Vagina foaming agent and preparation method thereof

Abstract

The invention provides a vagina foaming agent and a preparation method thereof, and belongs to the technical field of medicines. The invention provides the vaginal foaming agent taking the estradiol as the active component, the vaginal foaming agent is prepared from the estradiol, the compliance is good, the contact area in the vagina is wide, the estradiol is quickly released, the pertinence on diseases caused by lack of estrogen is strong, the effect is quick, the administration dosage is accurate, and the use is convenient.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a vaginal foam and a preparation method thereof. Background Art

[0002] Estrogen plays a wide range of physiological effects on the female body. In addition to acting on the reproductive system, it also acts on other target organs, including bones, cardiovascular, central nervous system, liver, skin and its appendages. Ovarian dysfunction caused by menopause or other reasons can lead to estrogen deficiency, which in turn affects the functions of these target organs. Specifically, it will cause atrophy of the vulva and vagina and decreased secretion in the reproductive organs. These are not limited by age groups and often include some young women. In addition to the need for estrogen supplementation caused by normal functional decline, there is also a pathological need for estrogen supplementation. There are three types of human estrogens, specifically estradiol, estrone and estriol. Estradiol is the most important and most active type of estrogen. It is one of the six conventional indicators of sex hormones. The structural formula of estradiol is as follows:

[0003]

[0004] At present, the more commonly used dosage forms and administration methods of estradiol include: 1. injection or oral estradiol (tablets, capsules, etc.), which have the disadvantages of large specifications and dosages, obvious side effects (high incidence of breast cancer and cervical cancer), and low bioavailability; 2. topical estradiol (patches, films, etc.), which have the disadvantages of significant film or film application feeling, poor compliance, and some patients are prone to allergies; 3. estradiol rings or estradiol implants, which have the disadvantages of large size. After being inserted into the human body, there will be a strong and uncomfortable foreign body sensation, poor compliance, and estradiol implants are relatively small, but the foreign body sensation is still relatively obvious, and the implants also have the disadvantage of being easy to fall off; 4. estradiol vaginal tablets or estradiol vaginal soft capsules, which have the disadvantages of obvious foreign body sensation, poor compliance, and slow release of estradiol, which have little effect on cardiovascular-related symptoms, but are not good for diseases that rely more on local concentrations of estrogen, such as sexual intercourse disorders, vaginal inflammation, and relief of symptoms of pudendal atrophy. Summary of the invention

[0005] The purpose of the present invention is to provide a vaginal foam and a preparation method thereof. The present invention prepares estradiol into a vaginal foam, which has good compliance, a wide contact area in the vagina, and a relatively fast release of estradiol. It is highly targeted at diseases caused by estrogen deficiency, has a rapid onset of effect, and has an accurate dosage and is easy to use.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a vaginal foam, the active ingredient of which is estradiol.

[0008] Preferably, the raw materials for preparing the vaginal foam include a base material and a propellant, and the raw materials for preparing the base material include estradiol, an amphoteric organic solvent, a hydrophobic component, a surfactant and water.

[0009] Preferably, the matrix material comprises the following raw materials, measured by mass percentage: 0.0001% to 0.01% of estradiol, 35% to 65% of an amphoteric organic solvent, 1.0% to 10% of a hydrophobic component, 0.1% to 4.0% of a surfactant, and the balance is water;

[0010] Based on the usage of the base material being 10 to 100 g / bottle, the usage of the propellant is 4 to 8 g / bottle.

[0011] Preferably, the amphoteric organic solvent is an alcohol solvent.

[0012] Preferably, the alcohol solvent includes one or more of butylene glycol, propylene glycol, glycerol and polyethylene glycol.

[0013] Preferably, the hydrophobic component includes one or more of C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds and oily components.

[0014] Preferably, the C12-C22 fatty alcohol compound includes hexadecanol and / or stearyl alcohol; the C12-C22 solid fatty acid ester compound includes one or more of monostearate glyceryl, distearate glyceryl and mono- and distearate glyceryl; the oily component includes one or more of liquid fatty acid ester compounds, mineral oil and vegetable oil.

[0015] Preferably, the liquid fatty acid ester compound includes one or more of isopropyl myristate, isopropyl palmitate and ethyl oleate; the mineral oil includes one or more of liquid paraffin, vaseline and white wax; the vegetable oil includes one or more of soybean oil, peanut oil and olive oil.

[0016] Preferably, the surfactant includes one or more of benzenesulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearic acid polyoxyethylene ether, fatty amine polyoxyethylene ether, alkylolamide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate, polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether and triethanolamine.

[0017] Preferably, the propellant comprises a hydrofluoroalkane.

[0018] Preferably, the hydrofluoroalkane comprises one or more of tetrafluoroethane, heptafluoropropane and difluoroethane.

[0019] Preferably, the pH value of the matrix material is 3.0-7.0.

[0020] The present invention provides a method for preparing the vaginal foam described in the above technical solution, comprising the following steps:

[0021] Mixing estradiol, an amphoteric organic solvent, a surfactant and water to obtain an aqueous phase;

[0022] Adding a hydrophobic component as an oil phase into the water phase, and subjecting the mixture to emulsification to obtain a matrix material;

[0023] The vaginal foam is obtained by filling the base material with a propellant.

