Vaginal foaming agent and method for preparing the same

Abstract

This invention provides a vaginal foaming agent containing estradiol as an active ingredient, and a method for preparing the same. [Solution] The present invention provides a method for preparing estradiol into a vaginal foaming agent. The raw materials for preparing the vaginal foaming agent include a matrix material and a propellant. The raw materials for preparing the matrix material include estradiol, an oil-water amphoteric organic solvent, a hydrophobic component, a surfactant, and water. The vaginal foaming agent of the present invention has good compliance, a large contact area in the vagina, rapid release of estradiol, strong targeting of diseases caused by estrogen deficiency, rapid effect, accurate dosage, and is convenient to use.

Description

Technical Field

[0001] The present invention relates to the technical field of medicine, particularly to vaginal foaming agents and their preparation methods.

Background Art

[0002] Estrogen has a wide range of physiological effects on the female body. In addition to its effects on the genital system, it also acts on other target organs such as bones, the cardiovascular system, the central nervous system, the liver, the skin and its appendages. Ovarian insufficiency caused by reasons such as menopause leads to estrogen deficiency, which affects the functions of these target organs. Particularly with regard to the genital organs, it causes atrophy of the vulva and vagina and a decrease in secretions. These are not limited to a specific age group and often include young women. In addition to the need for estrogen supplementation due to normal functional decline, there may also be a need for estrogen supplementation pathologically. There are three types of estrogen in the human body: estradiol, estrone, and estriol. Estradiol is one of the most important and highly active estrogens and is one of the six conventional biomarker substances of sex hormones. The structural formula of estradiol is as follows.

Chemical

[0003] Currently, the most common dosage forms and methods of administration of estradiol are as follows: 1. Injectable or oral estradiol (tablets, capsules, etc.). It has disadvantages such as large dosages and strengths, clear side effects (high incidence of breast and cervical cancer), and low bioavailability. 2. Topical estradiol (patches, films, etc.). It has disadvantages such as a noticeable feeling of adhesion from the film or membrane, low compliance, and some patients are prone to allergic reactions. 3. Estradiol rings or estradiol implants. Disadvantages of estradiol rings include their large size, strong and uncomfortable feeling of foreign body after insertion, and low compliance. Estradiol implants are relatively small, but the feeling of foreign body is still relatively clear, and the implants have the disadvantage of easily falling out. 4. Estradiol vaginal tablets or estradiol vaginal soft capsules. It has the drawbacks of causing a clear foreign body sensation, low compliance, slow estradiol release, and having little effect on cardiovascular symptoms, but being ineffective for symptoms that depend on local estrogen levels, such as sexual dysfunction, vaginitis, and genital atrophy. [Overview of the project] [Problems that the invention aims to solve]

[0004] The present invention aims to provide a vaginal foaming agent and a method for preparing the same. The present invention provides a method for preparing estradiol as a vaginal foaming agent that has good compliance, a large contact area in the vagina, rapid release of estradiol, strong targeting of diseases caused by estrogen deficiency, rapid effect, accurate dosage, and is convenient to use. [Means for solving the problem]

[0005] To achieve the objectives of the above invention, the present invention provides the following technical solutions.

[0006] The present invention provides a vaginal foaming agent containing estradiol as an active ingredient.

[0007] Preferably, the raw materials for preparing the vaginal foaming agent include a matrix material and a propellant, and the raw materials for preparing the matrix material include estradiol, an oil-water amphoteric organic solvent, a hydrophobic component, a surfactant and water.

[0008] Preferably, the matrix material comprises a preparation raw material in which, by mass percentage, estradiol 0.0001% to 0.01%, the oil-water amphoteric organic solvent 35% to 65%, the hydrophobic component 1.0% to 10%, the surfactant 0.1% to 4.0%, and the remainder being water. Based on the use of 10 to 100 g / bottle of the matrix material, the amount of propellant used is 4 to 8 g / bottle.

[0009] Preferably, the oil-water amphoteric organic solvent is an alcohol solvent.

[0010] Preferably, the alcohol solvent includes one or more of butylene glycol, propylene glycol, glycerol, and polyethylene glycol.

[0011] Preferably, the hydrophobic component includes one or more of the following: C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds, and oily components.

[0012] Preferably, the C12-C22 fatty alcohol compound comprises hexadecanol and / or octadecanol, the C12-C22 solid fatty acid ester compound comprises one or more of glyceryl monostearate, glyceryl distearate, glyceryl mono, and distearate, and the oily component comprises one or more of liquid fatty acid ester compounds, mineral oil, and vegetable oil.

[0013] Preferably, the liquid fatty acid ester compound comprises one or more of isopropyl myristate, isopropyl palmitate, and ethyl oleate; the mineral oil comprises one or more of liquid paraffin, petrolatum, and white wax; and the vegetable oil comprises one or more of soybean oil, peanut oil, and olive oil.

[0014] Preferably, the surfactant includes one or more of the following: benzenesulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ether, fatty amine polyoxyethylene ether, alkyl alcohol amide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate, polyoxyethylene ricinoleic acid, ethoxylated glycerol triricinoleic acid, diethylene glycol monoethyl ether, and triethanolamine.

[0015] Preferably, the propellant contains a hydrofluoroalkane.

[0016] Preferably, the hydrofluoroalkane comprises one or more of tetrafluoroethane, heptafluoropropane, and difluoroethane.

[0017] Preferably, the pH value of the matrix material is 3.0 to 7.0.

[0018] The present invention provides a method for preparing a vaginal foaming agent as described in the above technical solution. The steps include mixing the estradiol, the amphoteric organic solvent, the surfactant, and water to obtain an aqueous phase, The steps include adding the hydrophobic component as an oil phase to the aqueous phase and emulsifying it to obtain the matrix material, The process includes the step of filling the matrix material with the propellant to obtain the vaginal foaming agent.

