Estrogen vaginal foaming agent and preparation method thereof

Abstract

The invention relates to the technical field of vaginitis medicines, in particular to an estrogen vagina foaming agent and a preparation method thereof. The estrogen vaginal foaming agent is prepared from the following components in parts by weight: 0.1 part of estrogen, 6 to 10 parts of a foam stabilizer, 180 to 220 parts of poloxamer, 100 to 120 parts of tetrafluoroethane, 8 to 12 parts of a pH buffer agent, 100 to 150 parts of medium chain triglyceride, 1 part of d-limonene, 6 parts of N-acetylcysteine and the balance of water, wherein the total parts of the estrogen, the foam stabilizer, the poloxamer, the tetrafluoroethane, the pH buffer agent, the medium chain triglyceride, the d-limonene and the N-acetylcysteine are supplemented to 1000 parts. And the foam stabilizer is chitosan or sodium hyaluronate. The estrogen is prepared into the foaming agent, so that the contact area is increased, and the treatment effect is further enhanced; by adding chitosan, bubbles can be prevented from being combined and broken due to electrostatic repulsion, and the retention time of the bubbles is prolonged; sodium hyaluronate is added, so that a physical barrier can be formed among bubbles, vaginal epithelium repair is promoted, and the treatment effect is enhanced.

Description

Technical Field

[0001] This application relates to the technical field of vaginal anti-inflammatory drugs, specifically to an estrogen vaginal foam and its preparation method. Background Technology

[0002] Estrogen plays a wide range of physiological roles in the female body. Besides its effects on the reproductive system, it also acts on other target organs, including the bones, cardiovascular system, central nervous system, liver, and skin and its appendages. Menopause or other causes of ovarian dysfunction can lead to estrogen deficiency, which in turn affects the function of these target organs. Specifically, in the reproductive organs, this can cause vulvar and vaginal atrophy and decreased secretions. These effects are not age-limited and often include some young women. In addition to the estrogen supplementation needs caused by normal functional decline, there are also pathological estrogen supplementation needs. There are three types of estrogen in the human body: estradiol, estrone, and estriol. Estradiol is the most important and most active estrogen and is one of the six routine indicators of sex hormones.

[0003] Currently, the most commonly used dosage forms and administration methods of estrogen include: 1. Injectable or oral estrogen (tablets, capsules, etc.), the drawbacks of which are large dosages, significant side effects (high incidence of breast cancer and cervical cancer), and low bioavailability; 2. Topical estrogen (patch, film, etc.), the drawbacks of which are a significant film or film application sensation, poor compliance, and allergies in some patients; 3. Estrogen rings, the drawbacks of which are large size, strong and uncomfortable foreign body sensation after insertion, and poor compliance. Summary of the Invention

[0004] To address the problem that existing commonly used estrogen formulations are inconvenient for patients to use, this application provides an estrogen vaginal foam.

[0005] In a first aspect, this application provides an estrogen-based vaginal foaming agent, employing the following technical solution: An estrogen-based vaginal foaming agent comprises the following components in parts by weight: 0.1 parts estrogen, 6-10 parts foam stabilizer, 180-220 parts poloxamer, 100-120 parts tetrafluoroethane, 8-12 parts pH buffer, 100-150 parts medium-chain triglycerides, 1 part d-limonene, 6 parts N-acetylcysteine, and water to bring the total to 1000 parts; wherein the foam stabilizer is chitosan or sodium hyaluronate.