[0024] The present invention provides a vaginal foam with estradiol as an active ingredient. The vaginal foam prepared from estradiol has good compliance, a wide contact area in the vagina, fast release of estradiol, strong targeting and fast onset of effects on diseases caused by estrogen deficiency, accurate dosage and convenient use. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a photo of a drug delivery device used in an embodiment of the present invention;

[0026] Figure 2 It is a diagram of foam properties at various levels when evaluating foam properties in the embodiments of the present invention;

[0027] Figure 3 This is a diagram showing the test results of the product packaging material suitability in Example 43 of the present invention;

[0028] Figure 4 This is a diagram showing the test results of the product packaging material suitability in Example 44 of the present invention;

[0029] Figure 5 This is a diagram showing the test results of the product packaging material suitability in Example 45 of the present invention;

[0030] Figure 6 The dissolution curves of the estradiol foam in Example 46 of the present invention, the commercially available estradiol soft capsules and the vaginal tablets;

[0031] Figure 7 The pharmacokinetic curves of the estradiol foam in Example 46 of the present invention and the commercially available estradiol vaginal tablets in rabbits are shown below;

[0032] Figure 8 This is a pathological diagram of the effect of the estradiol foam in Example 46 of the present invention on the rabbit vaginal mucosal tissue. DETAILED DESCRIPTION

[0033] The present invention provides a vaginal foam, wherein the active ingredient is estradiol. The vaginal foam prepared by estradiol has good compliance, a wide contact area in the vagina, rapid release of estradiol, strong targeting for diseases caused by estrogen deficiency, rapid onset of effect, accurate dosage, and convenient use.

[0034] As an embodiment of the present invention, the raw materials for preparing the vaginal foam provided by the present invention may include a base material and a propellant, and the raw materials for preparing the base material may include estradiol, an amphoteric organic solvent, a hydrophobic component, a surfactant and water.

[0035] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0036] In the present invention, the matrix material preferably includes the following raw materials, calculated by mass percentage: 0.0001% to 0.01% estradiol, 35% to 65% amphoteric organic solvent, 1.0% to 10% hydrophobic component, 0.1% to 4.0% surfactant, and the balance is water; based on the dosage of the matrix material being 10 to 100 g / bottle, the dosage of the propellant is 4 to 8 g / bottle.

[0037] In the present invention, the raw materials for preparing the matrix material preferably include 0.0001% to 0.01% of estradiol, specifically 0.0001%, 0.0004%, 0.0008%, 0.001%, 0.004%, 0.008% or 0.01%, calculated by mass percentage.

[0038] In the present invention, the raw materials for preparing the matrix material preferably include 25% to 78% of an amphoteric organic solvent, specifically 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 78% by mass percentage. In the present invention, the amphoteric organic solvent is preferably an alcohol solvent; the alcohol solvent preferably includes one or more of butanediol, 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 butanediol, propylene glycol, glycerol or polyethylene glycol, or may be a mixture of propylene glycol and glycerol, or may be 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 1:2-10, and may specifically be 1:2.9, 1:5.4 or 1:9.4, and the mass content of the alcohol solvent in the matrix material is preferably 30-60%, and may specifically be 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 1:2.5-7.0, and may specifically be 1:2.9, 1:3.5 or 1:5.9, and the mass content of the alcohol solvent in the matrix material is preferably 35%-65%, and may specifically be 35%, 40%, 45%, 50%, 55%, 60% or 65%. The present invention preferably uses the above-mentioned type and amount of oil-water amphoteric organic solvents, which is conducive to ensuring smooth emulsification treatment, good foam formability, good compatibility with the propellant, and good compatibility with the quantitative dosing device of the foam agent; and the above-mentioned type of oil-water amphoteric organic solvents can also be used as a moisturizer or lubricant for cavity administration, ensuring that the foam agent has good efficacy.

[0039] In the present invention, the raw materials for preparing the matrix material preferably include 1.0% to 10% hydrophobic components, measured by mass percentage, 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 includes one or more of C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds and oily components, and is more preferably a mixture of C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds and oily components. At this time, the mass ratio of the C12-C22 fatty alcohol compounds, C12-C22 solid fatty acid ester compounds and oily components is preferably 0.4-4:0.1-1:3-10, more preferably 0.8-3:0.3-0.8:4-9, further preferably 1-2.5:0.4-0.7:5-8, and further preferably 1.5-2:0.5-0.6:6-7.

[0040] In the present invention, the C12-C22 fatty alcohol compound preferably includes hexadecanol and / or octadecanol, specifically hexadecanol or octadecanol, or a mixture of hexadecanol and octadecanol; the mass ratio of hexadecanol to octadecanol in the mixture of hexadecanol and 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 base material includes C12-C22 fatty alcohol compounds, the mass content of C12-C22 fatty alcohol compounds in the raw material for preparing the base 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%. The present invention preferably uses the above-mentioned types and amounts of C12-C22 fatty alcohol compounds, which can play a role in adjusting the viscosity of the system and at the same time play a supporting role as the skeleton component of the foam.