[0019] The present invention provides a vaginal foaming agent having estradiol as an active ingredient (hereinafter, may be simply referred to as "product").

Advantages of the Invention

[0020] The present invention prepares estradiol into a vaginal foaming agent, which has good compliance, a wide contact area in the vagina, rapid release of estradiol, strong targeting for diseases caused by estrogen deficiency, quick effects, accurate dosage, and convenient use.

Brief Description of the Drawings

[0021] [Figure 1] It is a photograph of a drug delivery device used in an embodiment of the present invention. [Figure 2] It is a diagram showing the foaming properties of each grade when evaluating the foaming properties in an embodiment of the present invention. [Figure 3] It is a diagram showing the test results of the applicability of the product packaging in Example 43 of the present invention. [Figure 4] It is a diagram showing the test results of the applicability of the product packaging in Example 44 of the present invention. [Figure 5] It is a diagram showing the test results of the applicability of the product packaging in Example 45 of the present invention. [Figure 6] It is an elution curve of the estradiol foaming agent, a commercially available estradiol soft capsule, and a vaginal tablet in Example 46 of the present invention. [Figure 7] It is a rabbit pharmacokinetic curve of the estradiol foaming agent in Example 46 of the present invention and a commercially available estradiol vaginal tablet. [[ID=^{34}]] [Figure 8] It is a pathological diagram of the effect of the estradiol foaming agent in Example 46 of the present invention on rabbit vaginal mucosal tissue.

Modes for Carrying Out the Invention

[0022] This invention provides a vaginal foaming agent containing estradiol as the active ingredient. This invention provides a vaginal foaming agent that has good compliance, a large contact area in the vagina, rapid release of estradiol, strong targeting of diseases caused by estrogen deficiency, rapid effect, accurate dosage, and is convenient to use.

[0023] As one embodiment of the present invention, the raw materials for preparing the vaginal foaming agent provided by the present invention may include a matrix material and a propellant, and the raw materials for preparing the matrix material may include estradiol, an oil-water amphoteric organic solvent, a hydrophobic component, a surfactant and water.

[0024] In the present invention, unless otherwise specifically described, all raw materials used are commercially available products well known to those skilled in the art or are obtained by methods well known to those skilled in the art.

[0025] In the present invention, the matrix material preferably contains, by mass percentage, estradiol 0.0001% to 0.01%, oil-water amphoteric organic solvent 35% to 65%, hydrophobic component 1.0% to 10%, surfactant 0.1% to 4.0%, and the remainder being water. Based on the amount of matrix material used being 10 to 100 g / bottle, the amount of propellant used is 4 to 8 g / bottle.

[0026] In the present invention, the preparation raw material includes, preferably, a matrix material by mass percentage of estradiol 0.0001% to 0.01%, specifically 0.0001%, 0.0004%, 0.0008%, 0.001%, 0.004%, 0.008%, or 0.01%.

[0027] In the present invention, the preparation raw material includes, by mass percentage, the matrix material preferably contains 25% to 78% of an oil-water amphoteric organic solvent, specifically 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 78%. In the present invention, the oil-water amphoteric organic solvent is preferably an alcohol solvent. The alcohol solvent preferably contains one or more of butylene glycol, propylene glycol, glycerol, and polyethylene glycol. The polyethylene glycol is preferably one or more of polyethylene glycol 200, polyethylene glycol 400, and polyethylene glycol 600, more preferably polyethylene glycol 200. In the present invention, the alcohol solvent may specifically be butylene glycol, propylene glycol, glycerol, polyethylene glycol, or a mixture of propylene glycol and glycerol, or a mixture of glycerol and polyethylene glycol. When the alcohol solvent is a mixture of propylene glycol and glycerol, the mass ratio of propylene glycol to glycerol is preferably 1:2 to 10, specifically 1:2.9, 1:5.4, or 1:9.4. In this case, the mass content of the alcohol solvent in the matrix material is preferably 30 to 60%, specifically 30%, 35%, 40%, 45%, 50%, 55%, or 60%. When the alcohol solvent is a mixture of glycerol and polyethylene glycol, the mass ratio of glycerol to polyethylene glycol is preferably 1:2.5 to 7.0, specifically 1:2.9, 1:3.5, or 1:5.9. In this case, the mass content of the alcohol solvent in the matrix material is preferably 35% to 65%, specifically 35%, 40%, 45%, 50%, 55%, 60%, or 65%. In the present invention, the above types and amounts of amphoteric organic solvents are preferably used. This ensures smooth emulsification, good foaming moldability, good compatibility with propellants, and good compatibility with foaming agent quantitative drug delivery devices. Furthermore, the above-mentioned oil-water amphoteric organic solvent can also be used as a humectant or lubricant for body cavity administration, ensuring the excellent efficacy of the foaming agent.

[0028] In the present invention, the matrix material includes a prepared raw material which may contain, by mass percentage, 1.0% to 10% of a hydrophobic component, specifically 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, or 10%. In the present invention, the hydrophobic component preferably comprises one or more of a C12-C22 fatty alcohol compound, a C12-C22 solid fatty acid ester compound, or an oily component, and more preferably a mixture of a C12-C22 fatty alcohol compound, a C12-C22 solid fatty acid ester compound, or an oily component. At this time, the mass ratio of the C12-C22 fatty alcohol compound, the C12-C22 solid fatty acid ester compound, and the oily component is preferably 0.4-4:0.1-1:3-10, more preferably 0.8-3:0.3-0.8:4-9, even more preferably 1-2.5:0.4-0.7:5-8, and even more preferably 1.5-2:0.5-0.6:6-7.

