CN116459212B - Water-soluble progesterone injection and preparation method thereof - Google Patents
Water-soluble progesterone injection and preparation method thereof Download PDFInfo
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- CN116459212B CN116459212B CN202310471820.8A CN202310471820A CN116459212B CN 116459212 B CN116459212 B CN 116459212B CN 202310471820 A CN202310471820 A CN 202310471820A CN 116459212 B CN116459212 B CN 116459212B
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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 223
- 239000000186 progesterone Substances 0.000 title claims abstract description 111
- 229960003387 progesterone Drugs 0.000 title claims abstract description 111
- 238000002347 injection Methods 0.000 title claims abstract description 65
- 239000007924 injection Substances 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 35
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000004695 Polyether sulfone Substances 0.000 claims abstract description 28
- 229920006393 polyether sulfone Polymers 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 20
- 238000000265 homogenisation Methods 0.000 claims abstract description 19
- 239000008215 water for injection Substances 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 16
- 230000001954 sterilising effect Effects 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 230000001502 supplementing effect Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 13
- 238000009472 formulation Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 208000008899 Habitual abortion Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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
- A61K47/30—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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
-
- 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
Abstract
The invention relates to the technical field of pharmaceutical preparations, and in particular discloses a water-soluble progesterone injection and a preparation method thereof. The invention can improve the water solubility of progesterone and reduce the dosage of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin by matching the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin with different sizes of annular hollow structures; by high-pressure homogenization, control of the temperature of water for injection and filtration of the multistage polyethersulfone filter core, the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin can be better compounded with the progesterone, and the solubility of the progesterone in water is improved. The water-soluble progesterone injection provided by the invention has very important significance for improving the medication safety of patients.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a water-soluble progesterone injection and a preparation method thereof.
Background
Progesterone is a sex hormone drug commonly used in clinic, and is mainly used for treating menstrual disorder, habitual abortion and premenstrual tension syndrome clinically, and is used with estrogen cycle to resist the action of pure estrogen on endomembrane.
Progesterone is insoluble in water and currently available in the market mainly comprises oral preparations and injections. The injection on the market in China usually takes oil as a solvent, the injection has large pain response and is easy to be allergic when being injected, the muscle tissue is easy to form a tumor after long-term injection, and the water-soluble progesterone injection can avoid the problems. Cyclodextrin derivatives are used to increase the water solubility of progesterone because of their specific structure, which is hydrophilic and hydrophobic in the outside, but the cyclodextrin derivatives are generally used in higher amounts when they are used alone as solubilizers. There are studies to reduce the amount of cyclodextrin derivative-based solubilizing agents by adding an organic solvent, other solubilizing agents or accelerators, but this brings about potential safety hazards to clinical medication.
Disclosure of Invention
In view of the above, the present invention provides a water-soluble progesterone injection and a preparation method thereof. The invention can further improve the water solubility of progesterone and reduce the dosage of the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin by using the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin in a matching way; by high-pressure homogenization, control of the temperature of water for injection and filtration of the multistage polyethersulfone filter core, the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin can be better compounded with the progesterone, and the solubility of the progesterone in water is improved.
In order to achieve the above purpose, the technical scheme provided by the invention is as follows:
the invention provides a water-soluble progesterone injection, which comprises progesterone, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin and water for injection.
The inventors have found by accident through extensive experiments that when hydroxypropyl-beta-cyclodextrin or hydroxypropyl-gamma-cyclodextrin is used alone as a solubiliser, a larger amount is often required to achieve better solubilisation of the progestin. The hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin with different sizes and ring-shaped hollow structures are matched for use and are compounded with the progesterone, so that the water solubility of the progesterone can be improved, the dosage of the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin is reduced, and the water-soluble progesterone injection provided by the invention has very important significance for improving the medication safety of patients.
Optionally, the weight ratio of the hydroxypropyl-beta-cyclodextrin to the hydroxypropyl-gamma-cyclodextrin is 2:1-3:1. By limiting the weight ratio of the hydroxypropyl-beta-cyclodextrin to the hydroxypropyl-gamma-cyclodextrin, the complexing effect of the hydroxypropyl-beta-cyclodextrin and the progesterone can be further improved, and the water solubility of the systemic ketone can be improved.
Optionally, the weight ratio of the total dosage of the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin to the progesterone is 4:1-8:1.
Alternatively, the water-soluble progesterone injection is 1mL:5mg,1mL:10mg,1mL:20mg.
The invention also provides a preparation method of the water-soluble progesterone injection, which comprises the following steps:
step a, adding injection water with the total volume of 50-60% and hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin with the prescription amount into a preparation tank, uniformly mixing, then adding progesterone with the prescription amount, supplementing the injection water to the total volume of preparation, and stirring to obtain progesterone suspension;
step b, carrying out high-pressure homogenization treatment on the progesterone suspension to obtain progesterone liquid medicine;
step c, filtering the progesterone liquid medicine through a multistage polyethersulfone filter element with sequentially reduced pore diameters, filling, sealing and sterilizing to obtain a water-soluble progesterone injection;
in the step a, the temperature of the water for injection is 50-60 ℃.