[0041] In the present invention, the C12-C22 solid fatty acid ester compounds preferably include one or more of monostearate glyceryl, distearate glyceryl and mono-distearate glyceryl, more preferably monostearate glyceryl; when the raw materials for the preparation of the matrix material include C12-C22 solid fatty acid ester compounds, the mass content of C12-C22 solid fatty acid ester compounds in the raw materials for the preparation of 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%. The present invention preferably uses the above-mentioned types and amounts of C12-C22 solid fatty acid ester compounds, which is conducive to ensuring that the foam has good appearance, is smooth and delicate.

[0042] In the present invention, the oily component preferably includes one or more of liquid fatty acid ester compounds, mineral oil and vegetable oil, and is more preferably liquid fatty acid ester compounds or mineral oil; the liquid fatty acid ester compounds preferably include one or more of isopropyl myristate, isopropyl palmitate and ethyl oleate, and is more preferably isopropyl myristate; the mineral oil preferably includes one or more of liquid paraffin, vaseline and white wax, and is more preferably liquid paraffin, and the liquid paraffin is preferably light liquid paraffin; the vegetable oil preferably includes one or more of soybean oil, olive oil and peanut oil. In the present invention, when the raw material for preparing the matrix material includes liquid fatty acid ester compounds, the mass content of the liquid fatty acid ester compounds 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%, 9.0%, 9.5% or 10%; when the raw material for preparing the matrix material includes mineral oil, the mass content of the mineral oil in the raw material 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%. The present invention preferably uses the above-mentioned types and amounts of liquid fatty acid ester compounds and mineral oil, which is conducive to ensuring that the foam has good appearance, is smooth and delicate.

[0043] In the present invention, the raw materials for preparing the matrix material preferably include 0.1% to 4.0% of surfactants, specifically 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5% or 4.0% by mass percentage. In the present invention, the surfactant preferably includes one or more of benzenesulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearic acid polyoxyethylene ester, fatty amine polyoxyethylene ether, alkyl alcohol amide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate (Tween), polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether and triethanolamine, more preferably Tween; the Tween is preferably Tween 60. The present invention preferably uses the above-mentioned types and amounts of surfactants, which also have emulsifying function and good compatibility with the propellant, which is conducive to ensuring that the foam has good physical stability.

[0044] In the present invention, the pH value of the base material is preferably 3.0 to 7.0, more preferably 3.0 to 5.0, and specifically can be 3.0, 3.5, 4.0, 4.5 or 5.0. The present invention preferably controls the pH value of the base material within the above range to ensure that the foam is suitable for the physiological pH environment of the vagina, and that the base material does not delaminate during the preparation of the foam, and has a good adaptation effect with the propellant, and also has a good adaptation effect with the quantitative dosing device of the foam. As shown in the test results in Examples 43 to 45, when the pressure-resistant aluminum can bottle is cut open and the coated inner wall of the aluminum can bottle is observed, no delamination phenomenon is observed.

[0045] In the present invention, when the pH value of the matrix material does not meet the above requirements, the raw materials for preparing the matrix material preferably also include a pH adjuster, and the amount of the pH adjuster is based on ensuring that the pH value of the matrix material is 3.0 to 7.0. In the present invention, the pH adjuster can be an acid reagent or an alkali reagent, and the acid reagent is preferably lactic acid.

[0046] In the present invention, the amount of the base material is 10-100g / bottle as a basis, and the amount of the propellant is 4-8g / bottle; specifically, the amount of the base material can be 10g / bottle, 20g / bottle, 30g / bottle, 40g / bottle, 50g / bottle, 60g / bottle, 70g / bottle, 80g / bottle, 90g / bottle or 100g / bottle; the amount of the propellant can be 4g / bottle, 4.5g / bottle, 5g / bottle, 5.5g / bottle, 6g / bottle, 6.5g / bottle, 7g / bottle, 7.5g / bottle or 8g / bottle. In the present invention, the propellant preferably includes hydrofluoroalkane; the hydrofluoroalkane preferably includes one or more of tetrafluoroethane, heptafluoropropane and difluoroethane, specifically tetrafluoroethane, heptafluoropropane or difluoroethane, more preferably tetrachloroethane. The present invention preferably uses the above-mentioned type and amount of propellant, and the prepared foam has a smooth and delicate appearance. Among them, in terms of ductility, fatty alkanes are stronger than hydrofluoroalkanes. The foam in the present invention is vaginally administered and reaches the vaginal cervical opening through a drug delivery device. Too strong ductility is not conducive to the safety and tolerance of patients. Therefore, the present invention preferably uses hydrofluoroalkanes as propellants.

[0047] As an embodiment of the present invention, one preferred formula of the vaginal foam of the present invention is as follows:

[0048] The raw materials for preparing the matrix material include, by mass percentage, estradiol content preferably being 0.0004% to 0.001%, more preferably 0.001%; ​​isopropyl myristate content preferably being 3% to 10%, more preferably 7%; hexadecanol content preferably being 0.2% to 2.0%, more preferably 1.33%; glyceryl monostearate content preferably being 0.1% to 1.0%, more preferably 0.20%; Tween 60 content preferably being 0.3% to 4.0%, more preferably The content of polyethylene glycol 200 is preferably 35% to 55%, more preferably 37.78%, the content of glycerol is preferably 0% to 10%, more preferably 8.59%; the content of lactic acid is preferably 0.05% to 0.2%, more preferably 0.10%, and the balance is water; based on the amount of the base material of 10 to 100 g / bottle (for example 40 g / bottle), the amount of the propellant is preferably 4 g to 5.5 g / bottle, more preferably 4.7 g / bottle.

