CN113288865B - Preparation method of progesterone vaginal gel - Google Patents

Preparation method of progesterone vaginal gel Download PDF

Info

Publication number
CN113288865B
CN113288865B CN202110717741.1A CN202110717741A CN113288865B CN 113288865 B CN113288865 B CN 113288865B CN 202110717741 A CN202110717741 A CN 202110717741A CN 113288865 B CN113288865 B CN 113288865B
Authority
CN
China
Prior art keywords
progesterone
stirring
preparation
gel
mixing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110717741.1A
Other languages
Chinese (zh)
Other versions
CN113288865A (en
Inventor
王咏
魏白
肖杨会
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Xianju Pharmaceutical Co Ltd
Original Assignee
Zhejiang Xianju Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Xianju Pharmaceutical Co Ltd filed Critical Zhejiang Xianju Pharmaceutical Co Ltd
Priority to CN202110717741.1A priority Critical patent/CN113288865B/en
Publication of CN113288865A publication Critical patent/CN113288865A/en
Application granted granted Critical
Publication of CN113288865B publication Critical patent/CN113288865B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants

Abstract

The invention belongs to the field of preparation of gynecological medicines, and particularly relates to a preparation method of progesterone vaginal gel, which comprises the steps of preparing a premix from a raw material medicine progesterone and a polymer, adding the premix into a water phase to obtain a hydrogel phase, adding a proper amount of sodium hydroxide solution, and adjusting the pH value to 2.5-3.5 to obtain the progesterone vaginal gel. The invention can effectively solve the problems of rapid swelling of polymers such as suspension gel, difficult control of content uniformity of raw material medicaments and the like in the preparation process of the progesterone vaginal gel, and simultaneously realizes the in vitro dissolution consistent with that of the original ground medicament.

