CN110215447A - The sperm killing contraceptive medicine of application and its preparation of the mefenamic acid in contraceptive - Google Patents
The sperm killing contraceptive medicine of application and its preparation of the mefenamic acid in contraceptive Download PDFInfo
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- CN110215447A CN110215447A CN201910517133.9A CN201910517133A CN110215447A CN 110215447 A CN110215447 A CN 110215447A CN 201910517133 A CN201910517133 A CN 201910517133A CN 110215447 A CN110215447 A CN 110215447A
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- sperm
- mefenamic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
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- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Gynecology & Obstetrics (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Sperm killing contraceptive medicine the invention discloses a kind of application of mefenamic acid in sperm killing contraceptive medicine, preparation includes compound shown in formula I.Mefenamic acid can quickly cause immobilization of spermatozoa as main spermicidal ingredient, lower to the irritation of vaginal mucosal epithelium cell, highly-safe.
Description
Technical field
The present invention relates to technological field of biochemistry, more particularly to a kind of mefenamic acid in sperm killing contraceptive medicine
In application and its preparation sperm killing contraceptive medicine.
Background technique
Spermaticide object, which refers to, is put into the drug that intravaginal causes immobilization of spermatozoa and reaches contraception purpose, usually by spermicidal
Specific dosage form is made in sub- agent and pharmaceutical carrier, is put into intravaginal before sexual life, is reached by chemical spermicidal and physical barriers effect
To contraceptive effect.Spermicidal contraceptive medicines and devices can independently be used by women, and can reach other effects by adding relative medicine.
Domestic spermaticide object is to live with nonionic surfactant nonoxinol (Nonoxynol-9, N-9) at present
Property ingredient, kind are extremely single.Although the spermicidal effect of N-9 is rapid and strong, external clinical research is it has been shown that Reusability
N-9 can damage vaginal mucosa epithelium, and the risk of propagation and the HIV infection of raising property disease, safety is by serious matter
It doubts.For this purpose, researching and developing novel efficient, less toxic, quality controllable sperm killing contraceptive medicine has become research hotspot.
Mefenamic acid (N-2,3- xylyl ortho-aminobenzoic acid) alias mefenamic acid, mefenamic acid, in U.S. FDA approval
The nonsteroidal anti-inflammatory analgetic object in city, has analgesia, antipyretic and anti-inflammatory effect, and oral dose 250-500mg can be used four daily
Secondary, mefenamic acid (MA-01) has also obtained Chinese CFDA approval listing, Chinese Pharmacopoeia is included in, for anti-inflammatory and analgesia.Current research
It was found that mefenamic acid also has preferable spermicidal activity, having research and development becomes the potentiality of novel sperm killing contraceptive medicine.
Therefore, how mefenamic acid to be applied to prepare in sperm killing contraceptive medicine and provide one kind with mefenamic acid for activity
The problem of contraceptive of ingredient is those skilled in the art's urgent need to resolve.
Summary of the invention
In view of this, the spermicidal of the application and its preparation that the present invention provides a kind of mefenamic acids in sperm killing contraceptive medicine
Contraceptive, contraceptive can quickly kill sperm, to vaginal mucosal epithelium using mefenamic acid as main spermicidal ingredient
The irritation of cell is lower, highly-safe.
To achieve the goals above, the present invention adopts the following technical scheme:
A kind of application of mefenamic acid in sperm killing contraceptive medicine.
What above technical scheme reached has the technical effect that mefenamic acid is usually anti-inflammation and analgesic drugs, and the present invention for the first time will
Mefenamic acid is applied to spermicidal contraception field, has opened up its new application prospect；The contraceptive effect of mefenamic acid is obvious, can be effective
Inhibit the activity of sperm, it is smaller to the damage of vagina mucosa.
A kind of sperm killing contraceptive medicine, including compound shown in formula I:
Drug of the invention is local administration, part action, and administration route is vagina administration.As currently preferred skill
Art scheme, the sperm killing contraceptive medicine are suitble to the dosage form of vagina administration to include: gelling agent, suppository, film, cream or sustained release
Agent.
Pharmaceutical carrier used in the present invention refers to the carrier for Therapeutic Administration, including various excipient and diluent, it
Itself be not necessary active constituent, and there is no excessive toxicity after applying.In addition, in these carriers, there is likely to be auxiliary
The substance of helping property, such as filler, bioadhesive polymer, disintegrating agent, lubricant, glidant, effervescent agent, emulsifier and preservative.
Reactive compound of the invention is mefenamic acid, is directly to contact sperm by vagina administration in intravaginal, make essence
Sub- loss of activity and achieve the purpose that contraception.Less than 25mg/ days, (with 10 times of MEC concentration, dosage was drug dose range
4mL meter).
