Novel estrogen-loaded temperature-sensitive gel as well as application and preparation method thereof

Abstract

The invention provides an intrauterine administration gel preparation containing an estrogen drug, the estrogen drug is modified by polypolyphenol and is suspended and dispersed in the gel, and the temperature-sensitive gel contains poloxamer. The invention also discloses a preparation method of the gel preparation, which comprises the following steps: mixing and grinding the polyphenol compound and the estrogen medicine by adopting wet medium grinding to prepare polypolyphenol-coated estrogen medicine crystals; the preparation method comprises the following steps: dissolving poloxamer in water to prepare blank gel; and suspending and dispersing the polypolyphenol-coated estrogen drug crystal in the blank gel. The gel preparation disclosed by the invention has a temperature-sensitive characteristic, is in a liquid state during administration, is convenient to extrude into a uterine cavity and flow into mucous membrane wrinkles, and is rapidly solidified to form a protective gel film under a body temperature state, so that the contact of wounds on two walls after a uterus operation is prevented, the purpose of preventing intrauterine adhesion after the uterus operation is achieved, and the gel preparation can be used for repairing endometrium.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular, to a novel estrogen-loaded temperature-sensitive gel, its use and preparation method. BACKGROUND

[0002] Estrogen drugs are one of the current means for treating endometrial damage. At present, they are mostly administered systemically by oral administration, which can easily cause a series of systemic side effects. In the treatment of endometrial damage or other gynecological diseases, vaginal administration is a very important administration route, which has the advantages of high local concentration of drugs at the affected site and small systemic side effects. The currently commonly used vaginal drug dosage forms can be roughly divided into the following three categories: the first category is solid dosage forms, including vaginal suppositories, vaginal tablets, vaginal effervescent tablets, and vaginal capsules. The drugs in this category are most likely to have uneven distribution in the vagina after being dissolved and dispersed by the liquid secreted in the vagina; the second category is semi-solid preparations, including vaginal ointments, vaginal creams, vaginal films, and vaginal gels. The drugs in this category need to be applied to the inner surface of the vagina with the aid of an applicator. Although the adhesion of the preparations to the mucosal surface of the vagina is good, it is difficult to ensure uniform application, and drug dead angles are likely to occur, and the administration is inconvenient; the third category is solutions, such as vaginal lotions. The drugs in this category are most likely to be evenly distributed when injected into the vagina with the aid of an instrument, but have poor adhesion and are easy to lose.

[0003] In summary, the current estrogen intrauterine local administration has one or more of the following technical problems:

[0004] Lack of a method for local treatment of endometrial damage with drugs: endometrial damage is an important factor affecting female fertility, and the current clinical treatment still mainly relies on oral administration of drugs. However, this method has obvious systemic side effects, large individual tolerance differences, and application limitations in some patients (such as abnormal liver function, drug allergy, etc.).

[0005] Poor patient compliance and administration convenience: the existing intrauterine devices (such as intrauterine implanters) have problems such as inconvenience in placement / taking out, foreign body sensation, and possible infection or discomfort, which leads to low patient compliance.

[0006] Low intelligence of drug delivery system: the existing technology lacks a drug delivery system that can realize intelligent phase transition according to the physiological environment (such as temperature) of the uterine cavity, which cannot realize the ideal state of "being a liquid when injected and rapidly transforming into a gel in the uterine cavity", and thus it is difficult to achieve precise and controllable drug release.

[0007] Intrauterine local inflammatory response: endometrial damage is often accompanied by local inflammatory response in the uterine cavity, which not only hinders the normal tissue repair process, but also may further aggravate the endometrial damage.

[0008] Hydrophilic gel is a polymer with hydrophilic groups, which has good permeability to low molecules and is widely used in biomedical field. However, the physiological structure and environment of cervix and vagina are relatively complex, and the human body itself will secrete various amounts of liquid at different times, which may affect the retention time, adhesion ability of the temperature-sensitive gel, and even the success of phase transition. The adhesion and the normal phase transition in the lesion are very important. The ordinary hydrophilic gel has poor adhesion, and it is difficult to realize intrauterine drug delivery, and it cannot be attached to the uterine cavity for a long time and continuously release drugs.

[0009] The temperature-sensitive gel is a temperature-sensitive polymer, which can be transformed from a solution state to a gel state under the stimulation of suitable environmental factors. Poloxamer polymer is the most widely studied and applied gel material. Pure poloxamer, such as poloxamer 407 solution, has a gelation temperature lower than 30℃, which is not suitable for application in human body alone.