[0049] The present invention provides a method for preparing the vaginal foam described in the above technical solution, comprising the following steps:

[0050] Mixing estradiol, an amphoteric organic solvent, a surfactant and water to obtain an aqueous phase;

[0051] Adding a hydrophobic component as an oil phase into the water phase, and subjecting the mixture to emulsification to obtain a matrix material;

[0052] The vaginal foam is obtained by filling the base material with a propellant.

[0053] In the present invention, estradiol, an amphoteric organic solvent, a surfactant and water are mixed 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.

[0054] After obtaining the aqueous phase, the present invention adds the hydrophobic component as the oil phase to the aqueous phase, and obtains the matrix material through emulsification treatment. The present invention preferably heats the hydrophobic component, and the heating temperature is preferably 75-85°C, more preferably 80°C; the present invention preferably heats the hydrophobic component and ensures that it is in a molten state. The present invention preferably adds the heated hydrophobic component as the oil phase to the heated aqueous phase under stirring or shearing conditions for emulsification treatment. In the present invention, the temperature of the emulsification treatment is preferably 75-85°C, more preferably 80°C; the time of the emulsification treatment is preferably 5-15min, more preferably 10min, and the time of the emulsification treatment is calculated from the completion of the addition of the oil phase; the emulsification treatment is preferably carried out under stirring or shearing conditions. After the emulsification treatment, the present invention preferably cools the obtained liquid to room temperature under stirring or shearing conditions to obtain the matrix material. In the present invention, when the raw materials for preparing the matrix material preferably also include a pH adjuster, the present invention preferably adds a pH adjuster to the liquid cooled to room temperature to obtain the matrix material. The matrix material of the present invention is a white or colorless liquid with a certain viscosity, which is conducive to the foaming agent having a sufficient retention time in the cavity and being able to fully contact with the cavity.

[0055] After obtaining the base material, the present invention charges the base material with a propellant to obtain the vaginal foam. The present invention has no particular limitation on the specific operation method of charging the base material with a propellant, and a method well known to those skilled in the art can be used.

[0056] In the present invention, the vaginal foam is preferably administered quantitatively, specifically, the vaginal foam is administered to the vaginal cervix through a drug delivery device. Figure 1This is a photo of the drug delivery device used in the embodiment of the present invention. The drug delivery device preferably includes a pressure-resistant bottle, a valve, a protective sleeve, a quantitative cap and a catheter, wherein the catheter is specifically connected to the protruding part of the protective sleeve for insertion into the vagina for drug delivery; the pressure-resistant bottle preferably includes a sodium calcium penicillin bottle, a medium borosilicate penicillin bottle, a PC bottle or an aluminum can bottle, and is more preferably an aluminum can bottle; the valve is preferably a quantitative valve, and the specification of the quantitative valve is preferably 1mL, that is, the volume of foam sprayed by pressing the quantitative cap once is preferably 1mL, and the mass of estradiol in 1mL of the foam is preferably 4-10μg, specifically 4μg, 5μg, 6μg, 7μg, 8μg, 9μg or 10μg; the catheter is preferably a disposable catheter. In the present invention, specifically, the base material is loaded into a pressure-resistant bottle, the quantitative valve is pressed, and then the propellant is filled, and the protective sleeve and the quantitative cap are added. In the present invention, the mass of the base material in each bottle of the vaginal foam can be 40g. Considering the safety of human medication and the impact on environmental pollution, the amount of propellant in each bottle of the vaginal foam of the present invention can be 4-8g, specifically 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g or 8g. The pressure in the bottle of each bottle of the vaginal foam can be 6-8bar, specifically 6bar, 6.5bar, 7bar, 7.5bar or 8bar. The vaginal foam product delivery uniformity result provided by the present invention meets RSD≤2%, which can achieve the purpose of quantitative administration and quality control.

[0057] The vaginal foam provided by the present invention has a smooth and delicate appearance and good stability. The vaginal foam provided by the present invention is simple to use, clean and hygienic, not limited by appliances and professional places, only needs to be pressed lightly when used, and only needs to replace a simple catheter each time it is used, and the cost is low; it has good compliance, no foreign body sensation, and a small amount of foam is almost insensible in the body; there is no need to worry about falling off, and it does not affect daily life. The vaginal foam provided by the present invention has good expected efficacy, and the foam forms a drug-containing film layer on the surface of the cavity wall in the body to ensure the administration time; it contains a propellant and has a certain impact pressure, which can fully expand so as to effectively fill and cover the deep part of the vagina and the folds, ensuring sufficient contact with the medication site; it adopts a fully enclosed high-pressure canning, which is conducive to improving product stability and preventing drug degradation; the foam is light, silky and fully filled, and has a good use effect for symptoms such as dyspareunia and dryness. The vaginal foam provided by the present invention is safe and effective, and the dosage is accurate and the quality is controllable.