The application method of drug are as follows: this product is the short-acting contraceptive of intravaginal, uses for 0~2 hour before sexual life, incite somebody to action this
After product preparation is placed in vagina depths, sexual life can be carried out.More effectively contraception can be obtained by, which reusing after sexual life, protects
Shield.
Note: described spermicidal effect in the art usually includes killing sperm effect (to cause injury of plasmalemmae of sperms dead
Die) or braking sperm effect (sperm is made to lose vigor completely), to reach contraceptive effect.
It can be seen via above technical scheme that compared with prior art, the present disclosure provides a kind of spermicidal contraceptives
The application of object and mefenamic acid in sperm killing contraceptive medicine, what is reached has the technical effect that
1) discovery mefenamic acid can be used for vagina sperm killing contraceptive medicine for the first time, be the new discovery in spermicide research；
2) mefenamic acid is low for vagina spermicidal contraception effective dose, high-efficient, and drug safety coefficient is high.
3) mefenamic acid can significantly inhibit human spermatogoa movement, and lower to vaginal mucosal epithelium cytotoxicity.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
The embodiment of invention for those of ordinary skill in the art without creative efforts, can also basis
The attached drawing of offer obtains other attached drawings.
Fig. 1 attached drawing is inhibiting effect figure of the mefenamic acid to sperm motility；
Fig. 2 attached drawing is sperm ultrastrueture figure；Wherein the first from left is the ultra microstructure figure of untreated sperm, central diagram
For with mefenamic acid treated sperm ultrastrueture figure, a right attached drawing is with the ultra microstructure figure of N-9 treated sperm；
Fig. 3 attached drawing is cytotoxicity figure of the mefenamic acid to vaginal epithelial cell VK2；
Fig. 4 attached drawing is cell membrane damage figure of the mefenamic acid to vaginal epithelial cell VK2.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment shall fall within the protection scope of the present invention.
Embodiment 1 verifies mefenamic acid to the inhibiting effect of sperm motility
Mefenamic acid in the present invention is purchased from Sigma company, and molecular formula is C15H15NO2, molecular weight 241.29, CAS is stepped on
Record number is 61-68-7.
Experimental method
Sperm collection: human sperm's samples sources are in the voluntary male contributor of fertility, and ascetic 3-7 days, the method for consoling oneself was adopted
Collect sperm into seminal fluid collecting ware, 37 DEG C of standing 30min wait for that it liquefies completely, obtain sperm swim-up liquid, spare；
Screening: it is filtered out referring to sperm swim-up method in " World Health Organization human seminal fluid checks and treatment of laboratory handbook "
High motile sperm；
Dilution: high motile sperm sample is adjusted to 1 × 10 with EBSS (1%BSA)7A/mL is placed in 37 DEG C of cultures
Case, it is spare.Mefenamic acid is dissolved in DMSO, the mefenamic acid stock solution that concentration is 0.5mol/L is made, by mefenamic acid stock solution
0.5,1,1.5,2 and 2.5mmol/L is successively diluted to EBSS；
It counts: sperm swim-up liquid is uniformly mixed in equal volume with the mefenamic acid dilution of various concentration, draw on a small quantity, add
Onto 37 DEG C of pre-temperature of counting plate for sperm in advance, counted under microscope.
Then according to the series of concentrations of drug and corresponding sperm motility data, data return with SPSS software and are divided
The minimum effective concentration (Minimum Effective Concentration, MEC) and half of braking sperm is calculated in analysis
Effective concentration (Median Effective Concentration, EC50).
Experimental result
Mefenamic acid is to the experimental result of the inhibiting effect of sperm motility referring to Fig. 1.Fig. 1 is shown, is when exposure duration
When 5min, with mefenamic acid concentration increase sperm motility present decreasing trend, show Sperm mobility and movement velocity by
Inhibit to obvious, and dose-dependent effect is presented.At this point, mefenamic acid is to smart concentration (MEC) value of 100% suppression of human sperm
2.5mmol/L, 50% presses down smart concentration (EC50) value be 1.0mmol/L.Mefenamic acid is prompted to move with stronger inhibition human spermatogoa
Effect, sperm can be made to lose mobility completely in > 2.5mmol/L concentration, to inhibit the combination of sperm and ovum,
Play the role of contraception.
2 sperm double action of embodiment test
Experimental method
Human spermatogoa upstream liquid in embodiment 1 is uniformly mixed in equal volume with mefenamic acid dilution, keeps its final concentration of
EBSS is washed 2 times after 2.5mmol/L, 5min, and resuspension is placed on 37 DEG C of incubators and is incubated for 30min.It is observed under phase contrast microscope
The recovery of sperm motility and metamorphosis after braking.Oscillating movement, which occurs, in sperm after braking is considered double action.