[0010] At present, there is no suitable intrauterine drug delivery preparation that can solve the above technical problems at the same time. Therefore, it is necessary to develop an intrauterine drug delivery preparation with long retention time in the uterine cavity, convenient drug delivery, intelligent phase transition according to the physiological environment of the uterine cavity (such as temperature), and local anti-inflammatory effect. SUMMARY

[0011] Technical problems to be solved by the present application

[0012] In view of the above deficiencies in the prior art, the present application aims to provide a temperature-sensitive gel for intrauterine drug delivery loaded with estrogen. The gel preparation can realize long retention time in the uterine cavity, convenient drug delivery, intelligent phase transition according to the physiological environment of the uterine cavity (such as temperature), and local anti-inflammatory effect.

[0013] Technical solutions for solving the technical problems

[0014] The present application uses a temperature-sensitive gel delivery system to load estrogen drugs, realizes local delivery and sustained release of drugs in the uterine cavity, and effectively promotes endometrial growth. The present application uses poloxamer 188 and poloxamer 407 to prepare a temperature-sensitive gel, which remains in a liquid state at room temperature, facilitating injection and drug delivery. After entering the uterine cavity, it undergoes phase transition under the action of physiological temperature, forms a solid gel and adheres to the surface of the endometrium, realizing local long-acting retention. The present application modifies the gel system by introducing polyphenol, which endows it with anti-inflammatory and antioxidant properties, further synergistically promoting endometrial repair and regeneration.

[0015] Specifically, the first aspect of the present application is an intrauterine drug delivery gel preparation loaded with estrogen drugs, wherein the estrogen drugs are suspended and dispersed in the gel, the estrogen drugs are modified by polyphenol, and the temperature-sensitive gel contains poloxamer.

[0016] In one embodiment, the poloxamer is a mixture of poloxamer 407 and poloxamer 188.

[0017] In one embodiment, the mass ratio of poloxamer 407 and poloxamer 188 is 1:2 to 2:1.

[0018] In one embodiment, the mass percentage of the polyphenol-modified estrogen drug in the thermosensitive gel preparation is 0.01-0.1%, for example, it can be 0.03%, 0.05%, 0.08%.

[0019] In one embodiment, the composition of the poloxamer thermosensitive gel is as follows: poloxamer 407 15-35 parts, poloxamer 188 10-30 parts, and distilled water 55-75 parts.

[0020] In one embodiment, the estrogen drug is selected from estradiol, ethinyl estradiol, and estriol.

[0021] In one embodiment, the polyphenol is selected from one or more of dopamine oligomers, tannin oligomers, epigallocatechin gallate (EGCG) and its oligomers, quercetin oligomers, and catechin oligomers. Considering its anti-inflammatory and antioxidant properties, dopamine oligomers are preferred.

[0022] The second aspect of the present application is a method for preparing an estrogen drug-loaded gel preparation, comprising:

[0023] (1) preparing polyphenol-coated estrogen drug crystals: mixing and grinding the polyphenol compound and the estrogen drug by wet medium grinding to prepare polyphenol-coated estrogen drug crystals;

[0024] (2) preparing a blank gel: dissolving poloxamer in water to prepare a blank gel;

[0025] (3) mixing the polyphenol-coated estrogen drug crystals with the blank gel, so that the drug crystals are suspended and dispersed in the blank gel to obtain an estrogen drug-loaded gel preparation.

[0026] In one embodiment, the poloxamer is a mixture of poloxamer 407 and poloxamer 188.

[0027] In one embodiment, the polyphenol compound is dopamine.

[0028] In one embodiment, the estrogen drug is selected from estradiol, ethinyl estradiol, and estriol.

[0029] In one specific embodiment, the blank temperature-sensitive gel is prepared by a cooling method, wherein poloxamer 407 and poloxamer 188 are dissolved in pure water, stirred in an ice water bath until a clear solution is obtained, and left to stand to remove air bubbles, thereby obtaining a colorless and transparent blank gel.

[0030] In one specific embodiment, the blank temperature-sensitive gel is prepared at a temperature of 0-8°C, preferably at 4°C.

[0031] The third aspect of the present application is the use of the gel preparation according to any one of the above in endometrial repair.

