CN114983929A - Stable progesterone sustained-release gel and preparation method thereof - Google Patents

Stable progesterone sustained-release gel and preparation method thereof Download PDF

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CN114983929A
CN114983929A CN202210529454.2A CN202210529454A CN114983929A CN 114983929 A CN114983929 A CN 114983929A CN 202210529454 A CN202210529454 A CN 202210529454A CN 114983929 A CN114983929 A CN 114983929A
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陶春蕾
孟广东
陈娟娟
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Anhui Wanbang Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a stabilizerThe progesterone sustained-release gel has a drug reservoir for realizing a milk drop-crystal balance body slowly released for 72 hours, wherein the concentration of a progesterone solution in the drug reservoir is more than or equal to 100mg/mL, and the particle diameter D of the milk drop is larger than or equal to 90 Not more than 10 μm, and particle diameter D of insoluble crystal 90 Less than or equal to 40 mu m. During preparation, one part of the raw material progesterone is dissolved in an oil phase, the other part of the progesterone is dispersed in a water phase matrix after being wetted by propylene glycol, and after the oil phase and the water phase are mixed, the pH value is adjusted to obtain the progesterone sustained-release gel with uniform particle size and uniform content; the particle size of the progesterone sustained-release gel obtained by adding the gradient cooling procedure is more uniform and more stable.

