CN105581977A - Thermosensitive nonoxinol gel preparation - Google Patents

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a temperature-sensitive vaginal in-situ gel preparation. The invention utilizes the temperature-sensitive property of poloxamer aqueous solution and the combination of different types of poloxamers to prepare nonoxynol vaginal The contraceptive gel formulation is used so that it can be administered in a liquid state at room temperature and forms a gel on the surface of the vaginal mucosa. The preparation has both contraceptive and lubricating effects, is convenient to use, and can delay the release of nonoxynol, reduce its mucosal irritation, improve patient compliance, prolong the residence time of nonoxynol in the vagina, and reduce the frequency of medication.

Description

A temperature-sensitive nonoxynol gel preparation

technical field

The invention belongs to the field of pharmaceutical preparations, and relates to a temperature-sensitive nonoxynol gel preparation for vaginal contraception and a preparation method thereof. The gel is in a liquid state at room temperature and can be injected into the vagina to form a gel at body temperature. It is easy to apply and can spread to the surface of the vaginal mucosa to form a uniform physical protective layer. The contact area of sperm, enhance the effect of killing sperm, effectively reduce the stimulation and damage of nonoxynol to the mucous membrane and so on. At the same time, the gel has strong mucoadhesion and can prolong the residence time of nonoxynol in the vagina.

Background technique

No matter for the society, the country, the family and the individual, contraception is of great significance.

Nonoxynol ether (UK approved name and international recommended non-proprietary name: Nonxoinol, US approved name: Nonoxynol, NP-9), chemical name nonylphenol polyoxyethylene (9) ether (see formula 1 for structural formula), The molecular formula is C ₃₃ H ₆₀ O ₁₀ , and the molecular weight is 616.8. The drug is a non-ionic surface-active spermicide approved by the International Family Planning Federation, and is currently the most widely used external contraceptive drug in clinical practice both at home and abroad.

Vaginal drug delivery system has unique advantages for contraception, such as women can self-administer drugs, do not need a doctor's prescription and monitoring, easy to use, good compliance, avoid hepatic first-pass effect and peaks and valleys caused by multiple administrations Phenomena and side effects, it is an effective contraceptive method. However, this type of preparation also has certain limitations, such as difficulty in maintaining a normal physiological environment in the vagina, short retention and action time of the drug in the vagina, and irritation and damage to the vaginal mucosa. Therefore, an ideal vaginal contraceptive preparation should have the characteristics of being able to widely cover the vaginal mucosa, having a long residence time, helping to maintain the stability of vaginal flora, high safety, and non-irritating.

The dosage form of nonoxynol ether (NP-9) mainly includes effervescent tablet, suppository, medicine film, sponge and traditional gel etc. on the market at present. The disadvantages of the above dosage forms are that the administration is inconvenient and the foreign body sensation is strong. For example, suppositories take effect within 10 minutes after administration, and it is necessary to wait for a period of time before intercourse after taking the medicine. The film will be sticky when used, which will affect the accuracy of the dosage. Not only is it inconvenient to insert into the vagina, but also the effective time is short, and it needs to be administered again after half an hour. The contraceptive sponge needs to be moistened with water when used, and its volume is relatively large, so it is extremely inconvenient to insert it into the vagina. According to the feedback information of clinical application, the gel has obvious advantages such as convenient administration, no foreign body sensation, no need to wait after use, and does not affect the quality of sexual life, and is more easily accepted by users (CN201010576885, CN200810053562, CN200810008397, CN200610037286, CN200510124511, CN200410040996, CN02135793).

Temperature-sensitive gels, also known as instant gels or in-situ gels, are prepared from polymers with a large number of hydrophilic groups in the main chain or branch chains, which can absorb a large amount of water to form a three-dimensional network structure. Immediately after in situ gel administration in solution state, a phase transition occurs at the application site to form a non-chemically cross-linked semi-solid formulation. The preparation has a gel hydrophilic three-dimensional network structure and good tissue compatibility. At the same time, the unique solution-gel transition properties make it easy to prepare, easy to use, and strong affinity with the drug site, especially mucosal tissues. , long residence time and other advantages.