Description

Preparation method of progesterone vaginal gel
Technical Field
The invention belongs to the field of medicine preparation, particularly relates to preparation of a gynecological medicine, and more particularly relates to a preparation method of progesterone vaginal gel.
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 the endometrium from the proliferative phase to the secretory phase, maintaining normal physiological changes.
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, wherein progesterone is partially dissolved in a water phase and an oil phase, most of the progesterone is dispersed in a gel system, so that a reservoir for prolonging the release of the medicament is formed, and when 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.
According to the description of the original drug patent literature (see DE ZIEGLER PROGESTERONE THERAPY WITH CONTROLLED BLEDING: WO99/20282, filing date: 1998.10.21), the gel preparation process is to prepare the polymer gel first, then add the raw materials into the gel for uniform dispersion, and finally add the gel phase to the oil phase for uniform mixing. 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.
Disclosure of Invention
Aiming at the problems and the defects of the prior art, the invention aims to solve the problems of rapid swelling of polymers such as suspension gel, difficult control of content uniformity of raw material medicines and the like in the preparation process of the progesterone vaginal gel, and simultaneously realize the consistency of in-vitro dissolution with the original ground medicines.
The purpose of the invention is implemented by the following technical scheme:
the invention provides a preparation method of progesterone vaginal gel, which comprises the following process steps:
(1) premix preparation
Uniformly mixing the raw material progesterone, the polymer carbomer and the polycarbophil in a mixing barrel according to the proportion of the prescription to obtain a premix of the progesterone, the polymer carbomer and the polycarbophil,
(2) preparation of aqueous phase
Adding sorbic acid and glycerin into purified water according to the proportion of the prescription, stirring for dissolving,
(3) preparation of hydrogel phase
Adding the premix obtained in the step (1) into the water phase obtained in the step (2) under the condition of stirring, heating and stirring to form a uniform hydrogel phase,
(4) preparation of the oil phase
Heating and melting liquid paraffin and hydrogenated palm oil, mixing uniformly,
(5) preparation of progesterone vaginal gel
Heating the hydrogel phase to the same temperature as the oil phase, and mixing the two phases; and then cooling, continuously stirring the uniformly mixed gel, cooling to room temperature, adding a proper amount of sodium hydroxide solution, and adjusting the pH value to 2.5-3.5 to obtain the progesterone vaginal gel.
The raw materials in the invention can be weighed according to the prescription (by mass percent) recorded in the existing literature:
Figure BDA0003135595530000021
the inventor researches and discovers that the progesterone serving as the raw material, the polymer carbomer and the polycarbophil are subjected to powder premixing firstly, the obtained premix is added into prepared glycerol and sorbic acid aqueous solution, the glycerol can promote wetting of the progesterone serving as the raw material and accelerate swelling of the polymer, the polymer can disperse the raw material while swelling, and the dispersion uniformity of the raw material is better. The process is simple to operate, can solve the problems of dispersion of suspended raw material medicines and swelling of polymers, enables the raw material medicines to be more uniformly embedded into a three-dimensional structure of the polymers, and achieves the biological adhesion and slow release results. The prepared sample has good mixing uniformity and the in vitro dissolution is similar to that of the original ground medicament.
Preferably, in the present invention, the main process parameters of the mixing in step (1) include the rotation speed of 5-30rpm and the time of 5-10 minutes.
Preferably, in the present invention, the main process parameters of the stirring in step (2) include the rotation speed of 10-40rpm and the time of 0.5-1 hour.
Preferably, in the present invention, the main process parameters of the stirring in step (3) include a rapid stirring speed of 10-40rpm, a slow stirring speed of 1000-3000rpm, and a time of 1-4 hours.
Preferably, in the present invention, the temperature for heating and melting in step (4) is 55 to 80 ℃.
Preferably, in the present invention, the main process parameters of the stirring in step (5) include a rapid stirring speed of 10-40rpm, a slow stirring speed of 1000-3000rpm, and a time of 1-4 hours.
Compared with the prior art, the invention has the following advantages: under the condition of not increasing production equipment, the problems of rapid swelling of polymer of suspension gel, difficult control of content uniformity of raw material medicines and the like in the prior art are effectively solved by adjusting production procedures, and the in-vitro dissolution is consistent with that of the original ground medicine.
The operation process is simple and is convenient for large-scale industrial production.
Drawings
FIG. 1 is a schematic diagram of the process for preparing progesterone gel of the present invention.
FIG. 2 is a schematic flow chart of the prior art (WO99/20282) process for preparing progesterone gel.
Figure 3 is a graph of dissolution profiles of comparative example 1 and comparative example 2 and the original drug.
FIG. 4 is a graph showing the dissolution profiles of example 1 and original drug of the present invention.
FIG. 5 is a graph showing the dissolution profiles of example 2 and original drug of the present invention.
FIG. 6 is a graph showing the dissolution profiles of example 3 and original drug of the present invention.
FIG. 7 is a graph showing the dissolution profiles of example 4 and original drug.
FIG. 8 is a graph showing the dissolution profiles of example 5 and original drug of the present invention.
FIG. 9 is a graph showing the dissolution profiles of example 6 and original drug of the present invention.
FIG. 10 is a graph showing the dissolution profiles of example 7 and original drug of the present invention.
FIG. 11 is a graph showing the dissolution profiles of example 8 and original drug of the present invention.
FIG. 12 is a graph showing the dissolution profiles of example 9 and original drug of the present invention.
FIG. 13 is a graph showing the dissolution profiles of example 10 and original drug.
FIG. 14 is a graph showing the dissolution profiles of example 11 and original drug of the present invention.
FIG. 15 is a graph showing the dissolution profiles of example 12 and original drug.
FIG. 16 is a graph showing the dissolution profiles of example 13 and original drug of the present invention.
FIG. 17 is a graph showing the dissolution profiles of example 14 and original drug of the present invention.
FIG. 18 is a graph showing the dissolution profiles of example 15 and original drug of the present invention.
Detailed Description
The present invention will be described in more detail with reference to examples. It is to be understood that the practice of the invention is not limited to the following examples, and that any variations and/or modifications may be made thereto without departing from the scope of the invention.
In the invention, all parts and percentages are weight units, and all equipment, raw materials and the like can be purchased from the market or are commonly used in the industry, if not specified. The methods in the following examples are conventional in the art unless otherwise specified.
One point of explanation:
the following formulation was used in the examples to prepare the raw materials (in mass percent):