[0029] In the present invention, the C12-C22 fatty alcohol compound preferably comprises hexadecanol and / or octadecanol, and may specifically be hexadecanol or octadecanol, or a mixture of hexadecanol and octadecanol. In the mixture of hexadecanol and octadecanol, the mass ratio of hexadecanol to octadecanol is preferably 1-3:1-3, specifically 1:1, 2:1, 1:2, 3:1, or 1:3. When the raw material for preparing the matrix material contains a C12-C22 fatty alcohol compound, the mass content of the C12-C22 fatty alcohol compound in the raw material for preparing the matrix material is preferably 0.4%-3.0%, specifically 0.4%, 0.8%, 1.0%, 1.33%, 1.5%, 1.62%, 1.85%, 2.0%, 2.5%, or 3.0%. In the present invention, the above-mentioned types and amounts of C12-C22 fatty alcohol compounds are preferably used, which can adjust the viscosity of the system and at the same time play a supporting role as a skeletal component of the foam.

[0030] In the present invention, the C12-C22 solid fatty acid ester compound preferably comprises one or more of glyceryl monostearate, glyceryl distearate, glyceryl mono, and distearate, more preferably glyceryl monostearate. When the raw material for preparing the matrix material contains the C12-C22 solid fatty acid ester compound, the mass content of the C12-C22 solid fatty acid ester compound in the raw material for preparing the matrix material is preferably 0.1% to 1.0%, specifically 0.1%, 0.12%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0%. In the present invention, the above types and amounts of C12-C22 solid fatty acid ester compounds are preferably used, which helps to ensure that the appearance of the foam is good, smooth, and delicate.

[0031] In the present invention, the oily component preferably comprises one or more of liquid fatty acid ester compounds, mineral oil, and vegetable oil, and more preferably liquid fatty acid ester compounds or mineral oil; the liquid fatty acid ester compound preferably comprises one or more of isopropyl myristate, isopropyl palmitate, and ethyl oleate, and more preferably isopropyl myristate; the mineral oil preferably comprises one or more of liquid paraffin, petrolatum, and white wax, and more preferably is liquid paraffin, the liquid paraffin preferably is light liquid paraffin; and the vegetable oil preferably comprises one or more of soybean oil, peanut oil, and olive oil. In the present invention, when the raw material for preparing the matrix material contains a liquid fatty acid ester compound, the mass content of the liquid fatty acid ester compound in the raw material for preparing the matrix material is preferably 1.0% to 10%, specifically 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%. The amounts may be %, 9.0%, 9.5%, or 10%, and if the raw materials for preparing the matrix material include mineral oil, the mass content of mineral oil in the raw materials for preparing the matrix material is preferably 3.0% to 10%, specifically 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, or 10%. In the present invention, the above types and amounts of liquid fatty acid ester compounds and mineral oil are preferably used, which helps to ensure that the appearance of the foam is good, smooth and delicate.

[0032] In the present invention, the preparation raw material comprises a matrix material which, by mass percentage, preferably contains 0.1% to 4.0% surfactant, specifically 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, or 4.0%. In the present invention, the surfactant preferably comprises one or more of the following: benzenesulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ether, fatty amine polyoxyethylene ether, alkyl alcohol amide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate (Tween), polyoxyethylene ricinoleic acid, ethoxylated glycerol triricinoleic acid, diethylene glycol monoethyl ether, and triethanolamine, more preferably Tween, and the Tween is preferably Tween 60. In the present invention, it is preferable to use the above-mentioned types and amounts of surfactants, which also have emulsifying properties, good compatibility with propellants, and help ensure good physical stability of the foam.

[0033] In the present invention, the pH value of the matrix material is preferably 3.0 to 7.0, more preferably 3.0 to 5.0, specifically 3.0, 3.5%, 4.0%, 4.5%, or 5.0%. In the present invention, it is preferable to control the pH value of the matrix material within the above range to ensure that the foaming agent is compatible with the physiological pH environment of the vagina, and that the matrix material does not peel off during the preparation of the foaming agent, has good compatibility with the propellant, and at the same time has good compatibility with the foaming agent quantitative drug delivery device. As shown in the test results of Examples 43 to 45, when the pressure-resistant aluminum can was cut open and the painted inner wall of the aluminum can was observed, no peeling of the film was observed.

[0034] In the present invention, if the pH value of the matrix material does not satisfy the above requirements, the raw materials for preparing the matrix material preferably include a pH adjusting agent, and the amount of the pH adjusting agent used is adjusted so that the pH value of the matrix material is 3.0 to 7.0. In the present invention, the pH adjusting agent may be an acidic reagent or an alkaline reagent, and the acidic reagent is preferably lactic acid.

[0035] In the present invention, based on the amount of matrix material used being 10 to 100 g / bottle, the amount of propellant used is 4 to 8 g / bottle. Specifically, the amount of matrix material used may be 10 g / bottle, 20 g / bottle, 30 g / bottle, 40 g / bottle, 50 g / bottle, 60 g / bottle, 70 g / bottle, 80 g / bottle, 90 g / bottle, or 100 g / bottle, and the amount of propellant used may be 4 g / bottle, 4.5 g / bottle, 5 g / bottle, 5.5 g / bottle, 6 g / bottle, 6.5 g / bottle, 7 g / bottle, 7.5 g / bottle, or 8 g / bottle. In the present invention, the propellant preferably contains a hydrofluoroalkane, and the hydrofluoroalkane preferably contains one or more of tetrafluoroethane, heptafluoropropane, and difluoroethane. Specifically, it may be tetrafluoroethane, heptafluoropropane, or difluoroethane, and more preferably tetrafluoroethane. In the present invention, preferably, the above-mentioned types and amounts of propellants are used, and the foam of the prepared foaming agent has a smooth and delicate appearance, in which aliphatic alkanes are more ductile than hydrofluoroalkanes, and the foaming agent of the present invention is administered vaginally and reaches the vaginal cervix via a drug delivery device. If the ductility is too strong, it adversely affects the patient's safety and tolerability. Therefore, in the present invention, hydrofluoroalkanes are preferably used as propellants.