Poloxamer is a kind of non-ionic tri-block copolymer composed of polyoxyethylene (PEO) and polyoxypropylene (PPO), the general chemical formula is HO[CH ₂ -CH ₂ O] _X [CH(CH ₃ )-CH2O] _y [CH ₂ -CH ₂ O] _X OH, with the change of x value and y value of the degree of polymerization, its hydrophilic and lipophilic properties will change accordingly, and it is currently the most commonly used method for preparing temperature-sensitive gels Polymer excipients. Among them, Poloxamer 407 (Poloxamer407) has been recorded in the United States Pharmacopoeia as a non-toxic and non-irritating pharmaceutical excipient. The trade name is Pluronic F127 (Pluronic F127), the PEO content is about 70%, and the HLB value is 21.5. Currently, the disclosed temperature-sensitive gel based on poloxamer can be used for injection administration (CN201310419784), mucosal administration (CN200910228686), ocular administration (CN021095035) and vaginal administration (CN2004100255825, CN2008102007160), etc.

According to the World Health Organization, nonoxynol is irritating to the vaginal mucosa. Even so, there is no other spermicide that can replace nonoxynol for clinical use. Therefore, it is particularly important to develop a vaginal nonoxynol preparation with little irritation and high safety. Compared with conventional gel formulations, temperature-sensitive gels can respond to changes in external temperature, that is, they are liquids at room temperature and form gels at body temperature after intravaginal application. This phase transition property makes drug administration more convenient, and the gel can spread to the surface of vaginal mucosa folds to form a uniform physical protective layer, effectively reducing the irritation and damage caused by the preparation itself to the mucosa. In-situ gel encapsulation of nonoxynol can effectively achieve drug sustained release and reduce the irritation of nonoxynol. The spread gel increases the contact area between the drug and sperm, which can enhance the spermicidal effect. At the same time, the gel has strong adhesion to the mucous membrane and can prolong the residence time of the drug in the vagina; The gelation properties of the Sharm solution are related to the ratio of PEO/PPO in the molecule. Nonoxynol is a PEO non-ionic surfactant. Unlike other drugs, loading nonoxynol into the gel will affect The ability of poloxamer to form a gel also increases the difficulty of making it into a temperature-sensitive gel (Wang Chengwei. Research on Nonoxynol Vaginal Sustained Release Gel. Shenyang Pharmaceutical University, 2004).

It has been reported that the combination of poloxamer and carbomer was used to prepare temperature-sensitive nonoxynol vaginal gel (Wang Chengwei et al. Preparation and evaluation of temperature-sensitive nonoxynol vaginal sustained-release gel. Chinese Journal of New Drugs, 2006,15(4):280-284) to prolong the residence time of drugs in the vagina. The composition of the formula is relatively complex, the polymer content is high, the viscosity is high at room temperature, and the application is inconvenient.

The inventors of the present application intend to prepare the temperature-sensitive nonoxynol vaginal gel with a simpler prescription, which can obtain the same long-term vaginal retention effect.

Contents of the invention

The purpose of the present invention is to prepare a temperature-sensitive vaginal in-situ gel preparation, which can reduce the irritation of nonoxynol to mucosal tissue, and provide a new dosage form with good compliance and contraceptive effect for clinical application .

Another object of the present invention is to provide a preparation method of the in-situ gel preparation.

The gel preparation of the present invention contains spermicide nonoxynol for contraception, is dissolved in buffer solution or pure water with auxiliary materials such as humectants and preservatives, and poloxamer is added to prepare the gel preparation. In the present invention, the reverse gelation property of the poloxamer solution is utilized, so that the preparation exists in a liquid state at room temperature and forms a semi-solid gel at body temperature (34-37° C.). When used for vaginal administration, the preparation can penetrate into the folds of the vaginal mucosa, and then form a gel with a sustained release effect, thereby exerting the effect of closely contacting the vaginal mucosa tissue and enhancing the therapeutic effect.