Figure BDA0003135595530000031
Figure BDA0003135595530000041
comparative example 1 (same procedure as described in WO99/20282)
Preparing raw materials according to the prescription,
the preparation method comprises 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 proportion of the formula, heating and stirring until a uniform gel phase is formed, 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, 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.
The evaluation process comprises the following steps:
(1) and (3) appearance, namely observing whether undispersed polymers and bulk drugs exist after the hydrogel phase and the final product are prepared respectively.
(2) Uniformity of mixing
After the steps (b) and (e) are respectively completed, respectively sampling 10 points of different parts of the paste making tank to detect the content, and detecting the relative standard deviation of the mixing uniformity.
(3) Degree of release
The release of the sample from the diffusion cell within 72 hours was examined.
Appearance results: after the hydrogel phase is prepared, obvious white block substances are unevenly dispersed in the gel, and a large amount of white block substances still exist after the final finished product is prepared.
Mixing uniformity results:
TABLE 1
1 2 3 4 5 6 7 8 9 10 RSD％
Content%
70 120 68 95 76 50 148 80 120 150 35.74％
The release results are shown in figure 3.
The results, as reported in table 1 and fig. 3, show that:
when the mode of adding the polymer and the raw material medicine in sequence is adopted, the mixture cannot be uniformly mixed in the preparation process, the mixing uniformity is more than 20 percent, but the dissolution curve is greatly different from that of the original ground medicine and is not similar.
Comparative example 2 (slightly different from the method described in WO99/20282, the former patent adds glycerol to the oil phase and this comparative example adds glycerol to the water phase)
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
a. preparing water phase, adding glycerol and sorbic acid into purified water according to the proportion of the prescription, and stirring for dissolving;
b. sequentially adding carbomer, polycarbophil and bulk drug progesterone into the water phase according to the proportion of the formula, heating and stirring until a uniform gel phase is formed, quickly stirring at 1500rpm, slowly stirring at 25rpm, and stirring for 2.5 hours;
c. preparing an oil phase, namely heating and melting liquid paraffin and hydrogenated palm oil, and uniformly mixing;
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.
The evaluation process comprises the following steps: same as comparative example 1
Appearance results: after the preparation of the hydrogel phase is finished, obvious white block substances are unevenly dispersed in the gel, and after the preparation of the final finished product is finished, the white block substances are reduced but still exist in a large amount.
Mixing uniformity results:
TABLE 2
1 2 3 4 5 6 7 8 9 10 RSD％
Content%
90 105 70 100 80 103 150 85 99 110 21.92％
The release results are shown in figure 3.
The results, as reported in table 1 and fig. 3, show that:
when a mode of sequentially adding the polymer and the bulk drug is adopted, even if the glycerin is adjusted to be in a water phase, the problem that the glycerin cannot be uniformly mixed in the preparation process can not be completely solved, the mixing uniformity is more than 20%, but the dissolution curve is greatly different from that of the original ground drug and is not similar to that of the original ground drug.
Example 1
Preparing raw materials according to the prescription,
the preparation method comprises 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 to 75 ℃ for melting, and uniformly 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.
The evaluation process comprises the following steps:
(1) and (3) appearance, and observing whether undispersed polymers and bulk drugs exist after the preparation of the gel phase and the final product is finished respectively.
(2) Uniformity of mixing
After the step (c) and the step (f) are respectively completed, respectively sampling 10 points of different parts of the paste making tank to detect the content, and detecting the relative standard deviation of the mixing uniformity.
(3) Degree of release
The release of the sample from the diffusion cell within 72 hours was examined.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 4.
Example 2
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 30rpm, and the time is 5 minutes; heating to 55 ℃ for melting in the step d.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 5.
Example 3
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25rpm, and the time is 10 minutes; in step c, the mixture was stirred rapidly at 1000 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 6.
Example 4
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step c, the mixture was stirred rapidly at 3000rpm for 1.5 hours.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 7.
Example 5
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step c, the mixture is stirred slowly at 10 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 8.
Example 6
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step c, stirring was carried out slowly at 40 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 9.
Example 7
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; stirring time in step c was 1 hour.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 10.
Example 8
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; stirring time in step c was 4 hours.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 11.
Example 9
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step e, the mixture is stirred rapidly at 1000 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 12.
Example 10
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step e, 3000rpm was rapidly stirred.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 13.
Example 11
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step e, the mixture is stirred slowly at 10 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. Release Rate results are shown in FIG. 14
Example 12
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; in step e, stirring is carried out slowly at 40 rpm.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 15.
Example 13
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; stirring time in step e was 1 hour.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 16.
Example 14
Preparing raw materials according to the prescription,
the preparation method comprises the following steps:
the other points are the same as example 1: in the step a, the mixing speed is 25 rpm; heating to 8 ℃ for melting in the step d; stirring time in step e was 4 hours.
The procedure was as in example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 17.
Example 15
Preparing raw materials according to a prescription, wherein the content of progesterone bulk drug is 4%,
the procedure was as in example 1.
The procedure was as in comparative example 1.
The results of the evaluation of appearance and mixing uniformity are shown in Table 3. The release results are shown in figure 18.
TABLE 3 blending uniformity and appearance results for examples 1-15
Figure BDA0003135595530000091
The results according to table 3 and the accompanying figures 4 to 18 of the specification show that:
according to the preparation method, the problem of mixing uniformity can be effectively solved by adopting a mode of premixing the bulk drugs and the polymer, and through detection, the relative standard deviation of the mixing uniformity in the examples 1-15 is less than 2%, and the dissolution curves of all groups are basically consistent with those of the original medicine.