[0058] The vaginal foam provided by the present invention does not need to use a large amount of surfactants or ethanol, thereby avoiding the problems of skin irritation, dryness, etc. caused by the use of a large amount of ethanol in sprays; and compared with vaginal suppositories, the vaginal foam has a good vaginal mucosal contact area, is convenient for administration, and does not require continuous cleaning of the cavity; in addition, due to the targeted effect of vaginal estrogen, it is not necessary to add azone and other transdermal enhancers in the prescription, the formula is simple, the preparation process is simple, the use is convenient, and the patient compliance and compliance are good.

[0059] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0060] The estradiol preparations involved in the following examples and comparative examples include a base material and a propellant, wherein the base material specifically refers to the components in the estradiol preparation other than the propellant, the total mass of the base material in each bottle of estradiol preparation is 40 g, the amount of each component added in the base material is calculated as a percentage of the total mass of the base material (i.e., the amount of each component added in the base material is 100%), and the amount of the propellant added is the added mass of the propellant in each bottle of estradiol preparation.

[0061] The foam properties of the products in the following examples and comparative examples were evaluated, specifically the sprayed foam properties were used to evaluate the quality of the prescriptions. Figure 2 The foam properties of each level are shown in the figure for evaluating foam properties. From left to right, they are grade A, grade B, grade C and grade D. Grade A refers to foam that is formed, delicate, soft and has good supporting power; Grade B refers to foam that is formed but not delicate, with slightly larger pores and slightly weaker supporting power; Grade C refers to foam that is in a foamy state but has no supporting power and is a reticular foam; Grade D refers to foam that is not in a foamy state and exists in liquid form.

[0062] The relative density of the foam of the products in the following embodiments and comparative examples was tested, and the specific method was as follows: take 3 samples and place them at 25°C for 24 hours. Note that the container needs to be shaken but not heated, and 5 to 10 mL of foam is discarded; prepare a flat weighing bottle with a volume of about 100 mL and a height of about 35 mm, accurately weigh its mass and record it as W; then place the nozzle at the bottom corner of the flat weighing bottle, press the quantitative cap, and fill the flat weighing bottle evenly with a circular motion. After the foam is fully expanded, use a scraper to scrape off the excess foam along the upper edge of the flat weighing bottle, clean it up, accurately weigh its mass and record it as W2; then fill the flat weighing bottle with purified water at 25°C, accurately weigh its mass and record it as W1; calculate the relative density according to the following formula: ρ = (W2-W) / (W1-W).

[0063] The high and low temperature physical stability of the products in the following examples were investigated, and the specific method was as follows: placing at a low temperature (2-8°C) for 20 hours, returning to room temperature (25°C) for 4 hours, placing at a high temperature (30°C) for 20 hours, and returning to room temperature for 4 hours, this was regarded as one cycle, and the experiment was repeated for 5 cycles.

[0064] Embodiments 1 to 4

[0065] Prepare the aqueous phase: weigh the prescribed amount of propylene glycol or polyethylene glycol 200, mix it with the prescribed amount of glycerol, Tween 60, estradiol and water, heat it to 80±5℃ to completely dissolve the components, and keep it warm for later use;

[0066] Preparation of oil phase: weigh the prescribed amount of isopropyl myristate or light liquid paraffin, mix with the prescribed amount of glyceryl monostearate and cetyl alcohol, and heat to 80±5℃ to completely melt the components;

[0067] Mixing: adding the oil phase to the water phase under stirring conditions, stirring for 10 minutes at 80±5°C after the addition is completed, then continuing to stir the resulting solution under room temperature conditions and cooling it to room temperature, adjusting the pH value to 3-5 with lactic acid, and obtaining a matrix material;

[0068] Filling: put the base material into an aluminum can, press the quantitative valve (1 mL), fill with tetrafluoroethane, and then add a protective cover and a quantitative cap.

[0069] The formulas of each product are shown in Table 1.

[0070] Table 1 Product formula in Examples 1 to 4

[0071]

[0072] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam of the well-formed prescription was tested. The specific test results are shown in Table 2. The results show that when the mass percentage of estradiol in the base material is within the range of 0.0004% to 0.001%, good foam can be formed, and the foam is fine and complete and can persist in the sprayed state.

[0073] Table 2 Foam properties and relative density of products in Examples 1 to 4

[0074] Test indicators Example 1 Example 2 Example 3 Example 4 Trait level A A A A Relative density 0.1041 0.1039 0.1025 0.1011

[0075] Examples 5 to 8 and Comparative Example 1

[0076] The method of Example 1 was used, and the formulas of the products are shown in Table 3.

[0077] Table 3 Product formulas in Examples 5 to 8 and Comparative Example 1

[0078]

[0079]

[0080] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam of the prescription with good molding 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 foam has good moldability, the foam is fine and complete, and can continue to exist in a sprayed state.

[0081] Table 4 Foam properties and relative density of products in Examples 5 to 8 and Comparative Example 1

[0082] Detection indicators Example 5 Example 6 Example 7 Example 8 Comparative Example 1 Trait level B A C C D Relative density 0.1003 0.1011 0.1056 0.1066 /

[0083] The high and low temperature physical stability of the products in Examples 5 to 6 was investigated, and the specific test results are shown in Table 5. The results show that the products in Examples 5 to 6 have excellent high and low temperature physical stability.