The object of the present invention is achieved by the following scheme:

Dissolve 0.5% to 6% (percentage by weight, w/w) of nonoxynol ether in sterile buffer solution or pure water, and take a total amount of 17.5% to 32% (percentage by weight, w/w) Or two different types of poloxamers are slowly added to the above solution, and placed at low temperature until the poloxamers are completely hydrated and dissolved; an appropriate amount of moisturizer and preservative are added, and the pH and osmotic pressure of the solution are adjusted to make It meets the requirements for preparations for vaginal use.

In the present invention, according to the type of poloxamer used and the ratio between different types of poloxamers, the phase transition temperature of the in-situ gel preparation can be adjusted to 21-37°C, preferably 25-35°C , more preferably 28 to 34°C.

In the gel of the present invention, the active substance having a contraceptive effect is the spermicide nonoxynol, and its consumption accounts for 0.5% to 6% (percentage by weight, w/w) of the total weight of the gel, preferably 1% to 4%. % (weight percent, w/w), more preferably 2% to 4% (weight percent, w/w).

The temperature-sensitive auxiliary material constituting the gel matrix in the gel of the present invention is poloxamer, preferably Poloxamer 407 (Poloxamer 407), whose trade name is Pluronic F127 (Pluronic F127). Poloxamer 407 can form a gel at a temperature range of 36.5°C to 21.5°C when the amount of poloxamer 407 accounts for 17.5% to 21.5% (w/w) of the total weight of the gel, and the preferred amount accounts for 18% of the total weight of the gel ～20% (weight percentage, w/w), can form gel in the temperature range of 34.0℃～26.8℃. See embodiment 1 for details.

Adding nonoxynol to interfere with the poloxamer 407 solution to form a gel in the prescription of the present invention; the nonoxynol ether with a concentration of 4% (weight percent, w/w) makes the gelation temperature of the poloxamer 407 solution drop on average 4 degrees, causing it to gel at room temperature, and the relevant content is described in detail in Example 2 of the present invention.

In order to obtain a suitable gelling temperature, a gelling temperature regulator, preferably Poloxamer 188, whose trade name is Pluronic F68, needs to be added in the prescription of the present invention. When the concentration of poloxamer 407 is 18% to 20% (percentage by weight, w/w), the amount of poloxamer 188 accounts for 1% to 14% (percentage by weight, w/w) of the total weight of the gel, which can be Raise the gelling temperature to 30°C to 35°C, preferably in an amount of 1% to 6% (w/w) of the total weight of the gel, to raise the gelling temperature to 31.5°C to 32.8°C. The relevant content is described in detail in Embodiment 3 of the invention.

The gel of the present invention contains a pH regulator. Under normal physiological conditions, the pH value of female vagina is 4.2-4.6, and the pH value of semen is 7.7-8.2. The acidic environment of the vagina forms a natural protective barrier, which can effectively resist sexually transmitted diseases. The invention proves through in vitro spermicidal experiments that the spermicidal effect of the gel is obviously enhanced under the environment of pH4 and pH5. Comprehensively considering the pH value of the female vagina under normal physiological conditions, the present invention sets the pH value of the gel prescription at pH 3.5-6.5, preferably pH 4.0-5.0.

In the present invention, the buffer system for adjusting pH is selected from phosphate or hydrogen phosphate, carbonate or bicarbonate, citrate and borate, and its concentration is 6mmol/L～1500mmol/L, and the concentration is preferably 15mmol/L L～60mmol/L; the pH regulator also plays a role in regulating the osmotic pressure at the same time, and the relevant content is described in detail in Example 4 of the present invention.