Description

Stable progesterone sustained-release gel and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a stable progesterone sustained-release gel and a preparation method thereof.
Background
Progesterone is an important component in the regulation of the female reproductive system, acting mainly on the uterus, ovary and its breast and Central Nervous System (CNS), and is present in high blood concentrations in women during the menstrual cycle and the luteal phase during pregnancy. Progesterone is produced in the corpus luteum during non-gestation and early gestation, and in the placenta during late gestation. Endogenous progesterone can convert endometrium from hyperplasia phase to secretion phase, and maintain normal physiological change.
Progesterone vaginal sustained release gels developed by Columbia and Pfizer, marketed by Actavis and Merck Serono, are used clinically primarily to assist in the supplemental treatment of progesterone in fertility technology. The preparation is a sustained-release system, progesterone is partially dissolved in a water phase and an oil phase, most progesterone is dispersed in a gel system, so that a reservoir for prolonging the release of the medicament is formed, and after the medicament in the water phase is absorbed, the progesterone stored in the oil phase and the suspended gel is continuously released and dissolved in the water phase due to concentration difference, thereby achieving the purpose of sustained release.
The original patent CN1147301C (WO99/20282) discloses a gel preparation process, which is to prepare a polymer gel first, then add the raw materials into the gel to disperse uniformly, and finally add the gel phase into the oil phase to mix uniformly. Because bulk density of the micronized bulk drugs is increased, and the viscosity of the polymer gel is high, mixing realizability in the step is poor, and the result that bulk drug aggregates cannot be dispersed can be generated.
Another gel preparation process disclosed in patent CN202110717741.1 is that a pre-mixture is first prepared from progesterone as a raw material and a polymer, then the pre-mixture is added into an aqueous phase to obtain a hydrogel phase, and then a proper amount of sodium hydroxide solution is added to adjust the pH value to 2.5-3.5. However, the progesterone gel produced by this process is aggregated and fused during cooling and storage.
Disclosure of Invention
The invention aims to provide a stable progesterone sustained-release gel and a preparation method thereof, which are used for solving the problems of poor stability of the particle size of a drug reservoir of a progesterone vaginal gel, non-uniform particle size of emulsion droplets in the conventional preparation process, fusion and aggregation of the particle size in the storage process and the like.
The technical scheme of the invention provides a stable progesterone sustained-release gel, which comprises an oil phase raw material and a water phase raw material, wherein the oil phase raw material comprises the following components in percentage by mass: 0.5-1.0% of progesterone, 4.2% of light liquid paraffin and 1.0% of hydrogenated palm oil glyceride; the water phase raw material comprises the following components in percentage by mass: 7.0-7.5% of progesterone 2, 12.9% of glycerol, 2.0% of carbomer 974p, 1.0% of polycarbophil, 0.08% of sorbic acid, 0.82% of sodium hydroxide and 70.0% of purified water.
In a preferred embodiment, the sum of the mass percentages of progesterone 1 and progesterone 2 is 8.0%.
A preparation method of a stable progesterone sustained-release gel comprises the following steps:
s1, aqueous gel preparation: adding sorbic acid and glycerol into purified water according to a certain proportion, boiling for dissolving, cooling to 50-55 ℃, adding polymer carbomer and polycarbophil, and stirring at constant temperature to obtain uniform water-phase gel;
s2, oil phase preparation: heating light liquid paraffin and hydrogenated palm oil glyceride to 50-55 deg.C for melting, adding progesterone 1, stirring for dissolving;
s3, preparation of progesterone vaginal gel: heating the water phase gel to the same temperature as the oil phase, mixing and homogenizing progesterone 2, the water phase gel preparation and the oil phase preparation, and adding sodium hydroxide to adjust the pH value to 2.5-3.5;
s4, gradient cooling and storage: and continuously stirring and homogenizing the uniformly mixed gel, carrying out gradient cooling, cooling to room temperature of 25 ℃ at the speed of 0.5-1 ℃/min, and storing at the temperature of 20-30 ℃.
In a preferred embodiment, the process parameters for mixing and homogenizing in S3 include a mixing speed of 35-40 rpm, a homogenizing speed of 1500-3000 rpm, and a time of 30-60 min.
The technical scheme of the invention has the beneficial effects that:
1. the progesterone sustained-release gel with stable particle size provided by the invention can maintain the particle size stability of a drug reservoir (emulsion drop-crystal), can realize slow drug release for 72 hours in vitro and in vivo, and is equivalent to the original preparation.
2. The invention provides a preparation process of progesterone sustained-release gel, wherein one part of raw material progesterone is dissolved in an oil phase, the other part of progesterone is dispersed in a water phase matrix after being wetted by glycerol, the oil phase and the water phase are mixed, the pH value is adjusted, the temperature reduction condition is strictly controlled, gradient temperature reduction is carried out, the temperature reduction homogeneity is not less than 1h, and the progesterone sustained-release gel with uniform particle size and uniform content is obtained.
Drawings
FIG. 1 is a flow chart of the preparation of a progesterone sustained release gel of the present invention;
FIG. 2 is a flow chart of the preparation of patent CN 1147301C;