The invention controls the temperature of water for injection and the filtration of the multistage polyethersulfone filter core through high-pressure homogenization treatment, so that the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin are better compounded with the progesterone, and the solubility of the progesterone in water is improved. Through high-pressure homogenization treatment, the particle size of the progesterone is crushed to be micro-level or even nano-level through the comprehensive actions of shearing force, collision effect, space explosive force and the like on the basis of not changing the original molecular structure of the progesterone, and then the solubilization effect on the progesterone is realized through the matched use of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin with different-size annular hollow structures.
The preparation method provided by the invention is simple, is convenient for realizing industrial production, and has a good application prospect.
Optionally, the high-pressure homogenization temperature is 50-60 ℃, the pressure is 20-30 MPa, the time is 25-30 min, and the cycle times are 1-3.
Optionally, the multi-stage filter element is a two-stage polyethersulfone filter element, wherein the aperture of the first-stage polyethersulfone filter element is 0.45 μm, and the aperture of the second-stage polyethersulfone filter element is 0.2 μm. The invention adopts the multilevel polyethersulfone filter core with specific aperture to filter in sequence, thereby ensuring that the bacterial and endotoxin contents of the product are qualified; the method does not adopt active carbon in the production process, reduces pollution to a clean area, lightens environmental protection pressure, reduces impurities and insoluble particles possibly introduced by the active carbon, and is beneficial to further improving the effectiveness, safety and stability of the product quality.
Optionally, in the step c, the sterilization is performed at 121 ℃ for 8-15 min. The invention adopts a terminal sterilization method, thereby improving the sterility level and sterilization efficiency of the product.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
In order to better illustrate the present invention, the following examples are provided for further illustration.
Example 1
The embodiment provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
Hydroxypropyl-beta-cyclodextrin 53.3g
Hydroxypropyl-gamma-cyclodextrin 26.7g
Water for injection (temperature controlled at 50 ℃) to 1000mL.
The preparation method comprises the following specific steps:
and a, adding injection water with the total volume of 50% and the prescription amount of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin into a preparation tank, uniformly mixing, then adding the prescription amount of progesterone, supplementing the injection water to the total volume of preparation, and stirring to obtain the progesterone suspension.
Step b, carrying out high-pressure homogenization treatment on the progesterone suspension, wherein the high-pressure homogenization temperature is 50 ℃, the pressure is 20MPa, the time is 25min, and the cycle times are 1 time, so as to obtain progesterone liquid medicine;
and c, filtering the progesterone liquid medicine through a second-stage polyethersulfone filter core, wherein the aperture of the first-stage polyethersulfone filter core is 0.45 mu m, and the aperture of the second-stage polyethersulfone filter core is 0.2 mu m. Then filling, sealing, sterilizing at 121deg.C for 8min to obtain water-soluble progesterone injection.
Example 2
The embodiment provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
120.0g of hydroxypropyl-beta-cyclodextrin
Hydroxypropyl-gamma-cyclodextrin 40.0g
Water for injection (temperature controlled at 60 ℃) to 1000mL.
The preparation method comprises the following specific steps:
and a, adding injection water with the total volume of 60% and the prescription amount of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin into a preparation tank, uniformly mixing, then adding the prescription amount of progesterone, supplementing the injection water to the total volume of preparation, and stirring to obtain the progesterone suspension.
Step b, carrying out high-pressure homogenization treatment on the progesterone suspension, wherein the high-pressure homogenization temperature is 60 ℃, the pressure is 30MPa, the time is 30min, and the cycle times are 3 times, so as to obtain progesterone liquid medicine;
and c, filtering the progesterone liquid medicine through a second-stage polyethersulfone filter core, wherein the aperture of the first-stage polyethersulfone filter core is 0.45 mu m, and the aperture of the second-stage polyethersulfone filter core is 0.2 mu m. Then filling, sealing, sterilizing at 121deg.C for 15min to obtain water-soluble progesterone injection.
Example 3
The embodiment provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
Hydroxypropyl-beta-cyclodextrin 85.7g
Hydroxypropyl-gamma-cyclodextrin 34.3g
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method comprises the following specific steps:
and a, adding injection water with the total volume of 55% and the prescription amount of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin into a preparation tank, uniformly mixing, then adding the prescription amount of progesterone, supplementing the injection water to the total volume of preparation, and stirring to obtain the progesterone suspension.