Claims (6)

1. A preparation method of progesterone vaginal gel is characterized by comprising the following process steps:
(1) premix preparation
Uniformly mixing the raw material progesterone, the polymer carbomer and the polycarbophil in a mixing barrel according to the proportion of the prescription to obtain a premix of the progesterone, the polymer carbomer and the polycarbophil,
(2) preparation of aqueous phase
Adding sorbic acid and glycerin into purified water according to the proportion of the prescription, stirring for dissolving,
(3) preparation of hydrogel phase
Adding the premix obtained in the step (1) into the water phase obtained in the step (2) under the condition of stirring, heating and stirring to form a uniform hydrogel phase,
(4) preparation of the oil phase
Heating and melting liquid paraffin and hydrogenated palm oil, mixing uniformly,
(5) preparation of progesterone vaginal gel
Heating the hydrogel phase to the same temperature as the oil phase, and mixing the two phases; and then cooling, continuously stirring the uniformly mixed gel, cooling to room temperature, adding a proper amount of sodium hydroxide solution, and adjusting the pH value to 2.5-3.5 to obtain the progesterone vaginal gel.
2. The method for preparing vaginal progesterone gel according to claim 1 wherein the main process parameters of mixing in step (1) include rotation speed of 10-30rpm for 5-10 minutes.
3. The method for preparing vaginal progesterone gel according to claim 1, wherein the main process parameters of the stirring in step (2) include the rotation speed of 10-40rpm for 0.5-1 hour.
4. The method for preparing progesterone vaginal gel according to claim 1, wherein the main process parameters of the stirring in step (3) include a fast stirring speed of 10-40rpm, a slow stirring speed of 1000-3000rpm, and a time of 1-4 hours.
5. The method for preparing vaginal gel of progesterone according to claim 1, wherein the heating and melting temperature in step (4) is 55-80 ℃.
6. The method for preparing progesterone vaginal gel according to claim 1, wherein the main process parameters of the stirring in step (5) include a fast stirring speed of 10-40rpm, a slow stirring speed of 1000-3000rpm, and a time of 1-4 hours.
CN202110717741.1A 2021-06-28 2021-06-28 Preparation method of progesterone vaginal gel Active CN113288865B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110717741.1A CN113288865B (en) 2021-06-28 2021-06-28 Preparation method of progesterone vaginal gel

