Preparation method of progesterone sustained-release gel

Abstract

The invention discloses a preparation method of progesterone sustained-release gel, which specifically comprises the following steps: adding progesterone into an oil phase to pre-form a bulk drug aggregate, and adding a water-phase gel matrix into the drug-containing oil phase to prepare the gel. According to the progesterone sustained-release gel, the medicine is suspended in the gel matrix according to the preparation characteristic design of the progesterone sustained-release gel, so that the problem that the raw material medicine cannot be completely wrapped by an oil phase and is adhered to form an aggregate can be solved, an oil-phase and water-phase double-layer sustained-release effect is provided, and the in-vivo release time of progesterone is prolonged.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for preparing a progesterone sustained-release gel. Background Art

[0002] The corpus luteum is the main source of steroid hormone secretion and is closely related to female pregnancy. When the corpus luteum is insufficient, it is difficult to maintain normal female pregnancy function, which can easily lead to miscarriage or even inability to conceive. Progesterone is a natural progestogen secreted by ovarian progesterone and placenta. It has no androgen-like effects and is currently the main progestogen for corpus luteum support. It is used to treat assisted reproduction, recurrent miscarriage, threatened miscarriage and threatened premature birth.

[0003] The main routes of administration of progesterone are intramuscular injection, oral administration and vaginal administration. Since progesterone is an oil-soluble drug, intramuscular injection will cause pain; similarly, after oral administration, the bioavailability of progesterone is reduced due to the first-pass effect of the liver, and the best therapeutic effect cannot be achieved; in contrast, vaginal administration can utilize the "uterus" first-pass effect, increase the accumulation of the drug in the uterus, improve the efficacy, and reduce the concentration in the blood, increase safety, and convenient administration can improve patient compliance. Progesterone gel currently accounts for a high proportion of commercially available products, but has been monopolized by imported products. Therefore, the present invention aims to design a vaginal progesterone sustained-release gel with high patient compliance and good therapeutic effect.

[0004] The 27th batch of "Generic Drug Reference Preparations Catalog" released by NMPA selected Merck Serono's As a reference preparation. Patent CN1282250A (WO99 / 20282) discloses that the preparation process of the reference preparation is to first prepare a polymer gel matrix, then add the API to the gel and disperse it evenly, and finally add the gel phase to the oil phase and mix it evenly. However, the inventors found in previous studies that due to the increase in bulk density of the API after micronization, the viscosity of the polymer gel phase is relatively large, and the feasibility of this step of mixing is relatively poor, resulting in the API agglomerating into blocks and being unable to disperse.

[0005] Patent CN113288865A discloses a method for preparing a progesterone vaginal gel, which specifically comprises first preparing a premix of the raw material progesterone and a polymer, then adding the premix to an aqueous phase to obtain a hydrogel phase, and then adding an appropriate amount of sodium hydroxide solution to adjust the pH value to 2.5-3.5. However, the progesterone gel prepared by this process will aggregate and fuse during cooling and storage.

[0006] Patent CN114983929A discloses a stable progesterone sustained-release gel and its preparation method, wherein the raw material progesterone is added to the oil phase and the water phase matrix respectively, the two are mixed and homogenized, and then the temperature is gradually reduced to room temperature 25°C to form a drug reservoir. However, the microstructure analysis of the progesterone gel formed by this process shows that after the oil phase adheres to the raw material drug particles to form emulsion droplets, the raw material drug crystal particles in the water phase adhere to the periphery of the emulsion droplets. Due to the loose adhesion, the crystals on the periphery of the emulsion droplets will be loose under a certain shear force, resulting in the problem of accelerated release. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing a progesterone sustained-release gel, comprising the following steps:

[0008] Step 1, mixing progesterone with light liquid paraffin, hydrogenated palm oil glyceride and glycerin to obtain a drug-containing oil phase;

[0009] Step 2, first dissolving sorbic acid in water, then dispersing carbomer and polycarbophil into the mixed solution, swelling, and obtaining an aqueous gel matrix;

[0010] Step 3, adding the aqueous gel matrix into the drug-containing oil phase, stirring and mixing, and then shearing, and then adjusting the pH to 2.5-3.5 to obtain the progesterone sustained-release gel.