Step b, carrying out high-pressure homogenization treatment on the progesterone suspension, wherein the high-pressure homogenization temperature is 55 ℃, the pressure is 25MPa, the time is 28min, and the cycle times are 2 times, so as to obtain progesterone liquid medicine;
and c, filtering the progesterone liquid medicine through a second-stage polyethersulfone filter core, wherein the aperture of the first-stage polyethersulfone filter core is 0.45 mu m, and the aperture of the second-stage polyethersulfone filter core is 0.2 mu m. Then filling, sealing, sterilizing at 121deg.C for 12min to obtain water-soluble progesterone injection.
Example 4
The embodiment provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 10.0g
Hydroxypropyl-beta-cyclodextrin 42.9g
Hydroxypropyl-gamma-cyclodextrin 17.1g
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method comprises the following specific steps:
and a, adding injection water with the total volume of 55% and the prescription amount of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin into a preparation tank, uniformly mixing, then adding the prescription amount of progesterone, supplementing the injection water to the total volume of preparation, and stirring to obtain the progesterone suspension.
Step b, carrying out high-pressure homogenization treatment on the progesterone suspension, wherein the high-pressure homogenization temperature is 55 ℃, the pressure is 25MPa, the time is 28min, and the cycle times are 2 times, so as to obtain progesterone liquid medicine;
and c, filtering the progesterone liquid medicine through a second-stage polyethersulfone filter core, wherein the aperture of the first-stage polyethersulfone filter core is 0.45 mu m, and the aperture of the second-stage polyethersulfone filter core is 0.2 mu m. Then filling, sealing, sterilizing at 121deg.C for 12min to obtain water-soluble progesterone injection.
Example 5
The embodiment provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 5.0g
Hydroxypropyl-beta-cyclodextrin 21.4g
Hydroxypropyl-gamma-cyclodextrin 8.6g
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method comprises the following specific steps:
and a, adding injection water with the total volume of 55% and the prescription amount of hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin into a preparation tank, uniformly mixing, then adding the prescription amount of progesterone, supplementing the injection water to the total volume of preparation, and stirring to obtain the progesterone suspension.
Step b, carrying out high-pressure homogenization treatment on the progesterone suspension, wherein the high-pressure homogenization temperature is 55 ℃, the pressure is 25MPa, the time is 28min, and the cycle times are 2 times, so as to obtain progesterone liquid medicine;
and c, filtering the progesterone liquid medicine through a second-stage polyethersulfone filter core, wherein the aperture of the first-stage polyethersulfone filter core is 0.45 mu m, and the aperture of the second-stage polyethersulfone filter core is 0.2 mu m. Then filling, sealing, sterilizing at 121deg.C for 12min to obtain water-soluble progesterone injection.
Comparative example 1
The comparative example provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
120.0g of hydroxypropyl-beta-cyclodextrin
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method of this comparative example was exactly the same as in example 3, except that in step a, injection water was added to the formulation tank in an amount of 55% of the total volume of formulation and hydroxypropyl-beta-cyclodextrin was added in the prescribed amount, and the other operations were the same as in example 3.
Comparative example 2
The comparative example provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
120.0g of hydroxypropyl-gamma-cyclodextrin
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method of this comparative example was exactly the same as in example 3, except that in step a, injection water was added to the formulation tank in an amount of 55% of the total volume of formulation and hydroxypropyl-gamma-cyclodextrin was added in the prescribed amount, and the other operations were the same as in example 3.
Comparative example 3
The comparative example provides a water-soluble progesterone injection, the dosage of the prescription is as follows:
progesterone 20.0g
Hydroxypropyl-beta-cyclodextrin 85.7g
Hydroxypropyl-alpha-cyclodextrin 34.3g
Water for injection (temperature controlled at 55 ℃) to 1000mL.
The preparation method of this comparative example was exactly the same as in example 3, except that injection water was added to the formulation tank in an amount of 55% of the total volume of formulation and the prescribed amounts of hydroxypropyl-gamma-cyclodextrin and hydroxypropyl-alpha-cyclodextrin in step a, and the other operations were the same as in example 3.
The solubility of the water-soluble progesterone injections prepared in examples 1 to 5 and comparative examples 1 to 3 was examined, wherein the water-soluble progesterone injections prepared in examples 1 to 5 were completely dissolved and were colorless transparent clear solutions; the water-soluble progesterone injections prepared in comparative examples 1 to 3 were not completely dissolved, wherein the water-soluble progesterone injections prepared in comparative examples 1 and 2 were layered, and the water-soluble progesterone injection prepared in comparative example 3 was precipitated.
The water-soluble progesterone injections prepared in examples 1 to 5 were accelerated for 6 months at 40.+ -. 2 ℃ and 75.+ -. 5% RH, and the results are shown in Table 1.
TABLE 1
As can be seen from the analysis in Table 1, after the accelerated test, the water-soluble progesterone injection prepared in examples 1 to 5 is still colorless transparent clear solution, the content and related substances are not changed significantly, and the water-soluble progesterone injection produced by the formulation and the preparation method of the invention has stable performance.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.
Claims (5)
1. A water-soluble progesterone injection, which is characterized by comprising progesterone, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin and water for injection;
the weight ratio of the hydroxypropyl-beta-cyclodextrin to the hydroxypropyl-gamma-cyclodextrin is 2:1-3:1; the weight ratio of the total dosage of the hydroxypropyl-beta-cyclodextrin and the hydroxypropyl-gamma-cyclodextrin to the progesterone is 4:1-8:1; the specification of the water-soluble progesterone injection is 1 mL/5 mg,1 mL/10 mg and 1 mL/20 mg;
the preparation method of the water-soluble progesterone injection comprises the following steps:
step a, adding injection water with the total volume of 50-60% and hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin with the prescription amount into a preparation tank, uniformly mixing, then adding progesterone with the prescription amount, supplementing the injection water to the total volume of preparation, and stirring to obtain progesterone suspension;
step b, carrying out high-pressure homogenization treatment on the progesterone suspension to obtain progesterone liquid medicine;
step c, filtering the progesterone liquid medicine through a multistage polyethersulfone filter element with sequentially reduced pore diameters, filling, sealing and sterilizing to obtain a water-soluble progesterone injection;
in the step a, the temperature of the water for injection is 50-60 ℃.
2. A method for preparing the water-soluble progesterone injection as claimed in claim 1, comprising the steps of:
step a, adding injection water with the total volume of 50-60% and hydroxypropyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin with the prescription amount into a preparation tank, uniformly mixing, then adding progesterone with the prescription amount, supplementing the injection water to the total volume of preparation, and stirring to obtain progesterone suspension;
step b, carrying out high-pressure homogenization treatment on the progesterone suspension to obtain progesterone liquid medicine;
step c, filtering the progesterone liquid medicine through a multistage polyethersulfone filter element with sequentially reduced pore diameters, filling, sealing and sterilizing to obtain a water-soluble progesterone injection;
in the step a, the temperature of the water for injection is 50-60 ℃.
3. The method for preparing water-soluble progesterone injection according to claim 2, wherein the high-pressure homogenization temperature is 50-60 ℃, the pressure is 20-30 MPa, the time is 25-30 min, and the cycle number is 1-3.
4. The method for preparing the water-soluble progesterone injection according to claim 2, wherein the multi-stage filter core is a two-stage polyethersulfone filter core, wherein the pore size of the first-stage polyethersulfone filter core is 0.45 μm and the pore size of the second-stage polyethersulfone filter core is 0.2 μm.
5. The method for preparing a water-soluble progesterone injection according to claim 2, wherein in step c, the sterilization is performed at 121 ℃ for 8-15 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310471820.8A CN116459212B (en) | 2023-04-27 | 2023-04-27 | Water-soluble progesterone injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202310471820.8A CN116459212B (en) | 2023-04-27 | 2023-04-27 | Water-soluble progesterone injection and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4596795A (en) * | 1984-04-25 | 1986-06-24 | The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services | Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives |
| EP1316317A1 (en) * | 2001-11-30 | 2003-06-04 | University of Liege | Hydrosoluble mixtures of cyproterone and/or an ester of it, processes to obtain them and uses thereof |
| CN1748705A (en) * | 2004-09-16 | 2006-03-22 | 奥特昂股份有限公司 | New injectable formulations containing progesterone |
| CN114209647A (en) * | 2021-12-14 | 2022-03-22 | 石家庄四药有限公司 | Hydroxyethyl starch injection and preparation method thereof |
| CN115501177A (en) * | 2021-06-07 | 2022-12-23 | 南京卡文迪许生物工程技术有限公司 | Progesterone water-soluble injection and preparation method thereof |
-
2023
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4596795A (en) * | 1984-04-25 | 1986-06-24 | The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services | Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives |
| EP1316317A1 (en) * | 2001-11-30 | 2003-06-04 | University of Liege | Hydrosoluble mixtures of cyproterone and/or an ester of it, processes to obtain them and uses thereof |
| CN1748705A (en) * | 2004-09-16 | 2006-03-22 | 奥特昂股份有限公司 | New injectable formulations containing progesterone |
| CN115501177A (en) * | 2021-06-07 | 2022-12-23 | 南京卡文迪许生物工程技术有限公司 | Progesterone water-soluble injection and preparation method thereof |
| CN114209647A (en) * | 2021-12-14 | 2022-03-22 | 石家庄四药有限公司 | Hydroxyethyl starch injection and preparation method thereof |
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| Title |
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| Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements;Vicatos AI等;Beilstein J Org Chem。;全文 * |
| Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems;Lahiani-Skiba M等;Drug Dev Ind Pharm.;全文 * |
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| CN116459212A (en) | 2023-07-21 |
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