[0032] Beneficial technical effects

[0033] Highly efficient targeted treatment of endometrial damage is achieved: by loading estrogen on the temperature-sensitive gel system, precise delivery and sustained release of the drug in the uterine cavity are achieved, which significantly improves the drug concentration at the lesion site and effectively promotes the repair and regeneration of the endometrium. At the same time, this local drug delivery method avoids the systemic side effects caused by traditional oral administration, and is particularly suitable for patients with abnormal liver function or drug allergy, thereby widening the clinical application population.

[0034] Patient compliance and drug delivery convenience are improved: the temperature-sensitive gel is in a liquid state at room temperature, which is convenient for injection into the uterine cavity through a conventional syringe; after entering the body, it rapidly transforms into a gel state at physiological temperature and adheres to the surface of the endometrium, without the foreign body sensation of traditional intrauterine devices, and does not need to be placed or removed by surgery, thereby significantly reducing the risk of infection and patient discomfort, and thus significantly improving the acceptance and persistence of treatment.

[0035] Intelligent phase transition and controllable release characteristics are achieved: the system is based on a composite temperature-sensitive material of poloxamer 188 and poloxamer 407, which realizes intelligent phase transition from "liquid to gel", not only facilitating drug delivery operation, but also forming a gel barrier in the uterine cavity under physiological conditions, thereby achieving sustained release and long-acting effect of estrogen, and improving the controllability of drug release and the predictability of treatment effect.

[0036] Combining anti-inflammatory and antioxidant functions to synergistically promote endometrial repair: by introducing polyphenol to modify the gel system, the system can not only deliver estrogen, but also effectively alleviate inflammation in the uterine cavity and remove excess reactive oxygen species, thereby creating a more favorable repair microenvironment for the endometrium, and thus synergistically promoting the overall regeneration of the endometrium in structure and function. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 Figure 2 shows the retention effect of the polyphenol-modified estradiol gel prepared in the example of the present application in animals.

[0038] Figure 2The anti-intrauterine adhesion ability of the polyphenol-modified estradiol gel prepared in the embodiments of the present application is shown.

[0039] Figure 3 The anti-inflammatory effect of the polyphenol-modified estradiol gel prepared in the embodiments of the present application on local inflammatory response is shown.

[0040] Figure 4 The effect of the polyphenol-modified estradiol gel prepared in the embodiments of the present application on endometrial repair is shown.

[0041] Figure 5 The effect of the polyphenol-modified estradiol gel prepared in the embodiments of the present application on local anti-inflammatory response is shown. DETAILED DESCRIPTION

[0042] Features, aspects, compounds described in connection with the embodiments or examples of the present application are to be understood to be applicable to any other embodiment or example described herein, unless incompatible therewith. All features and / or steps disclosed in the specification (including the claims, abstract, and drawings) can be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The application is not restricted to the details of any embodiment. The application extends to any novel one, or any novel combination, of the features disclosed in this specification (including the claims, abstract, and drawings), or to any novel one, or any novel combination, of the steps of any method or process disclosed in this specification (including the claims, abstract, and drawings).

[0043] Definitions

[0044] In the embodiments of the present application, all instruments, materials, chemical reagents, drugs, compounds, and experimental animals are commercially available and well known to those skilled in the art, unless otherwise specified. In the embodiments of the present application, the technical means used are conventional means well known to those skilled in the art, unless otherwise specified. The progress of the reaction in the present application can be monitored by conventional monitoring methods in the art (such as TLC, HPLC, LCMS, or NMR), and the reaction end point is generally when the substrate disappears.

[0045] The experimental methods in the embodiments of the specification are generally carried out according to conventional conditions in the art or according to the conditions recommended by the manufacturer. In the present application, unless otherwise specified, “above”, “below”, “within” means including the number. When “comprising”, “including” is used to describe the embodiments herein, other similar embodiments described by “consisting of” and / or “consisting essentially of” are also provided. When “consisting essentially of” is used to describe the embodiments herein, other similar embodiments described by “consisting of” are also provided.

[0046] In the present application, unless otherwise specified, the percentage, %, ratio represents mass percentage, mass %, mass ratio.

[0047] The first aspect of the present application is to provide an intrauterine administration gel preparation loaded with estrogen drugs, the estrogen drugs are suspended and dispersed in poloxamer temperature-sensitive gel, and the estrogen drugs are modified by polyphenol. Poloxamer temperature-sensitive gel serves as a carrier, and the estrogen drugs are loaded on the carrier.