[0036] As one embodiment of the present invention, a preferred formulation of the vaginal foaming agent of the present invention is as follows.

[0037] The matrix material preferably contains, by mass percentage, estradiol at 0.0004% to 0.001%, more preferably 0.001%, isopropyl myristate at 3% to 10%, more preferably 7%, hexadecanol at 0.2% to 2.0%, more preferably 1.33%, glyceryl monostearate at 0.1% to 1.0%, more preferably 0.20%, and Tween 60 at 0.3% to 4.0%, more preferably 2.0%. The preparation raw material comprises an ethylene glycol 200 content of preferably 35% to 55%, more preferably 37.78%, a glycerol content of preferably 0% to 10%, more preferably 8.59%, a lactic acid content of preferably 0.05% to 0.2%, more preferably 0.10%, with the remainder being water. Based on the amount of the matrix material used being 10 to 100 g / bottle (e.g., 40 g / bottle), the amount of the propellant used is preferably 4 g to 5.5 g / bottle, more preferably 4.7 g / bottle.

[0038] The present invention provides a method for preparing a vaginal foaming agent as described in the above technical solution. The steps include: mixing estradiol, an amphoteric organic solvent, a surfactant, and water to obtain an aqueous phase; The steps include adding a hydrophobic component as an oil phase to the aqueous phase and emulsifying it to obtain a matrix material, The process includes the step of filling the matrix material with a propellant to obtain the vaginal foaming agent.

[0039] The present invention involves mixing estradiol, an oil-water amphoteric organic solvent, a surfactant, and water to obtain an aqueous phase. In the present invention, the mixing is preferably carried out under heating conditions, and the heating temperature is preferably 75 to 85°C, more preferably 80°C.

[0040] In this invention, after obtaining an aqueous phase, a hydrophobic component as an oil phase is added to the aqueous phase and an emulsification treatment is performed to obtain a matrix material. Preferably, in this invention, the hydrophobic component is heated, and the heating temperature is preferably 75 to 85°C, more preferably 80°C. Preferably, in this invention, the hydrophobic component is heated and kept in a molten state. Preferably, in this invention, the heated hydrophobic component is added as an oil phase to the heated aqueous phase under stirring or shearing conditions and an emulsification treatment is performed. In this invention, the temperature of the emulsification treatment is preferably 75 to 85°C, more preferably 80°C. The duration of the emulsification treatment is preferably 5 to 15 minutes, more preferably 10 minutes, and the duration of the emulsification treatment is calculated from the completion of the addition of the oil phase. Preferably, the emulsification treatment is performed under stirring or shearing conditions. After the emulsification treatment, preferably, in this invention, the obtained material liquid is cooled to room temperature under stirring or shearing conditions to obtain the matrix material. In this invention, if the raw materials for preparing the matrix material preferably include a pH adjusting agent, preferably, in this invention, the pH adjusting agent is added to the material liquid cooled to room temperature to obtain the matrix material. The matrix material of the present invention is a white or colorless liquid having a certain viscosity, which helps the foaming agent to have a sufficient residence time in the body cavity and to be able to come into sufficient contact with the body cavity.

[0041] After obtaining a matrix material, the present invention provides a vaginal foaming agent by filling the matrix material with a propellant. In the present invention, there are no particular limitations on the specific method of filling the matrix material with the propellant, and any method well known to those skilled in the art may be used.

[0042] In the present invention, the vaginal foaming agent is preferably administered quantitatively, specifically by administering the vaginal foaming agent to the vaginal cervix via a drug delivery device. Figure 1 is a photograph of a drug delivery device used in an embodiment of the present invention. The drug delivery device preferably includes a pressure-resistant bottle, a valve, a protective sleeve, a metering cap, and a catheter. The catheter is specifically connected to a protruding portion of the protective sleeve and used for insertion into the vagina to administer the drug. The pressure-resistant bottle preferably includes a sodium calcium vial bottle, a borosilicate vial bottle, a PC bottle, or an aluminum can bottle, more preferably an aluminum can bottle. The valve is preferably a metering valve, and the specification of the metering valve is preferably 1 ml, i.e., the volume of foam ejected by pressing the metering cap once is preferably 1 ml, and the mass of estradiol in 1 mL of foam is preferably 4 to 10 μg, specifically 4 μg, 5 μg, 6 μg, 7 μg, 8 μg, 9 μg, or 10 μg. The catheter is preferably a disposable catheter. In this invention, specifically, the matrix material is placed in a pressure-resistant bottle, the metering valve is pressed, the propellant is filled in, and a protective cover and a metering cap are attached. In this invention, the mass of the matrix material per bottle of the vaginal foaming agent may be 40 g, and considering the safety of the drug to the human body and its impact on environmental pollution, the amount of propellant filled per bottle of the vaginal foaming agent in this invention may be 4 to 8 g, specifically 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, or 8 g, and the internal pressure per bottle of the vaginal foaming agent may be 6 to 8 bar, specifically 6 bar, 6.5 bar, 7 bar, 7.5 bar, or 8 bar. The vaginal foaming agent product provided by this invention has a delivery uniformity result that satisfies RSD ≤ 2%, thereby achieving the objectives of quantitative administration and controllable quality.