[0084] Table 5 High and low temperature physical stability test results of the products in Examples 5 to 6

[0085]

[0086]

[0087] The delivery of each press was evaluated by the foam sprayed, mainly to examine the delivery uniformity of each press, specifically, one can of sample was taken, shaken, the quantitative cap was pressed, vertically inverted for 10 seconds, the can was placed upright, the quantitative cap was loosened, the first press was discarded, the initial 3 doses, the middle 4 doses, and the last 3 doses were taken, a total of 10 delivery doses, and the RSD value was calculated. The specific test results are shown in Table 6. The results show that the delivery uniformity RSD of the products in Examples 5-6 is less than 2%.

[0088] Table 6 Delivery uniformity test results of products in Examples 5 to 6

[0089]

[0090] Examples 9 to 12 and Comparative Examples 2 to 3

[0091] The method of Example 1 was used, and the formulas of the products are shown in Table 7.

[0092] Table 7 Product formulas in Examples 9 to 12 and Comparative Examples 2 to 3

[0093]

[0094]

[0095] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam of the prescription with better molding was tested. The specific test results are shown in Table 8. The results show that when the total mass percentage of polyethylene glycol 200 and glycerol in the matrix material is in the range of 35% to 65%, the foam has good moldability, the foam is fine and complete, and can continue to exist in a sprayed state.

[0096] Table 8 Foam properties and relative density of products in Examples 9 to 12 and Comparative Examples 2 to 3

[0097] Detection indicators Example 9 Example 10 Embodiment 11 Example 12 Comparative Example 2 Comparative Example 3 Trait level B A B C D D Relative density 0.1002 0.1006 0.1009 0.1015 / /

[0098] The high and low temperature physical stability of the products in Examples 9 to 11 was investigated, and the specific test results are shown in Table 9. The results show that the products in Examples 9 to 11 have excellent high and low temperature physical stability.

[0099] Table 9 High and low temperature physical stability test results of the products in Examples 9 to 11

[0100]

[0101]

[0102] Examples 13 to 18

[0103] The method of Example 1 was used, and the formulas of the products are shown in Table 10.

[0104] Table 10 Product formula in Examples 13 to 18

[0105]

[0106] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam was tested. The specific test results are shown in Table 11. The results showed that when cetyl alcohol or octadecanol was used alone, the mass percentage of cetyl alcohol or octadecanol in the base material was in the range of 0.4% to 2%, the foam had good formability, the foam was fine and complete, and could continue to exist in a sprayed state.

[0107] Table 11 Foam properties and relative density of products in Examples 13 to 18

[0108] Detection indicators Embodiment 13 Embodiment 14 Embodiment 15 Example 16 Embodiment 17 Embodiment 18 Trait level C C B B C C Relative density / / 0.1023 0.1015 0.1003 0.1015

[0109] Examples 19 to 23

[0110] The method of Example 1 was used, and the formulas of the products are shown in Table 12.

[0111] Table 12 Product formula in Examples 19 to 23

[0112]

[0113]

[0114] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam was tested. The specific test results are shown in Table 13. The results showed that when cetyl alcohol and octadecanol were used in combination, the mass ratios of cetyl alcohol and octadecanol were 1:1, 2:1, 1:2, 3:1, and 1:3, and the total mass percentage of cetyl alcohol and octadecanol in the matrix material was in the range of 0.4% to 3.0%, which can play a role in adjusting the viscosity of the system and at the same time play a supporting role as the skeleton component of the foam. The foam has good formability, is fine and complete, and can continue to exist in a sprayed state.

[0115] Table 13 Foam properties and relative density of products in Examples 19 to 23

[0116] Example Embodiment 19 Embodiment 20 Embodiment 21 Embodiment 22 Embodiment 23 Characteristics C B A A B Relative density 0.1002 0.1032 0.1027 0.1014 0.1008

[0117] The high and low temperature physical stability of the products in Example 19, Example 21 and Example 22 was investigated, and the specific test results are shown in Table 14. The results show that the products in Example 19, Example 21 and Example 22 have good high and low temperature physical stability.

[0118] Table 14 High and low temperature physical stability test results of the products in Example 19, Example 21 and Example 22

[0119]

[0120]

[0121] Embodiments 24 to 29

[0122] The method of Example 1 was used, and the formulas of the products are shown in Table 15.

[0123] Table 15 Product formulations in Examples 24 to 29

[0124]

[0125] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam was tested. The specific test results are shown in Table 16. The results showed that the mass percentage of hydrophobic component fatty alcohol ester compounds such as 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 foam agent had good appearance, was smooth and delicate.

[0126] Table 16 Foam properties and relative density of products in Examples 24 to 29

[0127] Detection indicators Embodiment 24 Embodiment 25 Embodiment 26 Embodiment 27 Embodiment 28 Embodiment 29 Trait level B A B B A B Relative density 0.1012 0.1022 0.1012 0.1014 0.1014 0.1019

[0128] Examples 30 to 34 and Comparative Examples 4 to 5

[0129] The method of Example 1 was used, and the formulas of the products are shown in Table 17.

[0130] Table 17 Product formulas in Examples 30 to 34 and Comparative Examples 4 to 5

[0131]

[0132] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam was tested. The specific test results are shown in Table 18. The results showed that the mass percentage of the emulsifier in the base material of the products of Comparative Examples 4 to 5 was 0.1%, and the appearance of the foam was poor.