[0006] By employing the above-mentioned technical solution, when estrogen is prepared into a foam, the foam expands and fills the folds within the vagina upon application, significantly increasing the contact area compared to gels / suppositories, thus further enhancing the therapeutic effect. Chitosan or sodium hyaluronate, both selected as foam stabilizers, exhibit excellent promoting effects. Chitosan has a higher zeta potential, preventing bubbles from merging and rupturing due to electrostatic repulsion. Furthermore, chitosan utilizes mucus anions to form "ionic bonds + hydrogen bonds," prolonging bubble retention time. The protonated amino groups of chitosan bind to the negative charge of the mucosa, strengthening the foam framework; its positive charge adsorbs at the gas-liquid interface, also enhancing membrane rigidity. The polymer chains of sodium hyaluronate form a physical barrier between bubbles. Additionally, the molecular structure of sodium hyaluronate is similar to that of natural vaginal glycosaminoglycans, promoting vaginal epithelial repair.

[0007] This application improves the therapeutic effect by preparing estrogen into a foaming agent, increasing the contact area; the addition of chitosan prevents the bubbles from merging and rupturing due to electrostatic repulsion, thus prolonging the bubble retention time; the addition of sodium hyaluronate forms a physical barrier between the bubbles, while promoting vaginal epithelial repair and enhancing the therapeutic effect.

[0008] Preferably, the poloxamer is poloxamer 407.

[0009] By employing the aforementioned technical solution, poloxamer 407 has a higher PEO content compared to poloxamer 188 or poloxamer 338. This allows it to transform from air bubbles into a rigid gel network at vaginal temperature, solidifying in situ within the vagina to form a film, prolonging retention time and enhancing therapeutic efficacy. Furthermore, the PPO core (56 propylene oxide units) of poloxamer 407 can encapsulate estrogen, enhancing its solubility.

[0010] Preferably, the D50 of the estrogen is ≤10μm.

[0011] Preferably, the estrogen comprises at least one of estradiol, estriol, chloroquine-proestrene, proestrene, progesterone, misoprostol, terbinafine hydrochloride, and styrax.

[0012] By adopting the above technical solution, when the particle size of estrogen is too large, the dissolution effect is poor, which can easily affect the degree of human absorption and reduce the therapeutic effect.

[0013] Preferably, the foam stabilizer is chitosan.

[0014] By employing the above-mentioned technical solution, compared to sodium hyaluronate, chitosan undergoes protonation of its amino groups, allowing it to be directionally adsorbed onto the hydrophobic regions of air bubbles, forming a dense, positively charged interfacial film. This increases the zeta potential, enhances the electrostatic repulsion of the bubbles, prolongs the foam's half-life, and improves foam stability. Furthermore, chitosan adheres to the vaginal mucosa through a combination of electrostatic attraction and hydrogen bonding. Sodium hyaluronate, on the other hand, primarily adheres to the vaginal mucosa via hydrogen bonding; therefore, chitosan exhibits superior adhesion.

[0015] Preferably, the foam stabilizer is sodium hyaluronate, and the poloxamer is present in parts by weight of 180-200.

[0016] By employing the above-mentioned technical solution, the carboxyl groups of sodium hyaluronate form more hydrogen bonds with the ether bonds of poloxamer, while the amino groups of chitosan form fewer hydrogen bonds with the ether bonds of poloxamer. Furthermore, the flexible chains of sodium hyaluronate interweave within the poloxamer micelles to form a network scaffold, enhancing foam stability. Therefore, compared to chitosan, sodium hyaluronate requires only a smaller amount of poloxamer to reach the upper limit of therapeutic efficacy.

[0017] Preferably, the foam stabilizer is sodium hyaluronate, and also includes hydroxypropyl methylcellulose.

[0018] By employing the above technical solution, sodium hyaluronate, with its high elastic modulus, provides a rigid support network, inhibiting bubble coalescence. Hydroxypropyl methylcellulose, with its high viscosity modulus, enhances the viscosity of the liquid film, delaying drainage rupture. The synergistic effect of both further improves foam stability. Hydroxypropyl methylcellulose competitively inhibits hyaluronidase, protecting sodium hyaluronate from degradation and enhancing its penetration depth into the vagina. Furthermore, sodium hyaluronate forms a network structure, facilitating the rapid release of some estrogen to achieve the initial therapeutic concentration. Then, hydroxypropyl methylcellulose forms a gel layer, slowly releasing the remaining estrogen to maintain an effective concentration. This dual release timing ensures prolonged therapeutic efficacy.

[0019] Preferably, the mass ratio of sodium hyaluronate to hydroxypropyl methylcellulose is 10:3-5.

[0020] By adopting the above technical solution, when the content of hydroxypropyl methylcellulose is too low, the synergistic effect of the two is not obvious; when the content of hydroxypropyl methylcellulose is too high, the gel layer formed by hydroxypropyl methylcellulose is too thick, which reduces the estrogen diffusion coefficient and is not conducive to subsequent treatment. Therefore, after extensive research and experimental verification, the applicant finally determined that the mass ratio of sodium hyaluronate to hydroxypropyl methylcellulose in this application is as described above.

[0021] Secondly, this application provides a method for preparing an estrogen-based vaginal foam, employing the following technical solution: A method for preparing an estrogen-containing vaginal foam, comprising the following steps: Preparation of the aqueous phase: Dissolve the pH buffer in water, then add the foam stabilizer, poloxamer and N-acetylcysteine ​​and stir to obtain the aqueous phase; Preparation of the oil phase: Estrogen and d-limonene were added to the medium-chain triglycerides and stirred to obtain the oil phase; Homogenization: The oil phase is added to the aqueous phase and then homogenized to obtain the drug solution; Sealing: After cooling the liquid medicine, vacuum fill it into an aluminum can, install a valve, fill the aluminum can with tetrafluoroethane, and then seal it to obtain an estrogen vaginal foam.

[0022] In summary, this application has the following beneficial effects: 1. Because this application prepares estrogen into a foaming agent, it increases the contact area and further enhances the therapeutic effect; the addition of chitosan can prevent the bubbles from merging and rupturing due to electrostatic repulsion, thus prolonging the bubble retention time; the addition of sodium hyaluronate can form a physical barrier between the bubbles, while promoting vaginal epithelial repair and enhancing the therapeutic effect. 2. The foam stabilizer in this application is sodium hyaluronate, and the amount of poloxamer is less because sodium hyaluronate can form more hydrogen bonds with poloxamer, and can also form a network scaffold to enhance the stability of the foam. 3. The foam stabilizer in this application is sodium hyaluronate, and the addition of hydroxypropyl methylcellulose enhances its effect because the two work synergistically to further improve foam stability; simultaneously, hydroxypropyl methylcellulose protects sodium hyaluronate from degradation, enhancing its penetration depth into the vagina. Detailed Implementation

[0023] The raw materials in this application include the following: Estrogenous substances include: estradiol, estriol, chloroquine-proestrene, proestrene, progesterone, misoprostol, terbinafine hydrochloride, and styrax. All of the above-mentioned estrogenous substances can be used in this application; estradiol is used as an example only below.

[0024] Estradiol: Uses a commercially available product with CAS number 50-28-2; Chitosan: The product used is a commercially available product with CAS number 9012-76-4; Sodium hyaluronate: Uses commercially available products with CAS number 9067-32-7; Hydroxypropyl methylcellulose: Uses commercially available products with CAS number 9004-65-3; Tetrafluoroethane: Use commercially available products with CAS number 811-97-2; pH buffer: formed by pairing citric acid and sodium citrate, with a mass ratio of 2:5. That is, if 7g of pH buffer is added, only 2g of citric acid and 5g of sodium citrate need to be added respectively. Citric acid: Uses a commercially available product with CAS number 5949-29-1; Sodium citrate: Uses a commercially available product with CAS number 68-04-2; Medium-chain triglycerides: Miglyol® 812, using the commercially available product with CAS number 37332-31-3; d-Limonene: The commercially available product with CAS number 5989-27-5 is used; N-acetylcysteine: Use the commercially available product with CAS number 616-91-1; The present application will be further described in detail below with reference to embodiments and comparative examples.