[0043] The vaginal foaming agent provided by this invention has a smooth and delicate foam appearance and good stability. The vaginal foaming agent provided by this invention is easy to use, clean and hygienic, not limited by instruments or specialized locations, requires only a light press during use, and only a simple catheter needs to be replaced after each use, resulting in low cost, good compliance, no foreign body sensation, a small amount of foam that is hardly noticeable inside the body, no concern about detachment, and does not affect daily life. The vaginal foaming agent provided by this invention can be expected to have a good therapeutic effect, as the foam forms a drug-containing film layer on the surface of the vaginal wall inside the body, ensuring drug delivery time. Containing a propellant, it has a certain impact pressure, fully expands to effectively fill and cover the depths and folds of the vagina, ensuring sufficient contact with the drug delivery site. The use of a fully sealed high-pressure can is beneficial in improving product stability and preventing drug degradation. The foaming agent is light, smooth, and fully filled, and is effective in treating symptoms such as difficulty with intercourse and dryness. The vaginal foaming agent provided by this invention is safe and effective, with precise dosage and controllable quality.

[0044] The vaginal foaming agent provided by the present invention does not require the use of large amounts of surfactants or ethanol, and therefore avoids problems such as skin inflammation and dryness caused by the use of large amounts of ethanol in the spray. Compared to vaginal suppositories, the vaginal foaming agent has a larger contact area with the vaginal mucosa, is easy to administer, and does not require frequent vaginal washing. Furthermore, due to the targeted effect of vaginal estrogen, there is no need to add transdermal absorption enhancers such as azon to the prescription, the prescription is simple, the preparation process is easy, it is easy to use, and patient compliance and adherence to medication are good.

[0045] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the embodiments described are only a subset of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art without creative effort based on the embodiments of the present invention are all within the scope of the protection of the present invention.

[0046] The estradiol preparations according to the following examples and comparative examples include a matrix material and a propellant, wherein the matrix material specifically refers to the components of the estradiol preparation other than the propellant, the total mass of the matrix material contained in each bottle of the estradiol preparation is 40 g, the amount of each component added to the matrix material is calculated as a percentage of the total mass of the matrix material (i.e., the total amount of each component added to the matrix material is 100%), and the amount of the propellant added is the mass of the propellant added to each bottle of the estradiol preparation.

[0047] The foaming properties of the products in the following examples and comparative examples were evaluated, specifically, the quality of the formulation was assessed based on the foaming properties of the sprayed product. Figure 2 shows the foaming properties for each grade when evaluating the foaming properties. From left to right are Grade A, Grade B, Grade C, and Grade D. Grade A indicates that the foaming is delicate and soft and has good support. Grade B indicates that the foaming is not delicate, the pores are somewhat large, and the support is somewhat weak. Grade C indicates that it is in a foamed state but has no support and is a mesh-like foam. Grade D means that it is not in a foamed state and exists in a liquid state.

[0048] The relative density of the foam in the products in the following examples and comparative examples was tested. The specific method is as follows: Three samples were taken and left at 25°C for 24 hours. The containers were shaken uniformly without heating, and 5-10 mL of foam was discarded. A flat weighing bottle with a capacity of approximately 100 mL and a height of approximately 35 mm was prepared, and its mass was accurately weighed and designated as W. Next, the nozzle was placed against the bottom corner of the flat weighing bottle, the quantitative cap was pressed, and the bottle was filled uniformly in a circular motion. After the foam had fully expanded, the excess foam was scraped off along the top edge of the flat weighing bottle using a scraper, washed, and its mass was accurately weighed and designated as W2. Next, the flat weighing bottle was filled with purified water at 25°C, and its mass was accurately weighed and designated as W1. The relative density was calculated according to the following formula: ρ = (W2 - W) / (W1 - W).

[0049] The following examples investigate the physical stability of the product at high and low temperatures. The specific method is as follows: The product is left at a low temperature (2-8°C) for 20 hours, then returned to room temperature (25°C) for 4 hours, then left at a high temperature (30°C) for 20 hours, then returned to room temperature for 4 hours. This constitutes one cycle, and the experiment is repeated for 5 cycles.

[0050] Examples 1-4 Preparation of the aqueous phase: Weigh out the prescribed amount of propylene glycol or polyethylene glycol 200, mix with the prescribed amounts of glycerol, Tween 60, estradiol, and water, heat to 80±5°C to completely dissolve the components, and keep warm for later use. Preparation of the oil phase: The prescribed amount of isopropyl myristate or light liquid paraffin was weighed out and mixed with the prescribed amount of glyceryl monostearate and cetyl alcohol, and heated to 80±5°C to completely dissolve the components. Mixing: The oil phase was added to the aqueous phase while stirring. After the addition was complete, stirring was continued at 80±5°C for 10 minutes. The resulting chemical solution was then stirred at room temperature and cooled to room temperature. The pH was adjusted to 3-5 with lactic acid to obtain the matrix material. Filling: The matrix material was placed in an aluminum can, the metering valve (1 mL) was pressed, tetrafluoroethane was filled in, and a protective sleeve and metering cap were added.

[0051] The formulations of each product are shown in Table 1.

[0052] Table 1: Formulation of products from Examples 1-4 [Table 1]

[0053] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam of the better-formed formulation was tested. The specific test results are shown in Table 2. The results showed that when the mass percentage of estradiol in the matrix material was in the range of 0.0004% to 0.001%, good foam could be formed, and the foam was delicate, complete, and persistent in the sprayed state.

[0054] Table 2 Foaming properties and relative density of products from Examples 1-4 [Table 2]

[0055] Examples 5-8 and Comparative Example 1 The formulations for each product were obtained by following the procedure described in Example 1, and are shown in Table 3.