[0133] Table 18 Foam properties and relative density of products in Examples 30 to 34 and Comparative Examples 4 to 5

[0134]

[0135]

[0136] The high and low temperature physical stability of the products in Examples 30 to 33 was investigated, and the specific test results are shown in Table 19. The results show that when the mass percentage of the emulsifier in the base material is in the range of 0.3% to 4%, the prepared foam has good appearance, is smooth and delicate.

[0137] Table 19 High and low temperature physical stability test results of the products in Examples 30 to 33

[0138]

[0139] Embodiments 34 to 42

[0140] The method of Example 1 was used, and the formulas of the products are shown in Table 20.

[0141] Table 20 Product formula in Examples 34 to 42

[0142]

[0143]

[0144] The quality of the prescription was evaluated by the properties of the sprayed foam, and the relative density of the foam was tested. The specific test results are shown in Table 21. The results show that there is no obvious difference in the appearance of the foam of products prepared with different propellants, and the foam has a smooth and delicate appearance. The present invention preferably uses tetrafluoroethane as the propellant.

[0145] Table 21 Foam properties and relative density of products in Examples 34 to 42

[0146]

[0147] Embodiments 43 to 45

[0148] The method of Example 1 is used as reference, wherein the product formula is shown in Table 22.

[0149] Table 22 Product formulations in Examples 43 to 45

[0150]

[0151]

[0152] The factors affecting the stability at 40°C of the products in Examples 43 to 45 were investigated. Specifically, the products were placed at 40°C, and samples were tested at 0 days, 10 days, and 30 days to examine the changes in foam properties, pH value, content, and related substances. The applicability of the packaging material was observed at different stages of the investigation.

[0153] The test methods for content and related substances are as follows:

[0154] Content determination method: high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512) was used for determination; chromatographic conditions: octadecylsilane bonded silica gel was used as filler (Kromasil 4.6 mm × 250 mm, 5 μm or chromatographic column with equivalent performance); acetonitrile-water (45:55) was used as the mobile phase; the excitation wavelength was 240 nm, and 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.

[0155] Determination method for related substances: high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512) was used for determination; chromatographic conditions: octadecylsilane bonded silica gel was used as filler (MN RP184.6mm×100mm, 2.7μm or chromatographic column with equivalent performance); water was used as mobile phase A, acetonitrile was used as mobile phase B, and linear gradient elution was performed according to Table 23; the flow rate was 1mL / min; the column temperature was 35°C; the detection wavelength was 220nm; the injection volume was 10μL.

[0156] Table 23 Gradient elution method for related substances

[0157] Time (min) Mobile phase A (%) Mobile phase B (%) 2 90 10 20 45 55 20.1 10 90 30 10 90 30.1 90 10 40 90 10

[0158] Result requirements: total impurities ≤4.0%.

[0159] Table 24 is the 40°C stability test results of the products in Examples 43 to 45. The results show that when the products are placed at 40°C for 10 days compared with the initial 0 day, the appearance of the foam is supportive, and the amount of foam sprayed is accurate, smooth and delicate; the related substances and pH value have not changed significantly compared with the initial 0 day, and the samples show good stability. When the products are placed at 40°C for 30 days compared with the initial 0 day, the content and related substances have not changed significantly, and they have good compatibility with the propellant and the quantitative dosing device of the foaming agent. The pressure-resistant aluminum can bottle is cut open and the coated inner wall of the aluminum can bottle is observed. No delamination phenomenon is observed (the coating condition of the aluminum can bottle when the product is placed at 40°C for 30 days is as shown in the figure). Figure 3 to Figure 5 shown).

[0160] Table 24 Results of stability test of products at 40°C in Examples 43 to 45

[0161]

[0162] Embodiment 46

[0163] The method of Example 1 is used as reference, wherein the product formula is shown in Table 25.

[0164] Table 25 Product formulation in Example 46

[0165]

[0166]

[0167] Test Example 1

[0168] The product in Example 46 was investigated for factors affecting its stability at 40°C, and compared with commercially available estradiol soft capsules and vaginal tablets. The specific test methods and conditions refer to Example 43.

[0169] The content determination results are shown in Table 26. The results show that the content determination results are between 95% and 105%, and the product is qualified.

[0170] Table 26 Content determination results

[0171]

[0172] The results of the determination of related substances are shown in Table 27. The results show that the change trend of related substances in the product of Example 46 is better than that of vaginal tablets and soft capsules.

[0173] Table 27 Determination results of related substances

[0174]

[0175] Test Example 2

[0176] The delivery of each press was evaluated by the foam sprayed, mainly to examine the delivery uniformity of each press, specifically, one can of sample was taken, shaken, the quantitative cap was pressed, vertically inverted for 10 seconds, the can was placed upright, the quantitative cap was loosened, the first press was discarded, the initial 3 doses, the middle 4 doses, and the last 3 doses were taken, a total of 10 delivery doses, and the RSD value was calculated. The specific test results are shown in Table 28. The results show that the delivery uniformity RSD of the product in Example 46 is less than 2%.

[0177] Table 28 Delivery uniformity test results of the product in Example 46

[0178]

[0179] Test Example 3

[0180] The high and low temperature physical stability of the product in Example 46 was investigated, and the specific test results are shown in Table 29. The results show that the foaming agent prepared in Example 46 has good appearance, is smooth and delicate.

[0181] Table 29 High and low temperature physical stability test results of the products in Example 46

[0182]

[0183]

[0184] Test Example 4

[0185] The in vitro dissolution rate of the product in Example 46 was evaluated by the basket method, and the dissolution rate was compared with that of commercially available estradiol soft capsules and vaginal tablets. The cumulative dissolution amount was determined by the content determination method. The specific test conditions were as follows: the medium was 500 mL of phosphate buffer with a pH value of 4.75, the rotation speed was 40 rpm, and the sampling times were 1 h, 5 h, and 10 h, respectively.

[0186] Figure 6 The dissolution curves of the product in Example 46 and commercially available estradiol vaginal soft capsules and vaginal tablets are shown.

[0187] The results of the in vitro dissolution test are shown in Table 30. The results show 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.

[0188] Table 30 In vitro dissolution test results

[0189]

[0190] Test Example 5

[0191] In the animal PK test, 14 SPF New Zealand female rabbits (not in sexual cycle) weighing 2.0-2.5kg were divided into T, R, and P groups according to (6+6+2) (T is test, R is reference, and P is control). Group T was given one press of the drug, and group R was given one unit of preparation (1 tablet). 2mL of blood was collected before and 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, and the blood was allowed to stand to separate the serum. 0.3mL of serum was transferred into a PE tube and stored in a -20℃ refrigerator for testing.

[0192] 24 hours after blood collection, the animals were killed by ear vein air injection, the vaginal tissue was taken out, the surrounding connective tissue was removed, the vagina was longitudinally incised, and the surface moisture was absorbed with filter paper. The organs and the inner wall of the vagina were observed with the naked eye for congestion and edema, and then the vaginal tissue was placed in formalin solution for fixation for 24 hours, embedded in paraffin, sectioned, and stained with hematoxylin-eosin (HE) for pathological histological examination and evaluation.

[0193] The rabbit estradiol ELISA method was used to determine the content of estradiol in serum, and the blood drug concentration data measured in the experiment were subjected to mathematical statistics.

[0194] The results of animal PK tests on the test sample (product of Example 46) and commercially available estradiol vaginal tablets showed that the estradiol concentration in the serum of the test sample and commercially available estradiol vaginal tablets did not change significantly compared with the blank control group (Table 31, Figure 7 ), no erythema, edema or purulent secretions were observed in the periphery of vaginal tissue after medication, and no abnormalities were found in pathological sections of vaginal mucosa ( Figure 8 ), no mucosal irritation, indicating that the safety of this product is equivalent to that of the reference.

[0195] Table 31 In vivo pharmacokinetic results

[0196]

[0197] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A vaginal foam, characterized in that: The active ingredient is estradiol.

2. The vaginal foam according to claim 1, characterized in that The raw materials for preparing the vaginal foam include a base material and a propellant, and the raw materials for preparing the base material include estradiol, an amphoteric organic solvent, a hydrophobic component, a surfactant and water.

3. The vaginal foam according to claim 2, characterized in that The matrix material comprises the following raw materials by weight percentage: 0.0001% to 0.01% of estradiol, 35% to 65% of an amphoteric organic solvent, 1.0% to 10% of a hydrophobic component, 0.1% to 4.0% of a surfactant, and the balance is water; Based on the usage of the base material being 10 to 100 g / bottle, the usage of the propellant is 4 to 8 g / bottle.

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

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

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

7. The vaginal foam according to claim 6, characterized in that The C12-C22 fatty alcohol compounds include hexadecanol and / or stearyl alcohol; the C12-C22 solid fatty acid ester compounds include one or more of monostearic acid glyceryl, distearic acid glyceryl and mono- and distearic acid glyceryl; the oily component includes one or more of liquid fatty acid ester compounds, mineral oil and vegetable oil.

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

9. The vaginal foam according to claim 2 or 3, characterized in that The surfactant includes one or more of benzene sulfonate, fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, stearic acid polyoxyethylene ether, fatty amine polyoxyethylene ether, alkyl alcohol amide polyoxyethylene ether, lecithin, fatty acid monoglyceride, fatty acid diglyceride, sucrose fatty acid ester, polysorbate, polyoxyethylene ricinoleate, ethoxylated glycerol triricinoleate, diethylene glycol monoethyl ether and triethanolamine.

10. The vaginal foam according to claim 2 or 3, characterized in that The propellant includes a hydrofluoroalkane.

11. The vaginal foam according to claim 10, characterized in that The hydrofluoroalkane includes one or more of tetrafluoroethane, heptafluoropropane and difluoroethane.

12. The vaginal foam according to claim 2 or 3, characterized in that The pH value of the matrix material is 3.0-7.

0.

13. A method for preparing the vaginal foam according to any one of claims 2 to 12, comprising the following steps: Mixing estradiol, an amphoteric organic solvent, a surfactant and water to obtain an aqueous phase; Adding a hydrophobic component as an oil phase into the water phase, and subjecting the mixture to emulsification to obtain a matrix material; The vaginal foam is obtained by filling the base material with a propellant.

Images