CN117084967A - Preparation method and application of progesterone sustained-release gel for vaginal administration - Google Patents
Preparation method and application of progesterone sustained-release gel for vaginal administration Download PDFInfo
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- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 201
- 239000000186 progesterone Substances 0.000 title claims abstract description 100
- 229960003387 progesterone Drugs 0.000 title claims abstract description 100
- 238000013268 sustained release Methods 0.000 title claims abstract description 53
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000012071 phase Substances 0.000 claims abstract description 72
- 229920000148 Polycarbophil calcium Polymers 0.000 claims abstract description 55
- 229950005134 polycarbophil Drugs 0.000 claims abstract description 55
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 41
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 41
- 239000000661 sodium alginate Substances 0.000 claims abstract description 41
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 41
- 238000004090 dissolution Methods 0.000 claims abstract description 28
- 238000002156 mixing Methods 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 24
- 239000008346 aqueous phase Substances 0.000 claims abstract description 21
- 239000000843 powder Substances 0.000 claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims description 71
- 238000005303 weighing Methods 0.000 claims description 35
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 31
- 238000010438 heat treatment Methods 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 26
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 25
- 229940075582 sorbic acid Drugs 0.000 claims description 25
- 235000010199 sorbic acid Nutrition 0.000 claims description 25
- 239000004334 sorbic acid Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000008367 deionised water Substances 0.000 claims description 22
- 229910021641 deionized water Inorganic materials 0.000 claims description 22
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 11
- 235000011187 glycerol Nutrition 0.000 claims description 11
- 229940049654 glyceryl behenate Drugs 0.000 claims description 11
- 229940057995 liquid paraffin Drugs 0.000 claims description 11
- 238000002791 soaking Methods 0.000 claims description 11
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 9
- 238000000227 grinding Methods 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 230000035558 fertility Effects 0.000 claims description 2
- 229960005150 glycerol Drugs 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 238000013265 extended release Methods 0.000 claims 2
- 208000034423 Delivery Diseases 0.000 claims 1
- 230000009677 vaginal delivery Effects 0.000 claims 1
- 238000000338 in vitro Methods 0.000 abstract description 17
- 239000011159 matrix material Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000499 gel Substances 0.000 description 76
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 8
- 229920001992 poloxamer 407 Polymers 0.000 description 8
- 229940044476 poloxamer 407 Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000012216 screening Methods 0.000 description 6
- 229920001661 Chitosan Polymers 0.000 description 5
- 229940045110 chitosan Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 210000004996 female reproductive system Anatomy 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000000938 luteal effect Effects 0.000 description 1
- 230000029849 luteinization Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
Classifications
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- 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
- A61K47/30—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
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
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- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- 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
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- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Gynecology & Obstetrics (AREA)
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- Endocrinology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Urology & Nephrology (AREA)
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Abstract
The invention provides a preparation method and application of a progesterone sustained-release gel for vaginal administration. On one hand, the gel matrix is selected to be the combination of sodium alginate and polycarbophil, and the in-vitro dissolution release rate is highest when the use ratio of the sodium alginate to the polycarbophil is 2.6:1. On the other hand, the optimal process for preparing the progesterone sustained-release gel is as follows: the in vitro dissolution rate and the bioavailability of the obtained progesterone sustained-release gel are highest when the particle size of the progesterone micropowder is 15 mu m, the dosage ratio of the coarse powder of the progesterone raw material to the gel matrix (sodium alginate and polycarbophil) is 5:6, and the mixing temperature of the C aqueous phase gel and the C phase gel is 40 ℃.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method and application of a progesterone sustained-release gel for vaginal administration.
Background
Progesterone is an important component for regulating female reproductive system, and its main physiological function is to identify and maintain pregnancy of animals, and its action site is on uterus muscle and endometrium, and has auxiliary effect on fertilized ovum implantation, and is necessary hormone for maintaining pregnancy. Progestin will act in concert with estrogens to regulate various changes in the reproductive phase of the body.
Progesterone is widely used in gynecological diseases, especially in Hormone Replacement Therapy (HRT) with estrogen, and can effectively avoid adverse effects caused by estrogen. Progesterone is commonly administered orally, by injection, vaginally, but natural progesterone is poorly absorbed orally and has a strong first pass effect. Compared with oral preparations, the intramuscular injection of progesterone has long history of application, and the intramuscular injection of progesterone has more complete medicine absorption and relatively low price, but the use of the progesterone injection preparation requires patients to inject into hospitals, has traumata, and the oily preparation is the most common form, can cause the adverse reactions such as red swelling, itching, hard mass and the like at injection sites, and can cause abscess at the injection sites after long-term administration, and the adverse reactions usually require a period of several weeks to recover, and can cause inconvenient influence on the life of the patients during the period.