[0056] Table 3 Formulation of Products from Examples 5-8 and Comparative Example 1 [Table 3]

[0057] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam of the better-formed formulation was tested. The specific test results are shown in Table 4. The results show that when the total mass percentage of propylene glycol and glycerol in the matrix material is in the range of 30% to 60%, the foaming moldability is good, the foam is delicate and complete, and can be sustained in the sprayed state.

[0058] Table 4 Foaming properties and relative density of products from Examples 5-8 and Comparative Example 1 [Table 4]

[0059] The physical stability of the products in Examples 5 and 6 at high and low temperatures was investigated, and the specific test results are shown in Table 5. The results showed that the products in Examples 5 and 6 possessed physical stability at both high and low temperatures.

[0060] Table 5: Physical stability test results at high and low temperatures for products of Examples 5-6 [Table 5]

[0061] The delivery status of each pump was evaluated by the ejected foam, primarily investigating the uniformity of delivery for each pump. Specifically, one sample can was taken out, shaken, and the quantitative cap was pressed. After inverting the can vertically for 10 seconds, the can was made upright and the quantitative cap was removed. The first pump was discarded, and the first three doses, the middle four doses, and the last three doses—a total of 10 delivered doses—were collected. The RSD value was calculated, and the specific test results are shown in Table 6. The results showed that the RSD of the delivery uniformity of the products in Examples 5-6 was <2%.

[0062] Table 6: Delivery Uniformity Test Results of Products from Examples 5-6 [Table 6]

[0063] Examples 9-12 and Comparative Examples 2-3 The formulations for each product were obtained by following the procedure described in Example 1, and are shown in Table 7.

[0064] Table 7 Formulation of Products from Examples 9-12 and Comparative Examples 2-3 [Table 7]

[0065] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam of the better-formed formulation was tested. The specific test results are shown in Table 8. The results showed that when the total mass percentage of polyethylene glycol 200 and glycerol in the matrix material was in the range of 35% to 65%, the foaming moldability was good, the foam was delicate and complete, and it could be sustained in the sprayed state.

[0066] Table 8 Foaming properties and relative density of products from Examples 9-12 and Comparative Examples 2-3 [Table 8]

[0067] The physical stability of the products in Examples 9-11 at high and low temperatures was investigated, and the specific test results are shown in Table 9. The results showed that the products in Examples 9-11 possessed physical stability at both high and low temperatures.

[0068] Table 9: Physical stability test results at high and low temperatures for products in Examples 9-11 [Table 9]

[0069] Examples 13-18 The formulations for each product were obtained by following the procedure in Example 1, and are shown in Table 10.

[0070] Table 10 Formulation of products from Examples 13-18 [Table 10]

[0071] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam was detected. The specific test results are shown in Table 11. The results showed that when hexadecanol or octadecanol was used alone, the mass percentage of hexadecanol or octadecanol in the matrix material was in the range of 0.4% to 2%, indicating good foaming moldability, delicate and complete foaming, and the ability to persist in the sprayed state.

[0072] Table 11 Foaming properties and relative density of products from Examples 13-18 [Table 11]

[0073] Examples 19-23 The formulations for each product were obtained by following the procedure described in Example 1, and are shown in Table 12.

[0074] Table 12 Formulation of products from Examples 19-23 [Table 12]

[0075] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam was detected. The specific test results are shown in Table 13. The results showed that when hexadecanol and octadecanol were used in combination, the mass ratio of hexadecanol to octadecanol was 1:1, 2:1, 1:2, 3:1, and 1:3. The total mass percentage of hexadecanol and octadecanol in the matrix material was in the range of 0.4% to 3.0%. This indicated that they could play a role in adjusting the viscosity of the system while simultaneously acting as a supportive component of the foam's framework, resulting in good foam moldability, delicate and complete foaming, and sustained foaming in the sprayed state.

[0076] Table 13 Foaming properties and relative density of products from Examples 19-23 [Table 13]

[0077] The high-temperature and low-temperature physical stability of the products from Examples 19, 21, and 22 was investigated, and the specific test results are shown in Table 14. The results showed that the products from Examples 19, 21, and 22 exhibited good physical stability at both high and low temperatures.

[0078] Table 14 Test results of high and low temperature physical stability of products from Examples 19, 21, and 22 [Table 14]

[0079] Examples 24-29 The formulations for each product were obtained by following the procedure in Example 1, and are shown in Table 15.

[0080] Table 15 Formulation of products from Examples 24-29 [Table 15]

[0081] The quality of the formulation was evaluated by the foaming properties of the sprayed material, and the relative density of the foam was detected. The specific test results are shown in Table 16. The results showed that when the mass percentage of the hydrophobic component aliphatic alcohol ester compound (e.g., isopropyl myristate) in the matrix material was in the range of 1.0% to 10%, the mass percentage of light liquid paraffin was in the range of 2% to 10.0%, and the mass percentage of glyceryl monostearate was in the range of 0.1% to 1.0%, the prepared foaming agent had good appearance, being smooth and delicate.

[0082] Table 16 Foaming properties and relative density of products from Examples 24-29 [Table 16]

[0083] Examples 30-34 and Comparative Examples 4-5 The formulations for each product were obtained by following the procedure described in Example 1, and are shown in Table 17.

[0084] Table 17 Formulation of products from Examples 30-34 and Comparative Examples 4-5 [Table 17]

[0085] The quality of the formulation was evaluated based on the foaming characteristics of the sprayed product, and the relative density of the foam was detected. The specific test results are shown in Table 18. The results indicated that the products of Comparative Examples 4 and 5 had a mass percentage of emulsifier in the matrix material of 0.1%, and the appearance characteristics of the foam were poor.