Experimental result
For sperm after mefenamic acid braking after EBSS is washed, sperm mediun cannot restore its vigor after being incubated for 30min.
Prompt mefenamic acid has the function of stronger inhibition human spermatogoa movement, and the effect is irreversible.
Influence of 3 mefenamic acid of embodiment to sperm ultrastrueture
Experimental method
Human spermatogoa upstream liquid in experimental example 1 is uniformly mixed in equal volume with mefenamic acid dilution, keeps its final concentration of
2.5mmol/L is the control of existing marketed drugs with nonoxinol solution.EBSS is washed 2 times after 5min, and spermatoblast suspension is dripped
Piece air-dries, and fixes through 2.5% glutaraldehyde, through gradient alcohol dehydration, CO after washing2Critical point drying, metal coating, scanning electron microscope
Observation.
Experimental result
Referring to fig. 2, control group plasmalemmae of sperms is smooth, and acrosome structure keeps complete, mefenamic acid treated plasmalemmae of sperms
Completely, obvious damage is had no, it is seen that acrosome back boundary and rear ring；And obvious matter is presented in sperm head after positive control N-9 processing
Membrane damage, cytoplasm leakage, neck are broken.Illustrate that mefenamic acid braking sperm is not exclusively complete by destroying plasmalemmae of sperms
At, this is different from the N-9 spermicide of current clinical use.
Cytotoxicity of 4 mefenamic acid of embodiment to people's vaginal mucosal epithelium cell VK2/E6E7
Experimental method
Culture: VK2/E6E7 (being purchased from ATCC cell bank, passed on, frozen by this seminar) cell of logarithmic growth phase connects
Kind is in 96 well culture plates equipped with DefinedKeratinocyte-SFM (being purchased from GIBICO company) culture medium, and 1 × 105It is a
Cells/well is placed in CO237 DEG C of precultures of cell incubator are stayed overnight；
Culture medium in each culture hole is toppled over completely.100 μ L fresh cultures are added in blank group and control group, and processing group is every
The concentration that hole is added in 100 μ L embodiments 1 is respectively 0.5,1,1.5,2 and 2.5mmol/L mefenamic acid dilution；With
Defined Keratinocyte-SFM is blank control, with nonoxinol solution for existing marketed drugs positive control.Effect 4
After hour, fresh culture is replaced in each hole, and 10 μ L, concentration is added and is placed in 96 orifice plates for 5mg/mLMTT solution, in CO2Carefully
37 DEG C of born of the same parents' incubator are continued culture 4 hours；
Culture solution is removed, every hole is added 100 μ L DMSO solutions for cell cracking, measures each hole in 570nm wave with microplate reader
The OD value of strong point calculates cell viability inhibiting rate:
Cell viability inhibiting rate (%)=1- processing group OD570nm/ control group OD570nm× 100%
Experimental result
Referring to Fig. 3, the results show that after the mefenamic acid effect 4h of various concentration, the suppression to VK2/E6E7 cell viability
Rate processed is respectively 77.30%, 81.91%, 83.45%, 88.40% and 89.08.With same experimental conditions, nonoxinol exists
100% inhibits under the concentration of sperm motility, to the inhibiting rate of VK2/E6E7 cell viability up to 96.13%.Prompt mefenamic acid
Nonoxinol is not higher than to human vagina epithelial cell toxicity, there are research and development to become the potentiality of intravaginal sperm killing contraceptive medicine.
Damage of 5 mefenamic acid of embodiment to vaginal mucosal epithelium VK2/E6E7 cytoplasma membrane
Experimental method
The VK2/E6E7 cell inoculation of logarithmic growth phase is in 24 well culture plates, and 1 × 105A cells/well, is placed in CO2Carefully
37 DEG C of precultures of born of the same parents' incubator are stayed overnight；
Culture medium in each culture hole is toppled over completely.500 μ L fresh cultures are added in blank group and control group, and processing group is every
The concentration that hole is added in 500 μ L embodiments 1 is respectively 0.5,1,1.5,2 and 2.5mmol/L mefenamic acid dilution；With
DefinedKeratinocyte-SFM is blank control, with nonoxinol solution for existing marketed drugs positive control.Effect 4
After hour, each 2.5 μ l of SYBR-14 and PI is added in every hole, and its final concentration is made to respectively reach 100nM and 12nM, will be mixed after mixing
It closes liquid and is placed on 37 DEG C, 5%CO220min is incubated in incubator, in fluorescence microscopy microscopic observation.