[0048] The temperature-sensitive gel is a temperature-sensitive high polymer that can be transformed from a solution state to a gel state under the stimulation of suitable environmental factors. Poloxamer polymer is the most studied and applied gel material, and pure poloxamer, such as poloxamer 407 solution, has a gelation temperature lower than 30℃, which is not suitable for application in human body alone. In the present application, by adding poloxamer homologues, using a mixture of poloxamer 407 and poloxamer 188, and adjusting the ratio of the two, a suitable prescription is screened to have the required temperature-sensitive properties (i.e., liquid at room temperature, reduced flowability and solidification at body temperature) and good stability.

[0049] The second aspect of the present application is to provide a preparation method of a gel preparation loaded with estrogen drugs, comprising:

[0050] (1) preparing polyphenol-coated estrogen drug crystals: polyphenol compounds and estrogen drugs are mixed and ground by wet medium grinding to prepare polyphenol-coated estrogen drug crystals;

[0051] (2) preparing a blank gel: poloxamer is dissolved in water to prepare a blank gel;

[0052] (3) mixing the polyphenol-coated estrogen drug crystals with the blank gel, so that the drug crystals are suspended and dispersed in the blank gel to obtain a gel preparation loaded with estrogen drugs.

[0053] Polyphenol compounds can spontaneously polymerize to form polyphenol in an alkaline environment, so a wet medium grinding method can be used to mix and grind polyphenol compounds and estrogen drugs to prepare polyphenol-coated estrogen drug crystals in one step.

[0054] In a specific embodiment, the blank temperature-sensitive gel is prepared by cooling method, poloxamer 407 and poloxamer 188 are dissolved in pure water, stirred in an ice water bath until a clear solution is obtained, and then placed to remove air bubbles to obtain a colorless transparent blank gel.

[0055] In a specific embodiment, the blank temperature-sensitive gel is prepared by cooling method at 0-8℃, preferably at 4℃.

[0056] The preparation method of the present application can prepare the estrogen-loaded temperature-sensitive gel with good stability and rheological properties.

[0057] The third aspect of the present application is the use of the above-mentioned estrogen-loaded temperature-sensitive gel in endometrial repair. The novel estrogen-loaded temperature-sensitive gel provided by the present application realizes local intrauterine administration by loading polyphenol-coated estrogen drug crystals into the temperature-sensitive gel. This administration method can precisely release the drug at the site of endometrial injury, effectively increase the local drug concentration, and enhance the therapeutic effect. At the same time, compared with the systemic administration route, the distribution of the drug in other parts of the body is greatly reduced, thereby significantly reducing the risk of systemic side effects, and providing a safer and more effective choice for the treatment of endometrial injury.

[0058] Examples

[0059] Preparations

[0060] Example 1 Preparation of polyphenol-coated estradiol microcrystals

[0061] Take 120 mg of sodium bicarbonate, put it in a 50 mL beaker, accurately transfer 30 mL of purified water into the beaker, stir uniformly and reserve, and put it in a grinding cup. Take 60 mg of estradiol and 180 mg of dopamine hydrochloride, respectively, and add them to the sodium bicarbonate solution in the grinding cup, and put it in a ball mill cup. Weigh the grinding cup with a lid, grinding balls and materials, install it according to the ball mill operation procedures, and set the stirring speed to 400 r, stirring for 2 h (according to the intermittent mode). After standing for 12 h, filter out the free dopamine and collect the precipitated estradiol microcrystals to obtain polyphenol-coated estradiol microcrystals. Measure the particle size, and the D50 is 1.8 um.

[0062] Example 2 Preparation of a blank thermosensitive gel

[0063] Formulation 1

[0064] Take 20.00 g of poloxamer 407 and 15.00 g of poloxamer 188, and put them in a 250 mL dry beaker. Accurately measure 65 mL of purified water pre-cooled to 4°C, and place the beaker on a magnetic stirrer containing an ice-water mixture. Stir and disperse at about 4°C and 500 rpm until the powder is completely dissolved into a clear solution. Stop stirring, transfer the beaker to a 4°C refrigerator, and stand for 12 h to remove air bubbles. After taking it out, add 4°C purified water to a total weight of 100 g, and stir uniformly to obtain temperature-sensitive gel 1, which is stored at 4°C and sealed for future use.