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110717741.1A CN113288865B (en) 2021-06-28 2021-06-28 Preparation method of progesterone vaginal gel

Publications (2)

Publication Number Publication Date
CN113288865A CN113288865A (en) 2021-08-24
CN113288865B true CN113288865B (en) 2022-03-08

Family

ID=77329815

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110717741.1A Active CN113288865B (en) 2021-06-28 2021-06-28 Preparation method of progesterone vaginal gel

Country Status (1)

Country Link
CN (1) CN113288865B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113995715A (en) * 2021-11-16 2022-02-01 药大制药有限公司 Progesterone gel preparation and preparation process thereof
CN114983929A (en) * 2022-05-16 2022-09-02 安徽万邦医药科技股份有限公司 Stable progesterone sustained-release gel and preparation method thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306914B1 (en) * 1997-10-21 2001-10-23 Columbia Laboratories, Inc. Progestin therapy for maintaining amenorrhea
US10016442B2 (en) * 2005-06-16 2018-07-10 Allergan Pharmaceuticals International Limited Estrogen compositions for vaginal administration
CN101002788A (en) * 2006-01-20 2007-07-25 天津药物研究院 Nasal use gel containing active component of methyl astragaloside

Also Published As

Publication number Publication date
CN113288865A (en) 2021-08-24

Similar Documents

Publication Publication Date Title
CN113288865B (en) Preparation method of progesterone vaginal gel
EP0662320B1 (en) Dry gel composition
JP3105307B2 (en) Continuous production of solubilized β-carotene
CN109125276A (en) A kind of pharmaceutical composition and preparation method thereof of Abiraterone acetate tablet
CN102525884A (en) Thermosensitive in-situ gel preparation for vaginal administration
CN103494774B (en) Preparation method of decoquinate dry suspension
CN104721155B (en) A kind of temozolomide freeze-dried powder preparation and preparation method thereof
DE3503679C2 (en)
CN102727454B (en) Evodiamine dispersion tablets and preparation method thereof
Małolepsza-Jarmołowska et al. Studies on gynaecological hydrophilic lactic acid preparationsPart 5: The use of Eudragit® E-100 as lactic acid carrier in intravaginal tablets
WO2019205030A1 (en) Amantadine hydrochloride soft capsule and preparation method therefor
CN101732235B (en) Method for preparing solid dispersion of tamoxifen citrate
CN108785268B (en) Sotalol hydrochloride preparation and preparation method thereof
CN112336699A (en) Progesterone vaginal slow-release soft capsule and its preparation method
CN110123770A (en) A kind of Eliquis pharmaceutical composition and preparation method thereof
CN114983929A (en) Stable progesterone sustained-release gel and preparation method thereof
CN114601966A (en) Sodium hyaluronate gel lubricating liquid, filler, preparation method and application thereof
CN112121006B (en) Vitamin ADE composition for injection livestock and preparation method thereof
CN113520990A (en) Progesterone thermo-sensitive gel injection and its preparation method
CN114129507A (en) Progesterone gel composition and preparation method thereof
JP2556071B2 (en) Suppository
CN113995715A (en) Progesterone gel preparation and preparation process thereof
CN105106106A (en) Preparation method of vaccarin ointment
CN117771161A (en) De-specification cream and preparation method thereof
CN117084967A (en) Preparation method and application of progesterone sustained-release gel for vaginal administration

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant