tract.
2. The use according to claim 1, wherein the deoxypodophyllotoxin is derived from at least one extract selected from sabinarum furiosaeanum (Sabinavulgaris Ant), sinopodophyllum hexandrum (royle) Ying, southern mountain lotus leaf (Diphylleiiagrangyi), dysosma yunnanensis (Dysosmaaurantiacum (hand.) Hu), dysosma minitans (Dysosmadiformis (Hemsl.et Wils.) T.H.Wang ex Yung), dysosma giganteum (Dysosmajorensis (Gagnep.) Ying), dysosma hexandra (Dysosmajorensis Hance) Woodso (hand.) Woods), dysosma occidentalis (Dysosmajopsis hance), dysosma versicolor (Dysosmae. Wilson.) Woodsia, and dysosma sylvestris (Chesovie.S.S.), and dysosma sylvestris (Cheisy. Cheysene).
3. The use according to claim 1 or 2, wherein the pharmaceutical formulation is in the form of a gel or foam, wherein the gel or foam comprises 0.1-60 wt% of deoxypodophyllotoxin as an active ingredient, 1-99 wt% of water, and 0.9-98 wt% of an adjuvant.
4. The use according to claim 1 or 2, wherein the pharmaceutical preparation is in the form of a film or a suppository, wherein the content of the deoxypodophyllotoxin as an active ingredient is 0.1-60 wt% and the content of the auxiliary material is 40-99.9 wt%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1523722A (en) * | 1975-08-06 | 1978-09-06 | Davis G L R | Pharmaceutical compositions |
| AU6046580A (en) * | 1979-07-27 | 1981-03-05 | Geoffrey Lancelot Rutter Davis | Pharmaceutical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1523722A (en) * | 1975-08-06 | 1978-09-06 | Davis G L R | Pharmaceutical compositions |
| AU6046580A (en) * | 1979-07-27 | 1981-03-05 | Geoffrey Lancelot Rutter Davis | Pharmaceutical compositions |
Non-Patent Citations (1)
| Title |
|---|
| Effects of motility inhibitors during sea urchin fertilization:Microfilament Inhibitors Prevent Sperm Incorporation and Restructuring of Fertilized Egg Cortex,Whereas Microtubule Inhibitors Prevent Pronuclear Migrations;Gerald Schatten,et al.;《Experimental Cell Research》;19811231;第135卷;第311-330页 * |
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