Experimental result
Referring to fig. 4, control group VK2/E6E7 cell keeps complete because of plasma membrane, and PI cannot pass through complete cell membrane, SYBR-
14 can make cell in green fluorescence；Mefenamic acid processing group most cells are in green fluorescence, and only respective cells are broken because of plasma membrane
Bad, PI enters the fluorescence that takes on a red color in conjunction with DNA into the cell.As it can be seen that mefenamic acid is to vaginal mucosal epithelium VK2/E6E7 cell
The damage of plasma membrane is relatively slight.And the red fluorescence of nuclear structures is only presented in N-9 processing group, shows that cell membrane damage is serious,
Eucaryotic cell structure is imperfect.
Summarize: when mefenamic acid complete inhibition sperm motility concentration under, can holding part plasmalemmae of sperms integrality,
The serious damage that will not cause plasmalemmae of sperms, the mechanism for prompting its inactivating sperm are not completely dependent on destruction plasmalemmae of sperms, may be used also
It can play the role of inhibiting sperm motility by influencing mitochondria of sperms function or ion channel.And commercially available spermatocide nonylbenzene
The mechanism of the inactivating sperm of alcohol ether N-9 mainly destroys plasmalemmae of sperms, which can lead to it and make to the secondary of vagina mucosa damage
With.When therefore with mefenamic acid preparation intravaginal sperm killing contraceptive medicine, side effect is expected to be less than presently commercially available is with N-9
The intravaginal spermatocide of active constituent.
Each embodiment in this specification is described in a progressive manner, the highlights of each of the examples are with other
The difference of embodiment, the same or similar parts in each embodiment may refer to each other.For device disclosed in embodiment
For, since it is corresponded to the methods disclosed in the examples, so being described relatively simple, related place is said referring to method part
It is bright.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (3)
1. a kind of mefenamic acid is preparing the application in sperm killing contraceptive medicine.
2. a kind of sperm killing contraceptive medicine, which is characterized in that including compound shown in formula I:
3. a kind of sperm killing contraceptive medicine according to claim 2, which is characterized in that the administration way of the sperm killing contraceptive medicine
Diameter is vagina administration, and dosage form includes: gelling agent, suppository, film, cream or sustained release agent.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910517133.9A CN110215447A (en) | 2019-06-14 | 2019-06-14 | The sperm killing contraceptive medicine of application and its preparation of the mefenamic acid in contraceptive |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910517133.9A CN110215447A (en) | 2019-06-14 | 2019-06-14 | The sperm killing contraceptive medicine of application and its preparation of the mefenamic acid in contraceptive |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103976816A (en) * | 2008-07-03 | 2014-08-13 | 拜耳股份有限公司 | An intrauterine delivery system for contraception |
| CN105451737A (en) * | 2013-05-23 | 2016-03-30 | 拜耳医药股份有限公司 | Pharmaceutical composition and the use thereof, and application regime of said pharmaceutical composition for on-demand contraception |
| CN107072948A (en) * | 2014-09-30 | 2017-08-18 | 田纳西大学研究基金会 | The in-situ gel transmitted for depot drug product |
| US9861656B2 (en) * | 2007-08-08 | 2018-01-09 | Allergy Research Group, Llc | Phospholipid compositions and use thereof to enhance spermatozoa motility and viability |
-
2019
- 2019-06-14 CN CN201910517133.9A patent/CN110215447A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9861656B2 (en) * | 2007-08-08 | 2018-01-09 | Allergy Research Group, Llc | Phospholipid compositions and use thereof to enhance spermatozoa motility and viability |
| CN103976816A (en) * | 2008-07-03 | 2014-08-13 | 拜耳股份有限公司 | An intrauterine delivery system for contraception |
| CN105451737A (en) * | 2013-05-23 | 2016-03-30 | 拜耳医药股份有限公司 | Pharmaceutical composition and the use thereof, and application regime of said pharmaceutical composition for on-demand contraception |
| CN107072948A (en) * | 2014-09-30 | 2017-08-18 | 田纳西大学研究基金会 | The in-situ gel transmitted for depot drug product |
Non-Patent Citations (2)
| Title |
|---|
| A. VICENTE-CARRILLO等: "Boar spermatozoa successfully predict mitochondrial modes of toxicity:Implications for drug toxicity testing and the 3R principles", 《TOXICOLOGY IN VITRO》 * |
| 王承裕: "栓剂的生物利用度", 《药学通报》 * |
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Address after: 200032 Shanghai Xuhui District Xietu Road No. 2140 Applicant after: Shanghai Institute of biomedical technology Address before: 200032 Shanghai Xuhui District Xietu Road No. 2140 Applicant before: SHANGHAI INSTITUTE OF PLANNED PARENTHOOD RESEARCH |
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Application publication date: 20190910 |