[0025] Example 1 A method for preparing an estradiol vaginal foam includes the following steps: Preparation of aqueous phase: Dissolve 10g of pH buffer in 532.9g of water, then add 10g of chitosan, 200g of poloxamer 407 and 6g of N-acetylcysteine ​​and stir to obtain aqueous phase; Preparation of the oil phase: 0.1 g of estradiol (D50 of 5 μm) and 1 g of d-limonene were added to 130 g of medium-chain triglycerides and stirred to obtain the oil phase; Homogenization: The oil phase was added to the aqueous phase and then homogenized at 8000 rpm for 10 min to obtain the drug solution; Sealing: After cooling the liquid medicine to 5°C, vacuum fill it into an aluminum can, install the valve, then fill the aluminum can with 110g of tetrafluoroethane and seal it to obtain estradiol vaginal foam.

[0026] Example 2-3 Examples 2-3 are based on the preparation method of Example 1, with adjustments made to the content of each component of the estradiol vaginal foam agent, as shown in Table 1.

[0027] Comparative Example 1 Comparative Example 1 was prepared using the same method as in Example 1, but without the addition of 10g of chitosan.

[0028] Performance testing The estradiol vaginal foams of Examples 1-3 and Comparative Example 1 were subjected to the following performance tests, and the test results are shown in Table 1.

[0029] 1. Defoaming time At 33°C, spray the estradiol vaginal foam five times onto the silicone surface and record the time it takes for the foam to completely disappear; this is the defoaming time.

[0030] 2. Vaginal mucosal thickness increase value Pretreatment: Adult female New Zealand white rabbits weighing 3.0-3.5 kg underwent ovariectomy. Four weeks post-surgery, a blood estradiol level <5 pg / mL and a vaginal mucosal thickness ≤200 μm as measured by ultrasound were considered successful for model establishment.

[0031] Starting in the 5th week post-surgery, experimental animals that had successfully established the model using the above steps were divided into groups of 8. Each group was treated with the estradiol vaginal foam formulations from Examples 1-3 and Comparative Example 1, respectively, and the effects were compared. Each dose was 0.5-0.7g, administered continuously for 28 days. Vaginal mucosal thickness was measured by ultrasound. The initial vaginal mucosal thickness (A) of the experimental animals was recorded, and the vaginal mucosal thickness (B) after 28 days of continuous administration was recorded, yielding the vaginal mucosal thickness increase value (C=BA).

[0032] Table 1. Content (g) and performance test results of each component of the estradiol vaginal foam in Examples 1-3 and Comparative Example 1. Referring to Table 1, comparing Examples 1-3 and Comparative Example 1, it can be seen that the estradiol vaginal foam prepared according to the above formula has a good therapeutic effect on atrophic vaginitis. Chitosan has a significant promoting effect. This is because chitosan has a high Zeta potential, and the electrostatic repulsion between bubbles prevents them from merging and rupturing. Furthermore, chitosan utilizes mucus anions to form "ionic bonds + hydrogen bonds," prolonging the bubble retention time. The protonated amino groups of chitosan bind to the negative charge of the mucosa, strengthening the foam skeleton; its positive charge adsorbs at the gas-liquid interface, also enhancing membrane rigidity.

[0033] Furthermore, comparing Examples 1-3, it was found that Example 1 had the best performance; therefore, Example 1 was preferred.

[0034] Examples 4-5 Examples 4-5 are based on the preparation method of Example 1, but the types of poloxamer are adjusted. The specific adjustments are shown in Table 2.

[0035] The estradiol vaginal foams from Examples 4-5 were subjected to the performance tests described above, and the test results are shown in Table 2.