[0011] Further, in step 1, in order to ensure that the hydrogenated palm oil glyceride is completely melted, the particle size of the raw material drug aggregates in the drug-containing oil phase meets the requirements (within the range of 20 to 200 μm), and the progesterone is evenly distributed, the temperature and stirring speed need to be controlled during the preparation of the drug-containing oil phase. The heating temperature used in the present invention is 40°C to 99°C, and the stirring speed is 20rpm to 200rpm. The inventors found in the early experimental process that when the stirring speed is too low, the stirring force is insufficient and the progesterone cannot be fully mixed with the oil phase during the preparation of the drug-containing oil phase; when the stirring speed is too high, the stirring paddle runs idle, and the progesterone and the oil phase adhere to the wall of the reactor and cannot be stirred and mixed.

[0012] Furthermore, in step 2, whether the aqueous gel matrix is ​​uniform will affect the effective release of the subsequent sustained-release gel. In order to allow carbomer and polycarbophil to swell sufficiently to form a uniform gel matrix, carbomer and polycarbophil are dispersed and added to the mixed solution for swelling for 6 to 24 hours. The inventors found in the early experimental process that when the swelling time is too short, carbomer and polycarbophil swell insufficiently, and there are powder lumps of carbomer and polycarbophil in the matrix, and there are a large number of bubbles; when the swelling time is too long, the preparation time cost is large, and 6 to 24 hours has a better swelling result within an acceptable time. Preferably, the stirring speed when carbomer and polycarbophil are dispersed is 100rpm to 500rpm, and they are allowed to swell after dispersion.

[0013] Furthermore, in a specific embodiment of the present invention, in order to fully dissolve sorbic acid, part of glycerol is added to solubilize sorbic acid when it is dissolved in water, and the proportion of glycerol added is: 5% to 20% of the prescription amount, and the dissolution conditions are: temperature 50°C to 100°C.

[0014] Further, in step 3, the aqueous gel matrix and the drug-containing oil phase are preheated to the same temperature, and then the aqueous gel matrix is ​​added to the drug-containing oil phase, stirred and mixed, and then sheared, with a shearing speed of 5000-10000 rpm and a time of 1-10 min. The inventor found in the early experimental process that when the high-speed shearing speed is too low, the shearing force is small and the sample viscosity is large, and a shear cycle cannot be formed. When the shearing speed is too high, the shearing force is too large, the raw material drug aggregates are broken, and the in vitro release becomes faster, so the shearing speed is controlled to be 5000-10000 rpm.

[0015] Furthermore, before shearing, stirring is performed at a relatively low speed, the stirring speed is controlled at 10 to 200 rpm, and the stirring time is 10 to 50 minutes. The inventors found in the early experimental process that when the water-oil two-phase mixing time is short or the mixing stirring speed is low, the water-oil two-phase mixing is insufficient, and the drug-containing oil phase cannot be evenly dispersed in the water phase matrix; when the mixing time is long, it may cause water loss, so the mixing time is controlled to be 10 to 50 minutes. In a specific embodiment of the present invention, slow stirring is first performed at a speed of 10 to 100 rpm, and then rapid stirring is performed at a speed of 50 to 200 rpm.

[0016] Furthermore, the prescription of the progesterone sustained-release gel is as follows: every 100g of the progesterone sustained-release gel contains 8.0g of progesterone, 1g of carbomer 974P, 2.0g of polycarbophil, 12.9g of glycerol, 4.2g of light liquid paraffin, 1.0g of hydrogenated palm oil glyceride, 0.08g of sorbic acid and an appropriate amount of sodium hydroxide, and the balance is water.

[0017] Furthermore, squalene can be added to the drug-containing oil phase in step 1. Preferably, the amount of squalene is 1-2 g per 100 g of progesterone sustained-release gel.

[0018] Furthermore, sucrose can be added to the aqueous gel matrix in step 2. Preferably, the amount of sucrose is 10-13 g per 100 g of the progesterone sustained-release gel.

[0019] The inventors found in previous studies that in the prior art, when preparing progesterone sustained-release gel, the method of adding progesterone is mostly to first add progesterone to the aqueous phase matrix and then mix it with the oil phase, but this preparation method will cause the drug particles to not be completely wrapped by the oil phase to form emulsion droplets, thereby affecting drug release. Therefore, the present invention combines the formulation characteristics of the progesterone sustained-release gel to design the drug to be suspended in the gel matrix, and preferentially chooses to add progesterone to the oil phase, and utilizes the high viscosity of light liquid paraffin and hydrogenated palm oil glyceride in the oil phase to adhere to the drug particles and form a bulk drug aggregate, which can provide an inner layer sustained-release effect; after adding the gel matrix, carbomer and polycarbophil with a gel mesh structure provide an outer layer sustained-release effect, and because they can interact with mucosal proteins, they produce strong biological adhesion, and further form a long-acting sustained-release adhesive progesterone sustained-release gel.