[0065] Formulation 2

[0066] Poloxamer 407 30.00 g and poloxamer 188 15.00 g were weighed into a 250 mL dry beaker; 65 mL of purified water pre-cooled to 4°C was precisely measured and the beaker was placed on a magnetic stirrer with ice water mixture, stirred at about 4°C and 500 rpm until the powder was completely dissolved into a clear solution; the stirring was stopped and the beaker was transferred to a 4°C refrigerator for 12 h to remove bubbles; after taking out, 4°C purified water was added to a total weight of 100 g, and stirred uniformly to obtain a temperature-sensitive gel 2, which was stored at 4°C and sealed for later use.

[0067] Formulation 3

[0068] Poloxamer 407 20.00 g and poloxamer 188 25.00 g were weighed into a 250 mL dry beaker; 65 mL of purified water pre-cooled to 4°C was precisely measured and the beaker was placed on a magnetic stirrer with ice water mixture, stirred at about 4°C and 500 rpm until the powder was completely dissolved into a clear solution; the stirring was stopped and the beaker was transferred to a 4°C refrigerator for 12 h to remove bubbles; after taking out, 4°C purified water was added to a total weight of 100 g, and stirred uniformly to obtain a temperature-sensitive gel 3, which was stored at 4°C and sealed for later use.

[0069] Example 3 Preparation of polyphenol-modified estradiol gel

[0070] 100 g of the temperature-sensitive gel 1 prepared in Example 2 was precisely weighed into a 250 mL dry beaker, and 30 mg of the polyphenol-coated estradiol microcrystals prepared in Example 1 was added to prepare a suspended drug-loaded gel by dispersing at room temperature and 500 rpm.

[0071] The morphology of the polyphenol-modified estradiol gel was observed at room temperature and body temperature, respectively. The results showed that the gel was liquid at room temperature, and the fluidity decreased and solidified at body temperature (37°C), indicating that the gel had good temperature-sensitive properties.

[0072] Performance test

[0073] The rheological properties, stability, degradation properties, in-vitro release rate, and retention effect in animals and anti-intracavitary adhesion ability of the polyphenol-modified estradiol gel prepared in Example 3 (hereinafter sometimes referred to as “self-made gel”) were investigated.

[0074] I. Rheological properties, stability

[0075] The state of the polyphenol-modified estradiol gel of the present application was observed within 24 hours, and the results showed that the gel could maintain a stable suspension state for at least 24 hours, and the dispersion performance was good after standing for several days.

[0076] The morphology of the polyphenol-modified estradiol gel of the present application was observed at room temperature and at body temperature, and the results showed that the gel was liquid at room temperature (20-25°C), and the flowability was reduced and the gel was solidified at body temperature (37°C), indicating that the gel had good temperature-sensitive properties.

[0077] II. Retention in the animal body, ability to combat intrauterine adhesions

[0078] Two in vivo evaluation methods (female SD rats) were established, and the therapeutic effect of the estradiol gel preparation prepared in Example 3 of the present application was evaluated by comparison with the commercially available preparation Gongankang (intrauterine cross-linked sodium hyaluronate gel).

[0079] 1. Uterine injury model evaluation method:

[0080] A rat endometrial mechanical injury model was constructed, and a fluorescently labeled gel preparation was injected into the injured uterus to evaluate the retention time of the self-prepared estradiol gel preparation in the rat uterus. As shown in Figure 1 , the fluorescent signal of the self-prepared gel preparation was still detectable at 14 days, while the Gongankang preparation was not detectable at 10 days, and the self-prepared gel showed better retention in the uterus.

[0081] The prevention of uterine adhesion and the repair effect of the gel preparation of the present application on the uterus were investigated by histological examination, as shown in Figure 2 , the rats were sacrificed at 14 days and the uterine sections were stained with H&E and Masson. From the H&E staining image, it can be seen that the gel group has complete tissue structure, while the saline group produces papillary hyperplasia and forms adhesion. In the Masson staining image, it can be seen that the epidermis of the saline group is severely fibrotic, the endometrium of the gel group is less fibrotic, and the self-prepared gel group is less fibrotic than the Gongankang group, proving that the self-prepared gel has better anti-adhesion effect.