Compared with other administration systems, the vaginal administration system has a plurality of characteristics and advantages, such as the medicine absorbed by vagina can not only locally play a role, but also play a role in systemic treatment, the bioavailability is high, and the like, and the vaginal administration mode of progesterone has longer application, so that the preparation is convenient to take, can be automatically administered by patients, has no traumatism, directly acts on target positions, and is more fully absorbed. However, in the current preparation of vaginal administration preparations of progesterone, aggregation of bulk drugs cannot be dispersed or aggregation and fusion occur during cooling and storage, thereby affecting the absorption rate and the availability. Therefore, how to increase the bioavailability of progesterone has become a key issue in the use of progesterone.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method and application of a progesterone sustained-release gel for vaginal administration.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
firstly, the invention provides a preparation method of a progesterone sustained-release gel for vaginal administration, which comprises the following steps:
s1, weighing polycarbophil according to parts by weight, adding deionized water with the amount of 0.5-2 times that of the polycarbophil, soaking for 6-12 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing sorbic acid according to parts by weight, placing the sorbic acid into a container, adding deionized water with the dosage of 1.5-5.5 times of that of the sorbic acid, carrying out ultrasonic dissolution for 5-12min, then slowly adding sodium alginate with the formula proportion for a plurality of times, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 45-65 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing glycerol, liquid paraffin and glyceryl behenate according to parts by weight, heating at 35-42 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing coarse powder of the progesterone raw material according to parts by weight, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 10-30 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 40-55 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, adding triethanolamine, and regulating the pH value to 3.5-5.5 to obtain the progesterone sustained-release gel.
Further, the raw material dosage range is: 10-20 parts of progesterone raw material coarse powder, 0.5-5 parts of polycarbophil, 2-10 parts of sodium alginate, 0.1-1 part of sorbic acid, 2-6 parts of glycerin, 1-3 parts of liquid paraffin and 0.2-1.5 parts of glyceryl behenate.
Further, the dosage ratio of the sodium alginate to the polycarbophil is 2:1-3.2:1;
furthermore, the dosage ratio of sodium alginate to polycarbophil is 2.6:1.
Further, the deionized water dosage in the step S1 is 1.5 times, and the soaking time is 10 hours;
further, the deionized water dosage in the step S2 is 4 times, and the ultrasonic dissolution time is 8min;
further, the heating temperature in the step S3 is 55 ℃, and the heating temperature in the step S4 is 40 ℃;
further, the particle size of the progesterone micropowder in step S5 is 15 μm;
further, in step S6, the mixing temperature of the hydrogel and the C phase is 40 ℃, and the pH value is adjusted to 4.5.
Secondly, the invention provides application of the progesterone sustained-release gel in preparation of progesterone supplements in assisted fertility.
The beneficial effects of the invention are as follows:
(1) Through screening the common slow-release gel matrix raw materials, the inventor finds that the slow-release rate is not only stable in release, but also highest, and the release rate reaches about 95.5% after 24 hours of release by using the combination of sodium alginate and polycarbophil; on the basis, the optimal screening is carried out on the use proportion of the two, and the in-vitro dissolution release rate is highest, reaches about 96.6% and is stable when the use proportion of the two is 2.6:1.
(2) After determining the use proportion of sodium alginate and polycarbophil, the inventor performs screening of the optimal process on each parameter for preparing the progesterone sustained-release gel, and the optimal preparation process is as follows: the in vitro dissolution rate and the bioavailability of the obtained progesterone sustained-release gel are highest when the particle size of the progesterone micropowder is 15 mu m, the dosage ratio of the coarse powder of the progesterone raw material to the gel matrix (sodium alginate and polycarbophil) is 5:6, and the mixing temperature of the C aqueous phase gel and the C phase gel is 40 ℃.
(3) The progesterone sustained-release gel prepared by the invention has the advantages of simple preparation method, easy operation, suitability for industrial production, safe and non-toxic raw materials, very stable raw materials, high release rate and high bioavailability, can realize continuous drug release after vaginal administration, and is suitable for supplementing progesterone for women.
Drawings
FIG. 1 is a graph showing the effect of different matrix materials on the in vitro dissolution release rate of a progesterone sustained release gel;
FIG. 2 shows the effect of the ratio of sodium alginate to polycarbophil on the in vitro dissolution release rate of a progesterone sustained release gel.
Detailed Description
For a better understanding of the present invention, embodiments of the present invention are described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.