[0020] At the same time, combined with the actual application of progesterone sustained-release gel in women, patients with vaginal flora imbalance may use the preparation as a progesterone supplement, which affects the absorption and treatment of the drug. Therefore, it is very important to inhibit the growth of pathogenic bacteria and regulate the normal microbial homeostasis. To this end, the present invention, based on the original prescription, also introduces prebiotic sucrose that can promote the growth of lactobacilli as an active ingredient and natural lipid squalene with moisturizing and antibacterial properties through prescription redesign. In the redesigned prescription, the amount of sucrose added is 10% to 13%, squalene is 1% to 2%, and progesterone is 8%.

[0021] Compared with the prior art, the process advantage of the present invention is that when the oil phase fully infiltrates the surface of progesterone, it can ensure that all drugs can be bonded together to form aggregates, and after the gel matrix is ​​added, the inner aggregate and the outer gel matrix provide a double-layer sustained release effect. When the progesterone raw material drug is first mixed with the oil phase to form the raw material drug aggregate, and then the aggregate particle size is adjusted by the shear speed and time after the water and oil phases are mixed, the progesterone sustained-release gel of the present invention can achieve slow release within 72 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The polarizing microscope observation results of commercially available preparations are shown in Figure 2.

[0023] Figure 2 This is the polarizing microscope photographic result of the preparation of Comparative Example 1.

[0024] Figure 3 This is the polarizing microscope photographic result of the preparation of Comparative Example 2.

[0025] Figure 4 This is the polarizing microscope photograph result of the preparation in Example 1.

[0026] Figure 5 This is the polarizing microscope photograph result of the preparation in Example 2.

[0027] Figure 6 This is the in vitro release curve of the preparation of Example 2.

[0028] Figure 7 This is the polarizing microscope photographic result of the preparation in Example 3.

[0029] Figure 8 This is the polarizing microscope photograph result of the preparation in Example 4. DETAILED DESCRIPTION

[0030] The preferred embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that the following examples are provided only for the purpose of illustration and are not intended to limit the scope of the present invention. Those skilled in the art may make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0031] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0032] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0033] In the following examples, the commercially available preparation is Progesterone sustained-release vaginal gel.

[0034] Comparative Example 1

[0035] The preparation process of this embodiment is basically the same as that of the reference preparation patent CN1147301C (WO99 / 20282), except that all the glycerol is added into the water phase; and the oil phase is poured into the water phase and mixed.

[0036] Prepare the raw materials and excipients according to the following prescription. The specific prescription is as follows:

[0037] Composition Dosage (g / 100g) Progesterone 8.0 Carbomer 974P 1.0 Polycarbophil 2.0 glycerin 12.9 Light liquid paraffin 4.2 Hydrogenated Palm Glycerides 1.0 Sorbic acid 0.08 Sodium hydroxide Moderate Purified water to 100%

[0038] 1) Prepare according to the following steps:

[0039] ① Preparation of sorbic acid solution: Pour sorbic acid and glycerin into purified water according to the prescribed ratio, heat and stir at 92°C to completely dissolve the sorbic acid, then stop heating and let stand to cool.

[0040] ② Preparation of aqueous matrix: Add carbomer and polycarbophil to the sorbic acid solution according to the prescription ratio, stir and disperse the materials at 80 rpm, and stir at 70 rpm until the polymer is completely swollen.

[0041] ③ Preparation of oil phase: Heat hydrogenated palm oil glyceride and light liquid paraffin at 65°C according to the prescription ratio to melt the hydrogenated palm oil glyceride.

[0042] ④ Preparation of drug-containing aqueous phase: Add progesterone to the aqueous phase matrix according to proportion and mix evenly, then heat at 65°C and stir at 180 rpm until mixed evenly.

[0043] ⑤ Preparation of progesterone sustained-release gel: Heat the oil phase to the same temperature as the mixture in ④, quickly pour the oil phase into the drug-containing aqueous phase, stir at 50 rpm for 60 min, cool to room temperature, and obtain progesterone sustained-release gel.

[0044] 2) Evaluation methods:

[0045] ① Appearance: The preparation should be fine and smooth, and there should be no large white particles after the preparation is spread. The results are shown in Table 1.