[0082] 2. Abdominal adhesion model evaluation method:

[0083] A rat abdominal adhesion model was constructed by surgery (sterile cotton gauze was rubbed against the cecum wall of the rat until there were obvious bleeding points, the wound area was about 2 cm x 2 cm, a 2 cm x 2 cm wound surface was created by repeatedly scraping the abdominal wall with a scalpel, and the scalpel could see the scraped off tissue cells, and the two wound surfaces were sutured with a 4# surgical suture, an artificial adhesion model was created.), as shown in Figure 3 , a fluorescently labeled gel preparation was used and applied to the abdominal injury site, and the retention time of the self-prepared gel preparation at the abdominal adhesion site of the rat was evaluated by small animal live fluorescence imaging, and the self-prepared gel was significantly better than Gongankang.

[0084] The prevention effect of the gel preparation on abdominal adhesion was investigated by histological examination. As shown in Figure 4As shown, the rats were killed at 14 days and the abdominal adhesion sites were subjected to H&E and Masson staining. From the H&E staining diagram, it can be seen that the control group produced severe adhesion accompanied by severe inflammatory reaction, and the Gongan Kang group and the gel group only had slight inflammatory reaction, and the tissue structure was relatively complete. In the Masson staining diagram, it can be seen that the collagen fiber of the physiological saline group at the adhesion site proliferated seriously, and the collagen fiber of the Gongan Kang and self-made gel groups did not proliferate seriously, proving the local anti-adhesion ability of the self-made gel preparation.

[0085] III. Anti-inflammatory and antioxidant properties

[0086] The animal model of uterine injury adhesion was constructed by simulating the operation of curettage, and the local inflammatory reaction of the polyphenol modified estradiol uterine cavity gel of the application and its effect on endometrial repair were investigated in vivo. The results are shown in Figure 5 As shown, the left diagram is the physiological saline group, and the right diagram is the self-made gel group of the application. In the left diagram, it can be seen that the intestinal wall of the rat has completely adhered to the abdominal wall and there are many bleeding points. In the right diagram, only partial adhesion is produced at the connection between the intestinal wall and the abdominal wall, and there are fewer bleeding points and light inflammatory reaction. In the abdominal adhesion model, it is obviously observed that the abdominal adhesion and inflammatory reaction of the rats in the self-made gel group of the application are lighter than those in the physiological saline group. The experiment shows that the gel preparation is endowed with excellent anti-inflammatory and antioxidant properties by the surface modification and functionalization of polyphenol.

[0087] Although the application has been illustrated and described with reference to certain preferred embodiments thereof, it should be understood by those skilled in the art that the foregoing is a further detailed description of the application and is not intended to limit the application to the specific embodiments described. Various modifications and changes can be made in form and detail by those skilled in the art without departing from the spirit and scope of the application, including making several simple deductions or substitutions, which also belong to the part of the application.

Claims

1. An intrauterine drug delivery gel formulation loaded with an estrogen-like drug, wherein the estrogen-like drug is suspended and dispersed in the gel, the estrogen-like drug is modified with polyphenols, and the thermosensitive gel contains poloxamer.

2. The gel formulation of claim 1, wherein the poloxamer comprises poloxamer 407 and poloxamer 188.

3. The gel formulation according to claim 2, wherein the mass ratio of poloxamer 407 to poloxamer 188 is 1:2 to 2:

1.

4. The gel formulation according to claim 1, wherein the estrogen drug is selected from estradiol, ethinylestradiol, and estriol.

5. The gel formulation according to claim 1, wherein the polyphenol is selected from one or more of dopamine oligomers, tannic acid oligomers, epigallocatechin gallate and its oligomers, quercetin oligomers, and catechin oligomers.

6. Use of the gel formulation as described in any one of claims 1 to 5 in endometrial repair.

7. A method for preparing a gel formulation carrying an estrogen-like drug, comprising: Preparation of polyphenol-coated estrogen drug crystals: Polyphenolic compounds and estrogen drugs are mixed and ground using wet media milling to prepare polyphenol-coated estrogen drug crystals. Preparation of blank gel: A blank gel was prepared by dissolving poloxamer in water using a cooling method; Preparation of gel formulation: Prepare gel formulation by suspending and dispersing polyphenol-coated estrogen drug crystals in a blank gel.

8. The preparation method according to claim 7, wherein the poloxamer is a mixture of poloxamer 407 and poloxamer 188.

9. The preparation method according to claim 7 or 8, wherein the polyphenolic compound is selected from one or more of dopamine, tannic acid, epigallocatechin gallate and its oligomers, quercetin oligomers, and catechins.

10. The preparation method according to claim 7 or 8, wherein the estrogen drug is selected from estradiol, ethinylestradiol, and estriol.

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