Experimental example 1: screening of gel matrices
Gel matrices commonly used for preparing gel formulations were selected empirically: poloxamer 407, sodium alginate, polycarbophil and chitosan, and 4 raw materials are combined in pairs, and the combination is subjected to in vitro dissolution release rate measurement, so that the optimal matrix combination is determined. Firstly, poloxamer 407, sodium alginate, polycarbophil and chitosan are combined to obtain 1-6 groups which are respectively: poloxamer 407+sodium alginate, poloxamer 407+polycarbophil, poloxamer 407+chitosan, sodium alginate+polycarbophil, sodium alginate+chitosan, polycarbophil+chitosan.
The preparation method of the 1 st group comprises the following steps: weighing poloxamer 407 with the weight of 4g, adding 6g of deionized water, soaking for 8h, and fully stirring until the poloxamer 407 is fully swelled into a uniform polymer to obtain a phase A; placing 0.8g of sorbic acid in a container, adding 2.4g of deionized water, performing ultrasonic dissolution for 5min, slowly adding 10g of sodium alginate for many times, continuously stirring, and uniformly mixing to obtain phase B; heating at 50deg.C, slowly adding phase B into phase A under stirring, and stirring to form uniform water phase gel; weighing 5g of glycerol, 2.5g of liquid paraffin and 1.3g of glyceryl behenate, heating at 36 ℃ to melt, and fully and uniformly stirring to obtain a phase C; weighing 15g of progesterone raw material coarse powder, and carrying out superfine grinding to obtain progesterone micro powder with the particle size of 20 mu m; heating the aqueous phase gel and the C phase to 45 ℃, mixing the two phases, continuously stirring, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 3.5 to obtain the progesterone sustained-release gel. When the sustained-release gel is prepared in the 2-6 groups, poloxamer 407 and sodium alginate are respectively replaced by the combination in the 2-6 groups, and the rest methods and dosage parameters are the same as those of the preparation method in the 1 group. After the progesterone sustained-release gel prepared in groups 1-6 is obtained, the in vitro dissolution and release rate of the progesterone sustained-release gel in 24 hours is measured. The method for measuring the in vitro dissolution release rate comprises the following steps: the drug concentration is measured by high performance liquid chromatography and the dissolution rate is calculated, and referring to the relevant documents published by FDA, the in vitro dissolution of progesterone vaginal sustained-release gel is carried out by adopting a first method (basket method) device of pharmacopoeia, the dissolution medium is 1000mL of 20% methanol-water, the temperature is (37+/-1) DEG C, the rotating speed is 100rpm, 100 mg+/-2% of the preparation is placed in the center of a 0.45 mu m microporous filter membrane, the membrane is fixed at the bottom of the rotating basket, sampling is carried out at 0h, 2h, 4h, 8h, 16h and 24h, the sample is filtered by adopting a 0.45 mu m filter membrane, the concentration of the dissolved sample is measured by adopting an HPLC method, and the release rate is calculated. Each set of experiments was repeated 3 times. The results are shown in FIG. 1.
According to the results of fig. 1, it can be seen that the in vitro release rate of the luteal sustained-release gel prepared by using the combination of sodium alginate and polycarbophil as a gel matrix is highest and reaches about 95.5%, and the release is stable.
Experimental example 2: screening of sodium alginate and polycarbophil dosage proportion
From the results of experimental example 1, it was found that the release effect was the best when the gel matrix was sodium alginate+polycarbophil, and thus sodium alginate and polycarbophil were selected as the gel matrices for the subsequent experiments. According to the dosage ratio of sodium alginate to polycarbophil of 2.5:1 in experimental example 1, the dosage ratio of sodium alginate to polycarbophil is set as follows: 2:1, 2.3:1, 2.6:1, 2.9:1 and 3.2:1, and the preparation method is the same as that in experimental example 1, respectively preparing the progesterone sustained-release gel, and measuring the in vitro dissolution rate of the progesterone sustained-release gel by using the same method, wherein each group of experiments is repeated 3 times. The results are shown in FIG. 2.
According to the results of fig. 2, it can be seen that the in vitro release rate of the prepared luteal phase slow-release gel is highest and reaches about 96.6% when the dosage ratio of sodium alginate to polycarbophil is 2.6:1, and the release is stable. Therefore, the dosage ratio of the subsequent sodium alginate to the polycarbophil is 2.6:1.
Experimental example 3: screening of the best Process for the preparation method
As described above, the preparation method of the progesterone sustained-release gel is screened by the optimal process on the basis that the dosage ratio of sodium alginate to polycarbophil is 2.6:1. The specific preparation method was the same as in experimental example 1, and the orthogonal test was performed, and each set of test was repeated 3 times, and the in vitro dissolution rate of each set of sustained release gel was determined. Each set of experiments was repeated 3 times.