FIG. 3 is a flow chart of the preparation of patent CN 202110717741.1.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments. The embodiments of the present invention have been presented for purposes of illustration and description, and are not intended to be exhaustive or limited to the invention in the form disclosed. Many modifications and variations will be apparent to practitioners skilled in this art. The embodiment was chosen and described in order to best explain the principles of the invention and the practical application, and to enable others of ordinary skill in the art to understand the invention for various embodiments with various modifications as are suited to the particular use contemplated.
Example 1
The technical scheme of the invention provides a stable progesterone sustained-release gel, which comprises an oil-phase raw material and a water-phase raw material, wherein the mass percentages of the oil-phase raw material and the water-phase raw material are shown as follows:
Figure BDA0003645966320000031
Figure BDA0003645966320000041
the preparation process comprises the following steps:
s1, aqueous gel preparation: adding sorbic acid and glycerol into purified water according to a certain proportion, boiling for dissolving, cooling to 50-55 ℃, adding polymer carbomer and polycarbophil, and stirring at constant temperature to obtain uniform water-phase gel;
s2, oil phase preparation: heating light liquid paraffin and hydrogenated palm oil glyceride to 50-55 deg.C for melting, adding progesterone 1, stirring for dissolving;
s3, preparation of progesterone vaginal gel: heating the water-phase gel to the same temperature as the oil phase, mixing and homogenizing the progesterone 2, the water-phase gel and the oil phase at the mixing rotation speed of 35-40 rpm, the homogenizing rotation speed of 1500-3000 rpm for 30-60 min, and then adding sodium hydroxide to adjust the pH value to 2.5-3.5;
s4, gradient cooling and storage: and continuously stirring and homogenizing the uniformly mixed gel, carrying out gradient cooling, cooling to room temperature of 25 ℃ at the speed of 0.5-1 ℃/min, storing at the temperature of 20-30 ℃, and keeping from refrigeration and freezing.
TABLE 1 content uniformity of progesterone sustained release gels
Serial number 1 2 3 4 5 6 7 8 9 10 Mean value of RSD％
Content (wt.) 100.1 100.1 99.8 98.3 100.6 99.1 98.3 100.0 101.1 98.5 99.6 0.98
Figure BDA0003645966320000042
Example 2 (same procedure as described in patent CN 1147301C):
Figure BDA0003645966320000043
Figure BDA0003645966320000051
preparing raw materials according to a prescription, and preparing the raw materials according to the following steps:
a. preparing water phase, adding sorbic acid into purified water according to the proportion of a prescription, and stirring for dissolving;
b. sequentially adding carbomer, polycarbophil and bulk drug progesterone into the water phase according to the formula proportion, heating and stirring to form a uniform gel phase, quickly stirring at 1500rpm, slowly stirring at 25rpm, and stirring for 2.5 hours; c. preparing oil phase, heating and melting glycerol, liquid paraffin and hydrogenated palm oil glyceride, and mixing uniformly;
d. heating the gel phase to the same temperature as the oil phase, mixing the two phases, rapidly stirring at 1500rpm, slowly stirring at 25rpm, and stirring for 2.5 hours;
e. and (5) cooling, continuously stirring the uniformly mixed gel, and cooling to room temperature to obtain a finished progesterone gel product.
f. Adding a proper amount of sodium hydroxide solution, and adjusting the pH value to 2.5-3.5.
TABLE 2 content uniformity of progesterone sustained release gels
Serial number 1 2 3 4 5 6 7 8 9 10 Mean value of RSD％
Content (wt.) 94.9 95.1 101.7 97.2 72.5 91.9 108.6 103.6 78.2 93.8 93.8 11.75
Figure BDA0003645966320000052
Example 3 (same procedure as described in patent CN 202110717741.1):
Figure BDA0003645966320000061
preparing raw materials according to a prescription, and preparing the raw materials according to the following steps:
a. preparing a premix of the bulk drugs and the polymer, uniformly mixing the progesterone, the carbomer and the polycarbophil in a mixing barrel according to the proportion of a prescription, mixing the mixture at the rotating speed of 10rpm for 6 minutes to obtain the premix,
b. preparing a water phase, namely adding glycerol and sorbic acid into purified water according to a formula ratio, stirring and dissolving, and stirring at a rotating speed of 10rpm for 1 hour;
c. adding the premix into the water phase under stirring, heating and stirring to form a uniform gel phase, quickly stirring at 1500rpm, slowly stirring at 25rpm, and stirring for 2.5 hours to obtain a hydrogel phase;
d. preparing oil phase, heating liquid paraffin and hydrogenated palm oil glyceride to 75 deg.C for melting, and mixing;
e. heating the hydrogel phase to the same temperature as the oil phase, mixing the two phases, rapidly stirring at 1500rpm, slowly stirring at 25rpm for 2.5 hours,
f. and (5) cooling, continuously stirring the uniformly mixed gel, and cooling to room temperature to obtain a progesterone vaginal gel finished product.
h. Adding a proper amount of sodium hydroxide solution, and adjusting the pH value to 2.5-3.5.
TABLE 3 content uniformity of progesterone sustained release gels
Serial number 1 2 3 4 5 6 7 8 9 10 Mean value of RSD％
Content (wt.) 90.1 102.9 98.0 101.6 72.5 95.4 88.1 102.7 96.6 102.3 95.0 9.97
Figure BDA0003645966320000071
Example 4: human pharmacokinetics
In a single dose crossover study, 8 healthy postmenopausal women were treated with estrogen
Figure BDA0003645966320000072
8% of vaginally administered 90mg progesterone, the pharmacokinetic parameters are given in Table 4 below:
Figure BDA0003645966320000073
the results show that product 1 has T in the human body max And AUC 0→∞ The product has no obvious difference with the Xuenong, the confidence interval is between 80 percent and 125 percent, the product is bioequivalent, and the products 2 and 3 are not equivalent to the Xuenong.
It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by one of ordinary skill in the art and related arts based on the embodiments of the present invention without any creative effort, shall fall within the protection scope of the present invention. Structures, devices, and methods of operation not specifically described or illustrated herein are generally practiced in the art without specific recitation or limitation.