[0036] Table 2. Types and performance test results of poloxamer in Examples 1 and 4-5. Referring to Table 2, comparing Examples 1 and 4-5, it is evident that poloxamer 407 exhibits the best efficacy among the three poloxamer formulations. This is because poloxamer 407 has a higher PEO content compared to poloxamer 188 or poloxamer 338, allowing it to transform from air bubbles into a rigid gel network at vaginal temperature, solidifying in situ within the vagina to prolong retention time and enhance therapeutic efficacy. Furthermore, the PPO core (56 propylene oxide units) of poloxamer 407 can encapsulate estradiol, enhancing its solubility.

[0037] Examples 6-7 Examples 6-7 are based on the preparation method of Example 1, but the D50 of estradiol is adjusted. The specific adjustments are shown in Table 3.

[0038] The estradiol vaginal foams from Examples 6-7 were subjected to the performance tests described above, and the test results are shown in Table 3.

[0039] Table 3. D50 and performance test results of estradiol in Examples 1 and 6-7. Referring to Table 3, a comparison of Examples 1 and 6-7 shows that the effectiveness of the prepared estradiol foam gradually increases as the particle size of estradiol decreases. This is because as the particle size of estradiol decreases, it dissolves more easily during formulation and is more readily absorbed during treatment, thereby improving the therapeutic effect.

[0040] Examples 8-9 In Example 8, the preparation method of Example 1 was followed by replacing 10g of chitosan with 10g of sodium hyaluronate.

[0041] Example 9 is based on the preparation method of Example 8, with adjustments made to the preparation method, specifically as follows: In the preparation of the aqueous phase, 10g of pH buffer was dissolved in 528.9g of water, and then 10g of sodium hyaluronate, 4g of hydroxypropyl methylcellulose, 200g of poloxamer 407 and 6g of N-acetylcysteine ​​were added and stirred to obtain the aqueous phase.

[0042] The estradiol vaginal foams of Examples 8-9 were subjected to the above performance tests, and the test results are shown in Table 4.

[0043] Table 4. Types and mass ratios of foam stabilizers in Examples 1 and 8-9, and performance test results. Referring to Table 4, a comparison of Examples 1 and 8-9 shows that chitosan is superior to sodium hyaluronate as a foam stabilizer. This is because, compared to sodium hyaluronate, chitosan's amino groups are protonated, allowing it to be directionally adsorbed onto the hydrophobic regions of bubbles, forming a dense, positively charged interfacial film. This increases the zeta potential, enhances the electrostatic repulsion of bubbles, prolongs the foam half-life, and improves foam stability. Furthermore, chitosan adheres to the vaginal mucosa through both electrostatic attraction and hydrogen bonding. Sodium hyaluronate, on the other hand, mainly adheres to the vaginal mucosa through hydrogen bonding; therefore, chitosan exhibits better adhesion.

[0044] When the foam stabilizer uses a combination of sodium hyaluronate and hydroxypropyl methylcellulose, it is superior to adding chitosan or sodium hyaluronate alone. This is because sodium hyaluronate has a high elastic modulus, providing a rigid support network and inhibiting bubble coalescence. Hydroxypropyl methylcellulose has a high viscosity modulus, enhancing the viscosity of the liquid film and delaying drainage rupture. The synergistic effect of both further improves foam stability. Hydroxypropyl methylcellulose competitively inhibits hyaluronidase, protecting sodium hyaluronate from degradation and enhancing its penetration depth into the vagina. Additionally, sodium hyaluronate forms a network structure, facilitating the rapid release of some estradiol to achieve the initial therapeutic concentration. Then, hydroxypropyl methylcellulose forms a gel layer, slowly releasing the remaining estradiol to maintain an effective concentration. This dual release timing ensures a prolonged therapeutic effect.

[0045] Examples 10-11 Examples 10-11 are based on the preparation method of Example 9, but the amount of hydroxypropyl methylcellulose and water added is adjusted. The specific adjustments are shown in Table 5.

[0046] The estradiol vaginal foams of Examples 10-11 were subjected to the above performance tests, and the test results are shown in Table 5.