[0086] Table 18 Foaming properties and relative density of products from Examples 30-34 and Comparative Examples 4-5 [Table 18]

[0087] The physical stability of the products of Examples 30-33 at high and low temperatures was investigated, and the specific test results are shown in Table 19. The results showed that when the mass percentage of emulsifier in the matrix material was in the range of 0.3% to 4%, the prepared foaming agent had good appearance, being smooth and delicate.

[0088] Table 19: Physical stability test results at high and low temperatures for products in Examples 19-33 [Table 19]

[0089] Examples 34-42 The formulations for each product were obtained by following the procedure in Example 1, and are shown in Table 20.

[0090] Table 20 Formulation of products from Examples 34-42 [Table 20]

[0091] The quality of the formulation was evaluated by the foaming characteristics of the sprayed product, and the relative density of the foam was detected. The specific test results are shown in Table 21. The results showed no clear difference in the appearance of the foam of products prepared using different propellants, indicating that the appearance of the foam was smooth and delicate. In this invention, tetrafluoroethane is preferably used as the propellant.

[0092] Table 21 Foaming properties and relative density of products from Examples 34-42 [Table 21]

[0093] Examples 43-45 The product formulation was obtained by following the procedure of Example 1, and the results are shown in Table 22.

[0094] Table 22 Formulation of products in Examples 43-45 [Table 22]

[0095] For the products of Examples 43-45, factors affecting stability at 40°C were investigated. Specifically, the products were placed at 40°C, and samples were detected on day 0, day 10, and day 30. Changes in foaming properties, pH value, content, and impurities were investigated, and the applicability of the packaging material was observed at each stage of the investigation.

[0096] The test methods for content and impurities are as follows: The content was measured by high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, General Rules for Four Parts, No. 0512). Chromatography conditions: Octadecylsilane-bonded silica gel was used as the packing material (Kromasil 4.6 mm × 250 mm, 5 μm or equivalent performance chromatography column). Acetonitrile-water (45:55) was used as the mobile phase. The excitation wavelength was 240 nm, the emission wavelength was 310 nm, the flow rate was 1 mL / min, the column temperature was 40 °C, and the injection volume was 20 μL. Impurities were measured using high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, General Rules for Four Parts, 0512). Chromatography conditions: Octadecylsilane-bound silica gel was used as packing material (MN RP18 4.6 mm × 100 mm, 2.7 μm or equivalent performance chromatography column). Water was used as mobile phase A and acetonitrile as mobile phase B. Linear gradient elution was performed according to Table 23. The flow rate was 1 mL / min, the column temperature was 35°C, the detection wavelength was 220 nm, and the injection volume was 10 μL.

[0097] Table 23 Gradient elution method for impurities [Table 23]

[0098] Result requirement: Total impurity content ≤ 4.0%.

[0099] Table 24 shows the results of the 40°C stability test for products from Examples 43-45. The results show that when the product was left at 40°C for 10 days, compared to the first day (Day 0), the appearance of the foam was supportive, the amount of foam sprayed was accurate, smooth and delicate, and there was no significant change in impurities or pH values ​​compared to the first day (Day 0), indicating good sample stability. When the product was left at 40°C for 30 days, there was no significant change in content or impurities compared to the first day (Day 0), and it showed good compatibility with the propellant and the foaming agent metering device. When the pressure-resistant aluminum can was opened and the inner wall of the coating was observed, no peeling of the film was observed (the coating state of the aluminum can left at 40°C for 30 days is shown in Figures 3-5).

[0100] Table 24 Results of 40°C stability measurements of products from Examples 43-45 [Table 24]

[0101] Example 46 The product formulation was obtained by following the procedure of Example 1, and the results are shown in Table 25.

[0102] Table 25 Composition of the product in Example 46 [Table 25]

[0103] Test Example 1 For the product of Example 46, factors affecting stability at 40°C were investigated, and a comparative study was conducted with commercially available estradiol soft capsules and vaginal tablets. Specific test methods and conditions were described in Example 43.

[0104] The results of the content measurement are shown in Table 26. From the results, it can be seen that the content measurement results were 95% to 100%, indicating that the product is acceptable.

[0105] Table 26 Content measurement results [Table 26]

[0106] The results of the impurity measurement are shown in Table 27, and the results indicate that the trend in the change of impurities in the product of Example 46 was better than that of the vaginal tablets and soft capsules.

[0107] Table 27 Impurity measurement results [Table 27]

[0108] Test Example 2 The delivery status of each pump was evaluated by the ejected foam, primarily investigating the uniformity of delivery for each pump. Specifically, one sample can was taken out, shaken, and the quantitative cap was pressed. After inverting the can vertically for 10 seconds, the can was made upright and the quantitative cap was removed. The first pump was discarded, and the first three doses, the middle four doses, and the last three doses—a total of 10 delivered doses—were collected. The RSD value was calculated, and the specific test results are shown in Table 28. The results showed that the RSD of the delivery uniformity of the product in Example 46 was <2%.

[0109] Table 28: Delivery Uniformity Test Results of Product from Example 46 [Table 28]

[0110] Test Example 3 The physical stability of the product from Example 46 at high and low temperatures was investigated, and the specific test results are shown in Table 29. The results showed that the foaming agent prepared in Example 46 had good appearance, being smooth and delicate.

[0111] Table 29 Physical stability test results of the product of Example 46 at high and low temperatures [Table 29]

[0112] Test Example 4 The in vitro dissolution rate of the product in Example 46 was evaluated using the rotating basket method and compared with the dissolution rates of commercially available estradiol soft capsules and vaginal tablets. The cumulative dissolution amount was measured using a content measurement method. The specific test conditions were 500 mL of phosphate buffer with a pH of 4.75 as the culture medium, a rotation speed of 40 rpm, and sampling times of 1 hour, 5 hours, and 10 hours, respectively.