[0046] ②Observation of aggregate morphology under polarizing microscope: The API was encapsulated to form aggregates, but the particle size was uneven, and there were many small progesterone particles that were not encapsulated. Figure 2 shown.

[0047] Comparative Example 2

[0048] This embodiment adopts the prescription of comparative example 1 and the method steps recorded in patent CN113288865A.

[0049] 1) Prepare according to the following steps:

[0050] ① Preparation of sorbic acid solution: Pour sorbic acid and part of glycerol into purified water according to the prescription ratio, heat and stir at high temperature to completely dissolve the sorbic acid, then stop heating and let stand to cool.

[0051] ②Preparation of premix: Progesterone, carbomer and polycarbophil were mixed according to the prescription ratio, and after mixing evenly, they were added to the sorbic acid solution, and stirred slowly at 40 rpm, 55°C, and 3 h until the polymer and the drug were fully swollen.

[0052] ③ Preparation of oil phase: Heat hydrogenated palm oil glyceride and light liquid paraffin at 80°C according to the prescribed ratio to melt the hydrogenated palm oil glyceride.

[0053] ④ Preparation of progesterone sustained-release gel: Pour the oil phase into the premix, stir slowly at 60 rpm, stirring temperature 80°C, stirring time 30 min, and slowly cool to room temperature to obtain progesterone sustained-release gel.

[0054] 2) Evaluation methods:

[0055] ① Appearance: The preparation should be fine and smooth, and there should be no large white particles after the preparation is spread. The results are shown in Table 1.

[0056] ②Observation of aggregate morphology under polarizing microscope: The API was encapsulated to form aggregates, but the particle size was uneven, and there were many small progesterone particles that were not encapsulated. Figure 3shown.

[0057] Example 1

[0058] This example adopts the prescription of Comparative Example 1.

[0059] 1) Prepare according to the following steps:

[0060] ① Preparation of drug-containing oil phase: According to the prescription ratio, mix progesterone with light liquid paraffin at 65°C, then add hydrogenated palm oil glyceride and 85% of the prescription amount of glycerol, and stir at 80 rpm to mix evenly.

[0061] ② Preparation of blank gel matrix: Add sorbic acid and the remaining 15% glycerol to purified water, stir at 92°C to dissolve the sorbic acid. Add carbomer and polycarbophil to the sorbic acid solution according to the prescription ratio, stir at 300 rpm, and swell for 16 hours after complete addition.

[0062] ③ Preparation of vaginal progesterone sustained-release gel: Heat the blank gel matrix to the same temperature as ①, pour it into ①, stir at 22 rpm first, then at 70 rpm for 30 min, then shear at 8000 rpm for 1 min, and slowly cool to room temperature to obtain the product.

[0063] ④ Determine the pH value of the preparation sample. If it is not within the range of 2.5-3.5, use sodium hydroxide solution to adjust the pH to 2.5-3.5.

[0064] 2) Evaluation methods:

[0065] ① Appearance: The preparation should be fine and smooth, and there should be no large white particles after the preparation is spread. The results are shown in Table 1.

[0066] ②Observation of aggregate morphology under polarizing microscope: The API is wrapped to form aggregates. Figure 4 shown.

[0067] Example 2

[0068] This example adopts the prescription of Comparative Example 1.

[0069] 1) The preparation process is basically the same as that in Example 1, except that the shearing time in step ③ is 2 min.

[0070] 2) Evaluation method: Same as in Example 1.

[0071] At the same time, the release rate was tested according to the release method described in the article "In vitro study on the preparation and bioequivalence influencing factors of progesterone sustained-release gel" (DOI: CNKI: CDMD: 2.1018.868826.) to examine the release of the samples within 72 hours in vitro.

[0072] The appearance evaluation results are shown in Table 1, and the polarizing microscope results are shown in Table 1. Figure 5 The in vitro release curve is shown in Figure 6 The preparation prepared by this process can stably and slowly release the drug within 72 hours.

[0073] Example 3

[0074] This example adopts the prescription of Comparative Example 1.

[0075] 1) The preparation process is basically the same as that in Example 1, except that the shearing time in step ③ is 3 min.

[0076] 2) Evaluation method: Same as in Example 1.

[0077] The appearance evaluation results are shown in Table 1, and the polarizing microscope results are shown in Table 1. Figure 7 shown.

[0078] Example 4

[0079] In this example, sucrose and squalene are added to the commercially available preparation on the basis of its prescription composition to achieve the purpose of anti-inflammatory and antibacterial.