[0047] Table 5. Dosage of hydroxypropyl methylcellulose and water added and performance test results for Examples 1 and 9-11. Referring to Table 5, a comparison of Examples 1 and 10-11 shows that as the amount of hydroxypropyl methylcellulose added increases, the therapeutic effect of the prepared estradiol vaginal foam initially increases and then decreases. This is because as the amount of hydroxypropyl methylcellulose added increases, the synergistic effect between hydroxypropyl methylcellulose and sodium hyaluronate improves. However, beyond a certain range, the gel layer formed by hydroxypropyl methylcellulose becomes too thick, reducing the diffusion coefficient of estradiol and consequently decreasing the therapeutic effect.

[0048] Examples 12-14 Example 12 is based on the preparation method of Example 1, but the amount of poloxamer 407 and water added is adjusted. The specific adjustments are shown in Table 6.

[0049] Examples 13-14 are based on the preparation method of Example 8, but the amount of poloxamer 407 and water added is adjusted. The specific adjustments are shown in Table 6.

[0050] The estradiol vaginal foams of Examples 12-14 were subjected to the performance tests described above, and the test results are shown in Table 6.

[0051] Table 6. Dosage of Poloxamer 407 and Water and Performance Test Results in Examples 1, 8, and 12-14 Referring to Table 6, a comparison of Examples 1, 8, and 12-14 shows that when sodium hyaluronate and poloxamer 407 are combined, less poloxamer 407 is required. This is because the carboxyl groups of sodium hyaluronate form more hydrogen bonds with the ether bonds of poloxamer, while the amino groups of chitosan form fewer hydrogen bonds with the ether bonds of poloxamer. Furthermore, the flexible chains of sodium hyaluronate interweave within the poloxamer micelles to form a network scaffold, enhancing foam stability. Therefore, compared to chitosan, sodium hyaluronate requires less poloxamer to reach the upper limit of therapeutic efficacy.

[0052] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. An estrogen-based vaginal foam, characterized in that, The product comprises the following components in parts by weight: 0.1 parts estrogen, 6-10 parts foam stabilizer, 180-220 parts poloxamer, 100-120 parts tetrafluoroethane, 8-12 parts pH buffer, 100-150 parts medium-chain triglycerides, 1 part d-limonene, 6 parts N-acetylcysteine, and water to bring the total to 1000 parts; the foam stabilizer is chitosan or sodium hyaluronate.

2. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The poloxamer in question is poloxamer 407.

3. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The D50 of the estrogen is ≤10μm.

4. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The estrogens include at least one of estradiol, estriol, chloroquine-proestrene, proestrene, progesterone, misoprostol, terbinafine hydrochloride, and styrax.

5. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The foam stabilizer is chitosan.

6. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The foam stabilizer is sodium hyaluronate, and the poloxamer is present in parts by weight of 180-200.

7. The estrogen-containing vaginal foaming agent according to claim 1, characterized in that: The foam stabilizer is sodium hyaluronate, and also includes hydroxypropyl methylcellulose.

8. The estrogen-containing vaginal foaming agent according to claim 7, characterized in that: The mass ratio of sodium hyaluronate to hydroxypropyl methylcellulose is 10:3-5.

9. The method for preparing the estrogen vaginal foaming agent according to any one of claims 1-6, characterized in that: Preparation of the aqueous phase: Dissolve the pH buffer in water, then add the foam stabilizer, poloxamer and N-acetylcysteine ​​and stir to obtain the aqueous phase; Preparation of the oil phase: Estrogen and d-limonene were added to the medium-chain triglycerides and stirred to obtain the oil phase; Homogenization: The oil phase is added to the aqueous phase and then homogenized to obtain the drug solution; Sealing: After cooling the liquid medicine, vacuum fill it into an aluminum can, install a valve, fill the aluminum can with tetrafluoroethane, and then seal it to obtain an estrogen vaginal foam.

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