Claims (4)

1. The stable progesterone sustained-release gel is characterized by comprising an oil-phase raw material and a water-phase raw material, wherein the oil-phase raw material comprises the following components in percentage by mass: 0.5-1.0% of progesterone, 4.2% of light liquid paraffin and 1.0% of hydrogenated palm oil glyceride; the water phase raw material comprises the following components in percentage by mass: 7.0-7.5% of progesterone 2, 12.9% of glycerol, 2.0% of carbomer 974p, 1.0% of polycarbophil, 0.08% of sorbic acid, 0.82% of sodium hydroxide and 70.0% of purified water.
2. The stable sustained release gel of progesterone according to claim 1 wherein the sum of the mass percentages of progesterone 1 and progesterone 2 is 8.0%.
3. A process for the preparation of a stable progesterone sustained release gel according to any one of claims 1-2 comprising the steps of:
s1, aqueous gel preparation: adding sorbic acid and glycerol into purified water according to a certain proportion, boiling for dissolving, cooling to 50-55 ℃, adding polymer carbomer and polycarbophil, and stirring at constant temperature to obtain uniform water-phase gel;
s2, oil phase preparation: heating light liquid paraffin and hydrogenated palm oil glyceride to 50-55 deg.C for melting, adding progesterone 1, stirring for dissolving;
s3, progesterone vaginal gel preparation: heating the water phase gel to the same temperature as the oil phase, mixing and homogenizing progesterone 2, the water phase gel preparation and the oil phase preparation, and adding sodium hydroxide to adjust the pH value to 2.5-3.5;
s4, gradient cooling and storage: and continuously stirring and homogenizing the uniformly mixed gel, carrying out gradient cooling, cooling to room temperature of 25 ℃ at the speed of 0.5-1 ℃/min, and storing at the temperature of 20-30 ℃.
4. The method for preparing a progesterone sustained-release gel according to claim 3, wherein the process parameters of mixing and homogenizing in S3 include 35-40 rpm for mixing, 1500-3000 rpm for homogenizing, and 30-60 min.
CN202210529454.2A 2022-05-16 2022-05-16 Stable progesterone sustained-release gel and preparation method thereof Pending CN114983929A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282250A (en) * 1997-10-21 2001-01-31 哥伦比亚实验室(百慕大)有限公司 Progestin therapy with controlled bleeding
CN103239389A (en) * 2013-06-03 2013-08-14 南京泽恒医药技术开发有限公司 Preparation method of progestin sustained-release gel for treating threatened abortion
CN108635330A (en) * 2018-04-17 2018-10-12 胡柳嘉 A kind of long-acting slow-release progesterone gel agent composition
CN113288865A (en) * 2021-06-28 2021-08-24 浙江仙琚制药股份有限公司 Preparation method of progesterone vaginal gel
CN114129507A (en) * 2021-07-13 2022-03-04 浙江仙琚制药股份有限公司 Progesterone gel composition and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1282250A (en) * 1997-10-21 2001-01-31 哥伦比亚实验室(百慕大)有限公司 Progestin therapy with controlled bleeding
CN103239389A (en) * 2013-06-03 2013-08-14 南京泽恒医药技术开发有限公司 Preparation method of progestin sustained-release gel for treating threatened abortion
CN108635330A (en) * 2018-04-17 2018-10-12 胡柳嘉 A kind of long-acting slow-release progesterone gel agent composition
CN113288865A (en) * 2021-06-28 2021-08-24 浙江仙琚制药股份有限公司 Preparation method of progesterone vaginal gel
CN114129507A (en) * 2021-07-13 2022-03-04 浙江仙琚制药股份有限公司 Progesterone gel composition and preparation method thereof

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