Wherein, the orthogonal test is designed as follows: according to the main influencing factors of the production process, the particle size of the raw material medicine progesterone, the dosage proportion of the progesterone to the gel matrix (sodium alginate and polycarbophil) and the mixing temperature of the aqueous gel and the C phase, three-factor four-level orthogonal tests are carried out, and the factor level arrangement is shown in table 1.
TABLE 1 level of orthogonal test factors
The results of the orthogonal test are shown in Table 2.
TABLE 2 results of orthogonal experiments
As can be seen from table 2, the sustained-release gel prepared in test No. 13 has the highest dissolution release rate of 99.1±0.6%, i.e., the optimum production process of the progesterone sustained-release gel for vaginal administration according to the present invention is: the in vitro dissolution rate and the bioavailability of the obtained progesterone sustained-release gel are highest when the particle size of the progesterone micropowder is 15 mu m, the dosage ratio of the coarse powder of the progesterone raw material to the gel matrix (sodium alginate and polycarbophil) is 5:6, and the mixing temperature of the C aqueous phase gel and the C phase gel is 40 ℃.
From the above experimental results, it can be seen that, on one hand, when the gel matrix is a combination of sodium alginate and polycarbophil and the ratio of the two is 2.6:1, the in vitro dissolution release rate is the highest. On the other hand, the optimal process for preparing the progesterone sustained-release gel is as follows: the in vitro dissolution rate and the bioavailability of the obtained progesterone sustained-release gel are highest when the particle size of the progesterone micropowder is 15 mu m, the dosage ratio of the coarse powder of the progesterone raw material to the gel matrix (sodium alginate and polycarbophil) is 5:6, and the mixing temperature of the C aqueous phase gel and the C phase gel is 40 ℃. Therefore, the progesterone sustained-release gel prepared by the invention has the advantages of simple and easy operation, suitability for industrial production, safe and non-toxic raw materials, very stable and high release rate and high bioavailability, can realize continuous drug release after vaginal administration, and is suitable for supplementing progesterone for women.
Example 1:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 5g of polycarbophil, adding deionized water with the amount being 2 times that of the polycarbophil, soaking for 12 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 1g of sorbic acid, placing in a container, adding deionized water with the amount being 5.5 times that of sorbic acid, carrying out ultrasonic dissolution for 12min, slowly and repeatedly adding 10g of sodium alginate for a small amount, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 65 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 6g of glycerol, 3g of liquid paraffin and 1.5g of glyceryl behenate, heating at 42 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 20g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 30 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 50 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 5.5 to obtain the progesterone sustained-release gel.
Example 2:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 5g of polycarbophil, adding deionized water 1.5 times of the polycarbophil, soaking for 8 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 2g of sorbic acid, placing the sorbic acid in a container, adding deionized water with the amount being 3.5 times that of the sorbic acid, carrying out ultrasonic dissolution for 11min, then slowly adding 15g of sodium alginate for many times in a small amount, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 60 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 25g of glycerol, 12g of liquid paraffin and 3g of glyceryl behenate, heating at 40 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 100g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 20 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 55 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 5.0 to obtain the progesterone sustained-release gel.
Example 3:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 40g of polycarbophil, adding deionized water with the amount of 1.8 times that of the polycarbophil, soaking for 9 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 0.8g of sorbic acid, placing the sorbic acid in a container, adding deionized water with the amount being 2.8 times that of the sorbic acid, carrying out ultrasonic dissolution for 6min, then slowly adding 70g of sodium alginate for many times in a small amount, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 65 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 30g of glycerol, 15g of liquid paraffin and 2g of glyceryl behenate, heating at 38 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 150g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 12 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 40 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 4.0 to obtain the progesterone sustained-release gel.
Example 4:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 200g of polycarbophil, adding deionized water 1.8 times of the polycarbophil, soaking for 8 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 60g of sorbic acid, placing the sorbic acid in a container, adding deionized water with the amount being 2 times that of the sorbic acid, carrying out ultrasonic dissolution for 7min, then slowly adding 600g of sodium alginate for many times in a small amount, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 65 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 300g of glycerol, 100g of liquid paraffin and 20g of glyceryl behenate, heating at 35 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 1000g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 10 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 45 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 3.8 to obtain the progesterone sustained-release gel.