[0080]

[0081]

[0082] 1) The preparation process comprises:

[0083] ① Preparation of drug-containing oil phase: According to the prescription ratio, mix progesterone with light liquid paraffin at 65°C, then add hydrogenated palm oil glyceride, squalene and 85% of the prescription amount of glycerol, and stir at 100 rpm to mix evenly.

[0084] ② Preparation of blank gel matrix: Add sorbic acid, sucrose and the remaining 15% glycerol to purified water, stir at 95°C to dissolve the sorbic acid. Add carbomer and polycarbophil to the sorbic acid solution according to the prescription ratio, stir at 300 rpm, and swell overnight after complete addition.

[0085] ③ Preparation of vaginal progesterone sustained-release gel: Heat the blank gel matrix to the same temperature as ①, pour it into ①, stir at 20 rpm first, then at 70 rpm for 30 min, then shear at 8000 rpm for 2 min, and slowly cool to room temperature to obtain the product.

[0086] 2) Evaluation methods:

[0087] ① Appearance: The preparation should be fine and smooth, and there should be no large white particles after the preparation is spread evenly.

[0088] ②Observation of aggregate morphology under polarizing microscope: The raw material drug is wrapped to form aggregates.

[0089] The appearance evaluation results are shown in Table 1, and the polarizing microscope results are shown in Table 1. Figure 8 shown.

[0090] Table 1 Appearance evaluation and polarizing microscope observation results

[0091]

[0092] As can be seen from the table above, according to the preparation method of the present invention, progesterone is added to the oil phase to pre-form progesterone bulk drug aggregates, and after adding the blank gel matrix, a white and delicate O / W type emulsion gel can be formed by high-speed shearing. The aggregate particle size and morphology under polarizing microscope observation are similar to those of commercially available preparations. At the same time, the preparation prepared by this process can stably and slowly release the drug within 72 hours.

Claims

1. A method for preparing a progesterone sustained-release gel, characterized in that: The following steps are involved: Step 1, mixing progesterone with light liquid paraffin, hydrogenated palm oil glyceride and glycerin to obtain a drug-containing oil phase; Step 2, first dissolving sorbic acid in water, then dispersing carbomer and polycarbophil into the mixed solution, swelling, and obtaining an aqueous gel matrix; Step 3, adding the aqueous gel matrix to the drug-containing oil phase, stirring and mixing, and then shearing, and then adjusting the pH to 2.5-3.5 to obtain the progesterone sustained-release gel.

2. The preparation method according to claim 1, characterized in that: In step 1, when preparing the drug-containing oil phase, the heating temperature is 40°C~99°C and the stirring speed is 20rpm~200rpm.

3. The preparation method according to claim 1, characterized in that: In step 2, carbomer and polycarbophil are dispersed and added to the mixed solution for swelling for 6 to 24 hours.

4. The preparation method according to claim 3, characterized in that: The stirring speed when dispersing carbomer and polycarbophil is 100 rpm to 500 rpm, and after being completely dispersed, they are allowed to stand and swell.

5. The preparation method according to claim 1, characterized in that: In step 2, when sorbic acid is dissolved in water, part of glycerol is added for solubilization, and the proportion of glycerol added is 5% to 20% of the prescribed amount.

6. The preparation method according to claim 5, characterized in that: Dissolution conditions: temperature 50℃~100℃.

7. The preparation method according to claim 1, characterized in that: In step 3, the aqueous gel matrix and the drug-containing oil phase are preheated to the same temperature, and then the aqueous gel matrix is ​​added to the drug-containing oil phase, stirred and mixed, and then sheared. The shearing speed is 5000-10000 rpm and the time is 1-10 minutes.

8. The preparation method according to claim 7, characterized in that: The stirring conditions are 10~200rpm, 10~50min.

9. The preparation method according to any one of claims 1 to 8, characterized in that The prescription of the progesterone sustained-release gel is as follows: every 100g of the progesterone sustained-release gel contains 8.0g of progesterone, 1g of carbomer 974P, 2.0g of polycarbophil, 12.9g of glycerol, 4.2g of light liquid paraffin, 1.0g of hydrogenated palm oil glyceride, 0.08g of sorbic acid and an appropriate amount of sodium hydroxide, and the balance is water.

10. The preparation method according to claim 9, characterized in that: Squalene is also added to the drug-containing oil phase in step 1, and sucrose is also added to the aqueous gel matrix in step 2.

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