The gel of the present invention contains a moisturizing agent selected from glycerin and polyethylene glycol (PEG), wherein the concentration of glycerin accounts for 0.1% to 5% (percentage by weight, w/w) of the total weight of the gel, preferably 1 %～3% (weight percent, w/w). Glycerin concentration surpasses 6% (percentage by weight, w/w) of gel total weight and can affect the temperature sensitivity of gel, causes it to lose gelling ability; The preferred polyethylene glycol 400 of polyethylene glycol, its concentration accounts for gel 0.1%-4% (w/w) of the total weight, preferably 0.5%-2% (w/w). The concentration of polyethylene glycol 400 exceeding 5% (weight percentage, w/w) of the total weight of the gel will affect the temperature sensitivity of the gel, causing it to lose its gelling ability. The relevant content is described in detail in Example 5 of the present invention .

Contain bacteriostatic agent in the gel of the present invention, be selected from phenol, benzyl alcohol, parabens, benzalkonium chloride and benzalkonium bromide, its concentration is 0.001%～0.5% (weight percentage) of gel gross weight , w/w), preferably 0.01% to 0.2% (weight percent, w/w), the relevant content is described in detail in Example 6 of the present invention.

The present invention has the advantages of utilizing the temperature-sensitive nature of the poloxamer aqueous solution and the combination of different types of poloxamers to prepare the vaginal contraceptive gel preparation of nonoxynol so that it can be administered in a liquid state at room temperature. drug and forms a gel on the surface of the vaginal mucosa. The preparation has both contraceptive and lubricating effects, is convenient to use, and can delay the release of nonoxynol, reduce its mucosal irritation, improve patient compliance, prolong the residence time of nonoxynol in the vagina, and reduce the frequency of medication.

Description of drawings

Figure 1: Fluorescence retention curves in the vagina of mice after topical administration of the gel and solution in Example 10.

Figure 2: The retention curves of radioisotopes in the vagina of rats after topical administration of the gel and solution in Example 11.

detailed description

The following are examples of the present invention. The purpose of giving specific examples is to further clarify the present invention, but not to limit its protection scope.

The gelling temperature of embodiment 1 poloxamer 407 solution

Using Poloxamer 407 as the gel matrix, the gelation temperature of Poloxamer 407 solutions with different concentrations was investigated. F127 solutions with different concentrations of 17% to 21.5% (w/w) were prepared by cold method, and after they were fully swollen, the gelation temperature was measured by test tube inversion method. Take 4 to 5 drops of the sample into a 10ml round-bottomed glass test tube with a stopper that has been preheated at each temperature point for 15 minutes. After keeping the temperature for 2 minutes, it should be solidified or viscous; then put it in a cold water bath, 2 Be liquid in minutes. The lowest temperature at which a gel is formed is taken as the gelation temperature.

Table 1. Gelation temperature of different concentrations of Poloxamer 407 solutions

The 17% poloxamer 407 solution does not have the ability to form a gel. As shown in Table 1, as the concentration of poloxamer 407 increases from 17% to 21.5%, the gelation temperature of the solution decreases gradually from 36.5 °C to 21.5°C.

Embodiment 2 The influence of nonoxynol ether on the gelation temperature of poloxamer 407 solution

A poloxamer 407 solution with a concentration of 18% (w/w) was prepared, respectively loaded with 1% to 4% nonoxynol, and the gelation temperature was determined by inversion of the test tube. As shown in Table 2, as the concentration of nonoxynol increases, the gelation temperature decreases continuously, and the gelation temperature of the formulation containing 4% nonoxynol is 27°C.

4% nonoxynol ether was respectively loaded in the poloxamer 407 solution with a concentration of 18%-21% (w/w), and the gelation temperature was determined by the test tube inversion method. As shown in Table 2, after the poloxamer 407 solutions of various concentrations were loaded with 4% nonoxynol ether, the gelation temperature showed a downward trend, with an average decrease of about 4°C.

Table 2. Effect of nonoxynol on gelation temperature of Poloxamer 407 solution

Therefore, the temperature-sensitive gel containing nonoxynol could not be obtained by using poloxamer 407 alone to obtain a suitable gelling temperature.

Embodiment 3 The influence of poloxamer 188 on gelation temperature

Based on the prescription of 18% poloxamer 407 and 4% nonoxynol ether, add poloxamer 188 at a concentration of 1% to 14% (w/w), and use the test tube inversion method to investigate the gelation temperature .

When the concentration of poloxamer 188 is added between 1% and 5%, the gelation temperature is basically maintained at 31°C. Then, as the proportion of poloxamer 188 increases, the gelation temperature increases continuously. The gelation temperature of the sample containing 11% poloxamer 188 is 35 ° C, and then gradually decreases, and the sample contains 14% poloxamer. The gelation temperature of the 188 sample dropped to 30°C.

Table 3. Effect of poloxamer 188 on solution gelling temperature

The impact of embodiment 4 buffer salt on gel pH and gelling temperature

Prepare phosphate, carbonate, citrate and borate buffer solutions with a concentration of 1500mmol/L respectively, adjust the pH value to 4.0 with hydrochloric acid and then dilute to 1000, 500, 150, 100, 60, 30, 15 and 6mmol /L. The above buffer solution was used to prepare poloxamer gel containing nonoxynol, and the pH and gelation temperature of the gel were measured respectively.

Buffer salt with a concentration of 1500mmol/L decreased the gel strength. When the buffer salt concentration is 15mmol/L-60mmol/L, sufficient buffer capacity can be obtained, and the pH value of the gel is stable between 3.5-6.5, and has no effect on the gelation temperature. Buffer salt with a concentration of 30mmol/L-60mmol/L can stabilize the pH value of the gel between 4.0-5.0.

The influence of embodiment 5 humectant on gelling temperature

Glycerin and polyethylene glycol (PEG) with a concentration of 0.1% to 10% (w/w) are respectively added to the poloxamer gel formulation of nonoxynol as humectants.

Glycerin concentrations above 6% of the total weight of the formulation can affect the temperature sensitivity of the gel, causing it to lose its ability to gel. When the concentration of glycerin accounts for 0.1%～5% (percentage by weight, w/w) of the total amount of the prescription, the poloxamer solution can still form a gel, especially when the glycerol temperature is 1%～3% (percentage by weight, w/w). When w), there is almost no effect on properties such as gelation temperature and gel strength.

Polyethylene glycol is preferably polyethylene glycol 400, and its concentration exceeding 5% of the total weight of the prescription will affect the temperature sensitivity of the gel, causing it to lose its gelling ability. When the concentration of polyethylene glycol 400 accounts for 0.1% to 4% (weight percentage, w/w) of the total amount of the prescription, the poloxamer solution can still form a gel, especially when the concentration of polyethylene glycol 400 is 0.5% to 4%. When it is 2% (weight percentage, w/w), it has almost no effect on properties such as gelation temperature and gel strength.

The influence of embodiment 6 bacteriostatic agent on gelation temperature

Add phenol, benzyl alcohol, paraben, benzalkonium chloride and benzalkonium bromide respectively at a concentration of 0.001% to 0.5% (weight percent, w/w) in the poloxamer gel formulation of nonoxynol Ammonium acts as a bacteriostatic agent. The above-mentioned bacteriostatic agent has no effect on properties such as gelation temperature and gel strength in the concentration range of 0.001% to 0.5% (weight percentage, w/w), especially at 0.01% to 0.2% (weight percentage, w/w) The antibacterial effect is good within the concentration range.

Example 7 Gel in vitro spermicidal effect evaluation

Poloxamer gels containing nonoxynol were prepared at pH 4, 5, 6, and 7 respectively, and rat semen was used for in vitro spermicidal test. The results showed that the poloxamer gel containing nonoxynol at different pHs had an effective spermicidal concentration of less than 0.125 mg/ml in 20 seconds. Among them, the gels with pH4 and pH5 had the best spermicidal effect in vitro.

Embodiment 8 prepares gel sample

Dissolve 0.5% to 6% (percentage by weight, w/w) of the drug nonoxynol ether in sterile buffer solution or pure water, and take a total amount of 17.5% to 32% (percentage by weight, w/w) One or two different types of poloxamers were slowly added to the above solution, and placed at low temperature until the poloxamers were completely hydrated and dissolved. An appropriate amount of moisturizing agent and preservative are added, and the pH and osmotic pressure of the solution are adjusted to meet the requirements of vaginal preparations. The prescription composition of each group of samples is shown in Table 4. According to the poloxamer type used and the ratio between different types of poloxamers, the phase transition temperature of the in-situ gel preparation according to the present invention can be adjusted to 21-37°C. °C, preferably 25-35 °C, more preferably 28-34 °C.

Table 4. Recipe for Gel Samples

The rheological property of embodiment 9 gel

Get prescription 3 and prescription 5 among the embodiment 8, utilize rheometer (BohlinGeminiHR ^nano , Malvern, UK) to measure its gelation temperature, the rheological property before and after forming gel and transvaginal simulated fluid (VFS) after diluting Ability to form gels.

Table 4: Rheological Properties of Gels

Prescriptions 3 and 5 have very low viscosity at room temperature and can flow freely. At body temperature, the viscosity increases by 1 order of magnitude, the elastic modulus G' increases by 5 to 6 orders of magnitude, and the viscosity modulus G″ increases 4 orders of magnitude larger, indicating that both of them can gel with the increase of temperature, and the gelation temperature is 30°C and 31°C respectively. According to the ratio of drug dose to vaginal fluid, prescription 3 and prescription 5 were compared with vaginal simulated fluid (VFS) mixed, after dilution, the gelation temperature of the two increased to 35°C and 36°C, and gels could still be formed at body temperature.

Embodiment 10 The retention of gel in the mouse vagina

Female ICR mice weighing between 28 and 30 g were randomly divided into 3 groups, with 4 mice in each group, and the gels and solutions of prescription 3 and prescription 5 were administered intravaginally. The solution formulation is the same as the gel except that it does not contain poloxamer. The near-infrared fluorescent probe IR-783 was added to the gel and solution at a concentration of 1 μg/ml. Isoflurane was used to anesthetize the mice, and 10 μl was administered in the supine position. The IVIS Spectrum small animal in vivo imager was used to observe the fluorescence retention in the vagina of the tested mice. A region of interest (ROI) was delineated in the mouse vagina, the fluorescence intensity after deducting the background signal was measured, and the fluorescence elimination curve was drawn.

In the solution group, there was basically no obvious fluorescent signal detected in the vaginal area 1 hour after the administration. The gel gradually disappeared from time 0 to 4 hours after administration, and was basically completely excreted in the period from 4 to 6 hours (Fig. 1). There is a significant difference in the mean residence time (MRT) of the two dosage forms in the vagina of mice. The MRT of the gel group is about 3.6 times that of the solution group. The gel is calculated according to the area under the fluorescence retention percentage-time curve (AUC). The residence time in the mouse vagina is about 3.4 times that of the solution.

Example 11 Retention of Gel in Rat Vagina

SD rats weighing 200-230 g were randomly divided into 3 groups, 5 rats in each group. Take 3ml of the gel of prescription 6 and prescription 8 respectively, add 100μl of permethanate ^99m TcO ₄ ^- , vortex and mix well, the solution group is 3ml of the same solution as the gel prescription but without poloxamer, add 100μl of high Anthate ^99m TcO ₄ ^- , treated in the same way; rats were administered supine after ether anesthesia, and each rat was given 0.2ml of gel or solution. Immediately after administration, the small gamma camera was used for imaging. After imaging, the rats were free to move, and imaging was performed every 1 hour until the gel was completely excreted from the body;

Prescription 6 was eliminated slowly in the vagina of rats in the first 5 hours, then accelerated in 6 to 8 hours, and almost all the gel was excreted after 9 to 10 hours. The elimination of prescription 8 was slow in the first 2 hours, and the elimination was accelerated between 3 and 6 hours. After 7 hours, the gel was basically completely excreted from the body, and the solution group had no obvious signal at 1 hour.

Claims (14)

1. A temperature-sensitive nonoxynol gel preparation is characterized in that it is dissolved in buffer solution or pure water by spermicide nonoxynol and humectant and antiseptic, and adds poloxamer to make Gel formulation. 2. by the temperature-sensitive nonoxynol ether gel preparation of claim 1, it is characterized in that, in described preparation, with water or buffer solution as solvent, contain 0.5%～6% by weight, w/w , the topical spermicide nonoxynol, 17.5% to 32% by weight, w/w, one or two different types of poloxamers, 0.1% to 5% by weight, w/w, Moisturizing agent, 0.001% to 0.5% by weight, w/w, antibacterial agent; The preparation is a free-flowing liquid at a temperature lower than 20°C, and can form a gel at a temperature range of 21-37°C; and the pH value of the preparation is between 3.5-6.5. 3. by the temperature-sensitive nonoxynol gel preparation of claim 1, it is characterized in that, the dosage of described nonoxynol accounts for 1%～4% weight percent of described gel gross weight, w /w. 4. by the temperature-sensitive nonoxynol gel preparation of claim 1, it is characterized in that, the dosage of described nonoxynol accounts for 2%～4% weight percent of described gel gross weight, w /w. 5. by the temperature-sensitive nonoxynol gel preparation of claim 1, it is characterized in that, described poloxamer is poloxamer 407 and poloxamer 188; Described poloxamer 407 The content accounts for 17.5%-21.5% by weight of the total weight of the gel, w/w; the content of poloxamer 188 accounts for 1%-14% by weight of the total weight of the gel, w/w. 6. by the temperature-sensitive nonoxynol gel preparation of claim 1, it is characterized in that, described poloxamer is poloxamer 407 and poloxamer 188; Described poloxamer 407 The content accounts for 18%-20% by weight of the total gel weight, w/w; the content of poloxamer 188 accounts for 1%-6% by weight of the total gel weight, w/w. 7. by the temperature-sensitive nonoxynol ether gel preparation of claim 1, it is characterized in that, described humectant is selected from glycerin or macrogol 400; Wherein its content of glycerin accounts for 0.1 of gel gross weight %-5% by weight, w/w; polyethylene glycol 400, whose content accounts for 0.1-4% by weight of the total weight of the gel, w/w. 8. by the temperature-sensitive nonoxynol gel preparation of claim 1, it is characterized in that, described humectant is selected from glycerin or Polyethylene Glycol 400; Wherein its content of glycerin accounts for 1% of gel gross weight %-3% by weight, w/w; polyethylene glycol 400, whose content accounts for 0.5-2% by weight of the total weight of the gel, w/w. 9. by the temperature sensitive nonoxynol ether gel preparation of claim 1, it is characterized in that, described antibacterial agent is selected from phenol, benzyl alcohol, parabens, benzalkonium chloride or benzalkonium bromide , the content of the antibacterial agent accounts for 0.001% to 0.5% by weight of the total weight of the gel, w/w. 10. The temperature-sensitive nonoxynol ether gel preparation according to claim 9, wherein the content of the bacteriostatic agent accounts for 0.01% to 0.2% by weight of the total weight of the gel, w/w. 11. by the temperature-sensitive nonoxynol ether gel formulation of claim 1, it is characterized in that, described buffer solution is selected from the aqueous solution of phosphate, carbonate, citrate or borate, and its concentration is 15mmol/L～60mmol/L. 12. The temperature-sensitive nonoxynol ether gel preparation according to claim 1, wherein the buffer solution has a concentration of 30mmol/L˜60mmol/L. 13. The temperature-sensitive nonoxynol ether gel preparation according to claim 1, characterized in that the gel forming temperature is 25-35°C. 14. The temperature-sensitive nonoxynol ether gel preparation according to claim 1, wherein the pH value is 4.0-5.0.