[0113] Figure 6 shows the dissolution curves of the product used in Example 46, commercially available estradiol vaginal soft capsules, and vaginal tablets.

[0114] The results of the in vitro dissolution test are shown in Table 30, and from these results, it can be seen that the in vitro release rate of the product in Example 46 is much faster than that of the vaginal tablets and soft capsules at each time point.

[0115] Table 30 Results of in vitro dissolution tests [Table 30]

[0116] Test Example 5 In the animal PK study, 14 SPF New Zealand female rabbits (outside their estrous cycle) weighing 2.0-2.5 kg were divided into three groups (T: test, R: reference, P: control) according to a (6+6+2) rule. The T group received one pump of the formulation, and the R group received one unit (one tablet). 2 mL of blood was collected before administration, and 1, 2, 4, 6, 8, 12, and 24 hours after administration. The blood was allowed to stand to separate the serum, and 0.3 mL of serum was transferred to a PE tube and stored in a -20°C refrigerator before being used for the study. After collecting blood for 24 hours, the animals were killed by injecting air into the ear vein, vaginal tissue was removed, the surrounding connective tissue was removed, the vagina was cut lengthwise, and surface moisture was absorbed with filter paper. First, the presence or absence of congestion, edema, etc., in each organ and the vaginal wall was observed with the naked eye. Next, the vaginal tissue was fixed in formalin solution for 24 hours, embedded in paraffin, thinly sectioned, stained with hematoxylin-eosin (HE), and histopathological examination and evaluation were performed. The estradiol content in serum was measured using the rabbit estradiol ELISA method, and the blood drug concentration data measured in the experiment was subjected to mathematical and statistical analysis. In an animal PK study comparing the test sample (product of Example 46) with commercially available estradiol vaginal tablets, no significant changes in serum estradiol concentration were observed after administration of the test sample or commercially available estradiol vaginal tablets compared to the blank control group (Table 31, Figure 7). No erythema, edema, or purulent discharge was observed in the peripheral vaginal tissue after administration, and no abnormalities were found in histopathological sections of the vaginal mucosa (Figure 8). Since no mucosal irritation was observed, this product demonstrated safety equivalent to that of the reference group.

[0117] Table 31 In vivo pharmacokinetic results [Table 31]

[0118] The above describes only preferred embodiments of the present invention. It should be noted that a person ordinary in the art could make various improvements and modifications without departing from the principles of the present invention. These improvements and modifications should also be considered to fall within the scope of protection of the present invention.

Claims

1. A vaginal foaming agent characterized in that its active ingredient is estradiol.

2. The vaginal foaming agent according to claim 1, wherein the raw materials for preparing the vaginal foaming agent include a matrix material and a propellant, and the raw materials for preparing the matrix material include estradiol, an oil-water amphoteric organic solvent, a hydrophobic component, a surfactant, and water.

3. The matrix material comprises, by mass percentage, 0.0001% to 0.01% of estradiol, 35% to 65% of the oil-water amphoteric organic solvent, 1.0% to 10% of the hydrophobic component, 0.1% to 4.0% of the surfactant, and the remainder being water. The vaginal foaming agent according to claim 2, characterized in that, based on the amount of matrix material used being 10 to 100 g / bottle, the amount of propellant used is 4 to 8 g / bottle.

4. The vaginal foaming agent according to claim 2 or 3, characterized in that the aforementioned oil-water amphoteric organic solvent is an alcohol solvent.

5. The vaginal foaming agent according to claim 4, characterized in that the alcohol solvent contains one or more of butylene glycol, propylene glycol, glycerol, and polyethylene glycol.

6. The vaginal foaming agent according to claim 2 or 3, characterized in that the hydrophobic component comprises one or more of the following: C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds, and oily components.

7. The vaginal foaming agent according to claim 6, characterized in that the C12-C22 fatty alcohol compound comprises hexadecanol and / or octadecanol, the C12-C22 solid fatty acid ester compound comprises one or more of glyceryl monostearate, glyceryl distearate, glyceryl mono, and distearate, and the oily component comprises one or more of liquid fatty acid ester compounds, mineral oil, and vegetable oil.

8. The vaginal foaming agent according to claim 7, characterized in that the liquid fatty acid ester compound comprises one or more of isopropyl myristate, isopropyl palmitate, and ethyl oleate, the mineral oil comprises one or more of liquid paraffin, petrolatum, and white wax, and the vegetable oil comprises one or more of soybean oil, peanut oil, and olive oil.

9. The surfactant comprises one or more of the following: benzenesulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearate polyoxyethylene ether, fatty amine polyoxyethylene ether, alkyl alcohol amide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate, polyoxyethylene ricinoleic acid, ethoxylated glycerol triricinoleic acid, diethylene glycol monoethyl ether, and triethanolamine. The propellant comprises a hydrofluoroalkane. The hydrofluoroalkane comprises one or more of tetrafluoroethane, heptafluoropropane, and difluoroethane. The vaginal foaming agent according to claim 2 or 3, characterized in that the pH value of the matrix material is 3.0 to 7.

0.

10. A method for preparing a vaginal foaming agent according to claim 2 or 3, The steps include mixing the estradiol, the amphoteric organic solvent, the surfactant, and water to obtain an aqueous phase, The steps include adding the hydrophobic component as an oil phase to the aqueous phase and emulsifying it to obtain the matrix material, A preparation method characterized by comprising the step of filling the matrix material with the propellant to obtain the vaginal foaming agent.

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