Example 5:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 4g of polycarbophil, adding deionized water 1.5 times of the polycarbophil, soaking for 8 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 0.8g of sorbic acid, placing the sorbic acid in a container, adding deionized water 3 times of the sorbic acid, performing ultrasonic dissolution for 5min, slowly and repeatedly adding 10g of sodium alginate for a small amount, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 55 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 5g of glycerol, 2.5g of liquid paraffin and 1.3g of glyceryl behenate, heating at 36 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 15g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 15 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 40 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 3.5 to obtain the progesterone sustained-release gel.
Example 6:
a method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing 10g of polycarbophil, adding deionized water 1.5 times of the polycarbophil, soaking for 10 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing 1g of sorbic acid, placing in a container, adding deionized water with the amount being 4 times that of the sorbic acid, carrying out ultrasonic dissolution for 8min, slowly and repeatedly adding 26g of sodium alginate, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 55 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing 8g of glycerol, 5g of liquid paraffin and 2g of glyceryl behenate, heating at 40 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing 30g of coarse powder of the progesterone raw material, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 15 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 40 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, and adding triethanolamine to adjust the pH value to 4.5 to obtain the progesterone sustained-release gel.
The applicant states that the present invention is illustrated by the above examples as a method for preparing and using a sustained-release gel for vaginal administration of progesterone according to the present invention, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced by relying on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A method for preparing a progesterone sustained release gel for vaginal administration, comprising the steps of:
s1, weighing polycarbophil according to parts by weight, adding deionized water with the amount of 0.5-2 times that of the polycarbophil, soaking for 6-12 hours, and fully stirring until the polycarbophil is fully swelled into a uniform polymer to obtain a phase A for later use;
s2, weighing sorbic acid according to parts by weight, placing the sorbic acid into a container, adding deionized water with the dosage of 1.5-5.5 times of that of the sorbic acid, carrying out ultrasonic dissolution for 5-12min, then slowly adding sodium alginate with the formula proportion for a plurality of times, continuously stirring, and uniformly mixing to obtain a phase B for later use;
s3, heating at 45-65 ℃, slowly adding the phase B into the phase A while stirring, and continuously stirring until uniform aqueous phase gel is formed for later use;
s4, weighing glycerol, liquid paraffin and glyceryl behenate according to parts by weight, heating at 35-42 ℃ to melt, and fully and uniformly stirring to obtain a C phase for later use;
s5, weighing coarse powder of the progesterone raw material according to parts by weight, and carrying out superfine grinding to obtain progesterone micropowder with the particle size of 10-30 mu m for later use;
s6, heating the aqueous phase gel and the C phase to 40-55 ℃, mixing the two phases, continuously stirring, stirring uniformly, adding a small amount of progesterone micropowder for many times while stirring uniformly, adding triethanolamine, and regulating the pH value to 3.5-5.5 to obtain the progesterone sustained-release gel.
2. The method for preparing a sustained-release gel for vaginal administration according to claim 1, wherein the raw materials are used in the following range: 10-20 parts of progesterone raw material coarse powder, 0.5-5 parts of polycarbophil, 2-10 parts of sodium alginate, 0.1-1 part of sorbic acid, 2-6 parts of glycerin, 1-3 parts of liquid paraffin and 0.2-1.5 parts of glyceryl behenate.
3. The method for preparing a sustained-release gel for vaginal administration as claimed in claim 2, wherein the dosage ratio of sodium alginate to polycarbophil is 2:1-3.2:1.
4. A method of preparing a vaginal delivery extended release gel of progesterone according to claim 3 wherein the ratio of sodium alginate to polycarbophil is 2.6:1.
5. The method for preparing a sustained-release gel for vaginal administration according to claim 1, wherein the deionized water is used in the step S1 in an amount of 1.5 times and the soaking time is 10 hours.
6. The method for preparing a sustained-release gel for vaginal administration according to claim 1, wherein the deionized water is used in the step S2 in an amount of 4 times and the ultrasonic dissolution time is 8min.
7. The method for preparing a sustained-release gel for vaginal administration according to claim 1, wherein the heating temperature in step S3 is 55 ℃ and the heating temperature in step S4 is 40 ℃.
8. The method for preparing a sustained-release gel for vaginal administration as claimed in claim 1, wherein the particle size of the fine powder of progesterone in step S5 is 15 μm.
9. The method for preparing a sustained-release gel for vaginal administration as claimed in claim 1, wherein the mixing temperature of the aqueous gel and the C phase in step S6 is 40 ℃, and the pH is adjusted to 4.5.
10. Use of a progesterone extended release gel prepared by the method of any one of claims 1-9 for the preparation of a progesterone supplement for assisted fertility.
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