CN109966306A - Application of the Triton x-100 ointment in treatment pruitus - Google Patents
Application of the Triton x-100 ointment in treatment pruitus Download PDFInfo
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- CN109966306A CN109966306A CN201910155502.4A CN201910155502A CN109966306A CN 109966306 A CN109966306 A CN 109966306A CN 201910155502 A CN201910155502 A CN 201910155502A CN 109966306 A CN109966306 A CN 109966306A
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
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Abstract
The invention discloses application of the Triton x-100 ointment in treatment pruitus.Present invention discover that Triton x-100 can be effectively blocked the channel Nav1.7, Nav1.8 and Nav1.9, these channels and the basis mechanism that itch occurs are closely related, however itch is by epidermis and corium afferent nerve endings, this can hinder itch to pass through epidermis and corium afferent nerve endings that is to say, the drug is illustrated, to achieve the effect that treat itch, this discovery is of great significance to effective treatment of pruitus.
Description
Technical field
The present invention relates to application of the Triton x-100 ointment in treatment pruitus.
Background technique
Itch causes from many factors, including dermatitis, acute inflammation, eczema or about scaly skin
The chronic dermatosis of rash, psoriasis (a kind of autoimmune disease for causing rubefaction and stimulation).Itch passes through some spies
The specific ion channel determined in nerve fibre is conducted, they are sodium channel and C and A δ fiber respectively.Due to environment, sky
The variation such as gas, living habit, operating pressure, dermopathic disease incidence is very high always, becomes a kind of common disease, frequently-occurring disease.It is related
Statistics show that national total prevalence rate is 1.23%, i.e., there are about 0.16 hundred million people to suffer from different degrees of skin disease.Due to lacking
Good animal model and special sensitive research method.People are not fully understood the mechanism of itch.In addition the course for the treatment of
Time is long and more easy to recur, and morbidity crowd and medical constant increase so that pharmaceutical market demand be always maintained at it is vigorous.Therefore
It is very huge for treating the market value of itch drug, and in sustainable growth.It is especially multiple at 10 years 2006~2016 years
It closes growth rate and is maintained at 10% or so, market scale just has reached 23,000,000,000 yuan within 2016.Because such disease has huge illness
Thus crowd brings huge market development space, and amplification is always maintained at relatively steadily, attracts the eye in numerous pharmaceutical factories
Ball.Skin covers whole body as the maximum organ of human body area, since externally applied drug can directly contact disease sites,
In the selection of skin disease drug formulation, externally applied drug accounts for eighty per cant or more specific gravity, and it is generally clear to classify from the pharmacological action of drug
Several aspects such as clean, protection, antipruritic, convergence, antibacterial, wherein antibacterial, it is antipruritic be the relatively large number of kind of sales volume, can regard sb. as an outsider again
It is huge with the development space of antipruritic.
Twycross etc. is classified as follows according to origin of itching: (1) skin source property (itch): itch source nerve is in its sensory nerve
The original that tip caused to itch activates.(2) neurogenic (itch): the itch that ill or damage itch source neuron generates.(3) refreshing
Through source property (itch): itching in the case where lacking neurotrosis and induced by central interaction medium.This classification is beneficial to nerve
The research of itching of biology, describes potential itch neurotomy mechanism.Wherein many common antipruritic ointment are thin to skin on the market
The injury of born of the same parents' tissue is greatly, to be very easy to cause to infect, or even tetanic situation can be caused to occur；In addition it is many only
Drug of itching contains hormone, although hormone cannot use, separately for a long time for that can inhibit in the treatment pruitus short time
There is strict demand for the crowd of benefiting from outside.
There are different kinds of ions channel on neuron, these ion channels are the bases of nerve impulse transmitting, wherein sodium ion
The inward electric current of channel street action potential depolarising, plays a key role in the conduction of early nerve signal.Whether sodium channel
It can be blocked by tetraodotoxin (TTX), be divided into two class of TTX responsive type and TTX non-sensitive type.Nav1.7 is TTX responsive type, and
Nav1.8 and then Nav1.9 are then the sodium channel of non-sensitive type.These three sodium channels are that neurogenic pain or itch pass through
Three crucial ion channels of epidermis and corium afferent nerve endings.Accurately judge that drug is logical to these by patch clamp technique
The effect in road.Triton x-100 (Triton X-100) molecular formula is (CH3) 3CCH2C (CH3) 2C6H4
(OCH2CH2) 10OH, molecular weight 646.85.Triton x-100 is a kind of nonionic surface active agent, and for it is transparent,
The sticky liquid slightly to turn to be yellow is shown slightly, its energy solubilizing lipids can increase cell membrane to the permeability of antibody, life micro- for bacterium etc.
Object does not have lethal effect, and Triton x-100 is relatively more safe and reliable less than 0.1% as external preparation concentration.The present invention will illustrate
Triton x-100 without hormone, is suitable for most of by skin in the middle as a kind of antipruritic external plaster drug, Triton x-100
Skin source property leads to the group of itch, finds that its mechanism of action of the active N-9 of Zanfel is to pass through blocking since early stage studies report
Potassium, sodium-ion channel and realize reduction pruritis, however, Zanfel in Welgreen pharmacy, the U.S. as OTC drug product,
It is that external application applies cream for pruritus caused by skin aging and contact dermatitis.We are present invention firstly discovers that Triton x-100
The channel Nav1.7, Nav1.8 and Nav1.9 equally can be effectively prevented, illustrates that the drug has N-9 same mechanism, this is also into one
Step illustrates that the drug can hinder itch by epidermis and corium afferent nerve endings, and people is allowed to be detectable itch, can be quick
The transmitting of the itch effectively prevented.
Summary of the invention
The purpose of the present invention is to provide the new applications of Triton x-100 ointment, i.e., newly answering in treatment pruitus
With.
To better understand the essence of the present invention, below by with the pharmacological testing of Triton x-100 ointment and result come
Illustrate its new application in pharmaceutical field.
The technical solution used in the present invention is: application of the Triton x-100 ointment in treatment pruitus.
The present invention is by the way that experimental results demonstrate find that Triton x-100 can be effectively blocked Nav1.7, Nav1.8 for the first time
With the channel Nav1.9, these channels and the basis mechanism that itch occurs are closely related, however itch is by epidermis and the incoming mind of corium
Through tip, this can hinder itch by epidermis and corium afferent nerve endings that is to say, the drug is illustrated, to reach treatment
The effect of itch, this discovery are of great significance to effective treatment of pruitus.
Detailed description of the invention
Fig. 1 is the IC50 matched curve and its current graph of Triton x-100 effect and hERG potassium channel in the present invention.
Fig. 2 is the IC50 matched curve and its current graph of Triton x-100 effect and the channel Nav1.5 in the present invention.
Fig. 3 is the IC50 matched curve and its current graph of Triton x-100 effect and the channel Nav1.7 in the present invention.
Fig. 4 is the IC50 matched curve and its current graph of Triton x-100 effect and the channel Nav1.8 in the present invention.
Fig. 5 is IC50 matched curve and its trajectory diagram of the Triton x-100 effect with the channel Nav1.9 in the present invention.
Specific embodiment
The present invention is further illustrated combined with specific embodiments below, and however, it is not limited to this.
Application of the Triton x-100 ointment in treatment pruitus.
The present invention by patch clamp technique test discovery Triton x-100 can effectively inhibit itch by epidermis and
The crucial ion channel (Nav1.7, Nav1.8 and Nav1.9) of three of corium afferent nerve endings, in addition hERG and Nav1.5 makees
For the ion channel of the wide expression on heart, in the case where ointment concentration is less than 40 μM, Triton x-100 is as external application
Applying cream will not cause because to cardiac safety risk caused by the effect in the channel hERG and Nav1.5.
Experimental method includes that human body hERG, Nav1.5, Nav1.7 channel gene prepares, cell culture and rat dorsal root
Gangliocyte separation and culture, re-record the kinetic effect in compound on ion channel, and following step is taken in experiment and analysis
It is rapid to carry out:
Prepare hERG, Nav1.5, Nav1.7 channel gene first.
HERG channel gene composition: 84%DMEM, 15% fetal calf serum and 1% 100x Pen .- Strep；Nav1.5
Channel gene composition: 89%DMEM/F12,10% fetal calf serum, 1% 100X Pen .- Strep and G418；The channel Nav1.7
Gene composition: 89% HAM/F12,10% fetal calf serum, 0.9% penicillin, 0.011% Sodium Pyruvate and 0.1% hygromycin.
Then cell is cultivated.
Cell culture: hERG, Nav1.5, Nav1.7 channel gene surely go to HEK-293 cell.In 37 DEG C, 5% CO2
HEK-293 cell is cultivated in incubator.When cell density is up to 80%, phosphate buffer prerinse is first used, tryptose is then used
Enzyme/EDTA digestive juice vitellophag, carries out secondary culture, and cell density is 2 × 106/ware.The preparation of cell is respectively used to
The channel hERG, Nav1.5 and Nav1.7 electrophysiologic testing.
The separation of rat DRG cell acute and culture: taking adult rat 29-31 days, weighs, and 500 U/ of heparin sodium is injected intraperitoneally
After kg, 30 min, penta bar of 40mg/kg is injected intraperitoneally and is anaesthetized, scratched with scalpel along rat back vertebra, until seeing
Vertebra exposure breaks vertebra by the DRG(the 4th the 5th or the 6th of taking-up waist L4, L5 and/or L6 in bilateral taper hole with rongeur
Neuromere) it is placed in sterile DPBS(Du Shi phosphate buffer) in, then cut off on neuromere with eye scissors under a dissecting microscope
The junctor tissue and coating of attachment, the neuromere for separating clean is transferred in DMEM and is shredded, and the neuromere handled well is put into
In advance in configured digestive juice, 30 min or so are digested in 37 DEG C of CO2 incubators, take out cell, addition contains 10%FBS
It terminates and digests with the fresh DMEM of 10 units/ml penicillin/streptomycin, then by suspension with 800rpm centrifugation 4 minutes, then
Cell precipitation is resuspended in and is supplemented in 10%FBS and the fresh DMEM of 10 units/ml penicillin/streptomycin, is uniformly layered on 24
On the glass cover-slip of poly- D-Lys (0.1mg/ml) processing in the steriled tissue culture plate of hole, and 5% at 37 DEG C
Kept for 2-3 hours in 2 incubator of CO, after carrying out the experiment of subsequent Nav1.8 and Nav1.9 electro physiology.
Finally tested with cultured cell.
Experimental example is as follows:
Experiment uses whole-cell recording technique pattern recording channel electric current.Perfusion extracellular fluid first, stablizing to electric current is electricity in 5 min
Stream decaying (Run-Down) is less than 5 %, and when tail current is not less than 300 pA, extracellular fluid of the perfusion containing drug to be measured.Containing to
The extracellular fluid concentration for surveying drug is 0.12-300 micromole, each 4 min of concentration perfusion.
Experimental example 1
As shown in Figure 1, the channel hERG stimulation protocol, trustworthy turn of HEK-293 cell, which is depolarized to 40mv/50ms, to be activated
Then cell clamp is returned to -50mv/s with the inactivation of recording channel by hERG potassium channel, frequency of stimulation is that 15s is primary, -
The maximum current that 50mv is recorded is the hERG channel current amplitude to be recorded.
Y-axis in left figure indicates the inhibiting rate relative to control electric current, and X-axis indicates concentration, analyzes Triton x-
The effect of 100 pairs of hERG potassium channels, as a result, it has been found that the IC that Triton x-100 inhibits hERG potassium channel50For 41.73 μM of (cells
0.0027%) concentration is.
Experimental example 2
As shown in Figures 2 and 3, the channel Nav1.5 and Nav1.7 stimulation protocol, trustworthy turn of HEK-293 cell depolarized to-
10mv/100ms activates the channel Nav1.5 and Nav1.7, cell clamp is then returned to -130mv/10ms, then -80mv is clamped to 8s,
Then cell depolarization to -10mv/100ms being activated the channel Nav1.5 and Nav1.7 again, most forceps major returns to -130mv,
Frequency of stimulation is that 30s is primary, and the maximum inward electric current being recorded in-the 10mv clamped down on twice is the Nav1.5 to be recorded
With Nav1.7 channel current amplitude.
As shown in Fig. 2, Y-axis indicates the inhibiting rate relative to control electric current in left figure, X-axis indicates concentration, analysis
Effect of the Triton x-100 to the channel Nav1.5, as a result, it has been found that the IC that Triton x-100 inhibits Nav1.5 potassium channel50For
10.15 μM (cell concentration 0.00067%).
As shown in figure 3, Y-axis indicates the inhibiting rate relative to control electric current in left figure, X-axis indicates concentration, analysis
Effect of the Triton x-100 to the channel Nav1.7, as a result, it has been found that the IC that Triton x-100 inhibits the channel Nav1.750For
7.49 μM (cell concentration 0.00049%).
Experimental example 3
As shown in figure 4, the channel Nav1.8 stimulation protocol, the DRG cell of rat is clamped down on and activates Nav1.8 to lead in -70mv/8s
Then road is clamped down in -100mv/5ms again, then cell depolarization 0mv/50ms, most forceps major returns -100mv, frequency of stimulation 15s
Once, recording maximum inward electric current in 0mv is Nav1.8 channel current.
Y-axis indicates the inhibiting rate relative to control electric current in left figure, and X-axis indicates concentration, analyzes Triton x-100
Effect to the channel Nav1.8, as a result, it has been found that Triton x-100 is 55.2 μM to the IC50 that the channel Nav1.8 inhibits, (cell is dense
0.0036%) degree is.
Experimental example 4
As shown in figure 5, the channel Nav1.9 stimulation protocol, the DRG cell depolarization of rat to -60mv/150ms is activated
Then cell clamp is returned -100mv by the channel Nav1.9, frequency of stimulation is that 10s is primary, is in -60mv record maximum current
Nav1.9 channel current.
Y-axis indicates the inhibiting rate relative to control electric current in left figure, and X-axis indicates concentration, analyzes Triton x-100
Effect to the channel Nav1.9, as a result, it has been found that the IC that Triton x-100 inhibits the channel Nav1.950For 32.1 μM of (cell concentrations
For 0.0021%).
By Fig. 1-2, the results show that IC of the drug Triton x-100 to the inhibition of hERG and Nav1.550Respectively
41.73 μM and 10.15 μM, hERG and Nav1.5 are the ion channels that heart is expressed extensively above, again for cardiac safety evaluation
It is most important, therefore cream drug is applied for external application, will not causes to lead because of the effect of hERG less than 40 μM in ointment concentration
The ventricular arrhythmia of cause.By Fig. 3-5, the results show that compound Triton x-100 is to Nav1.7, Nav1.8 and Nav1.9
Three kinds of ion channels have the inhibiting effect of micromole's rank, especially have stronger inhibiting effect, IC to Nav1.750It is 7.49
μM, because Nav1.7, Nav1.8 and Nav1.9 ion channel are the key that itch passes through epidermis and corium afferent nerve endings
It is incoming by epidermis and corium to illustrate that Triton x-100 can block itch and then blocking three kinds of ion channels for channel
Nerve endings.And Triton x-100 is a kind of drug without containing hormone.
In conclusion Triton x-100 is a kind of novel effective treatment pruitus external application painting cream drug, it is suitable for
The group for leading to itch by skin source property, the room property caused by it will not cause because of the effect of hERG under ointment concentration is less than 40 μM
Arrhythmia cordis.The ointment has target user extensive, the advantage of Quick itch stopping and safety.
Claims (1)
- Application of the 1.Triton x-100 ointment in treatment pruitus.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910155502.4A CN109966306A (en) | 2019-03-01 | 2019-03-01 | Application of the Triton x-100 ointment in treatment pruitus |
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| CN201910155502.4A CN109966306A (en) | 2019-03-01 | 2019-03-01 | Application of the Triton x-100 ointment in treatment pruitus |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1166958A (en) * | 1980-12-29 | 1984-05-08 | Edmund M. Buras, Jr. | Poison ivy prevention |
| WO2004039820A1 (en) * | 2002-10-30 | 2004-05-13 | Danisco A/S | Material |
| CN101940577A (en) * | 2010-09-27 | 2011-01-12 | 崔秀梅 | Compound-type aqueous multiple-effect environmentally-friendly bactericide as well as preparation method and applications thereof |
-
2019
- 2019-03-01 CN CN201910155502.4A patent/CN109966306A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1166958A (en) * | 1980-12-29 | 1984-05-08 | Edmund M. Buras, Jr. | Poison ivy prevention |
| WO2004039820A1 (en) * | 2002-10-30 | 2004-05-13 | Danisco A/S | Material |
| CN101940577A (en) * | 2010-09-27 | 2011-01-12 | 崔秀梅 | Compound-type aqueous multiple-effect environmentally-friendly bactericide as well as preparation method and applications thereof |
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Application publication date: 20190705 |