CN107198677B - Progesterone suspension type long-acting injection, preparation method thereof and progesterone suspension injection powder - Google Patents
Progesterone suspension type long-acting injection, preparation method thereof and progesterone suspension injection powder Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, and discloses a progesterone suspension type long-acting injection, a preparation method thereof and a progesterone suspension injection powder for treating threatened abortion and assisted reproductive corpus luteum support. The embodiment of the invention can be prepared into progesterone suspension or freeze-dried powder injection and the like by micron-sizing and nano-sizing and adding some stabilizing agents, and can be used for intramuscular or subcutaneous injection administration. The suspension solves the problem of indissolvable drug administration, uses few auxiliary materials and has large drug-loading rate, can obviously improve bioavailability, achieves the slow-release effect of one week or more, reduces administration times, has good biocompatibility and small irritation, and simultaneously improves the compliance of patients. The preparation method can adopt a medium grinding method, a solvent replacement-high pressure homogenization method or a micro-jet method and the like. The preparation process of the preparation is simple and controllable, and industrial production can be realized.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel dosage form of progesterone, in particular to a progesterone suspension type long-acting injection and a preparation method thereof, and a progesterone suspension injection powder.
Background
Progesterone (Progesterone), also known as Progesterone, is a white or yellowish crystalline powder, has a melting point of 127-131 ℃, is odorless, stable in air, optically dextrorotatory, insoluble in water, and soluble in ethanol, diethyl ether, chloroform, acetone, dioxane and concentrated sulfuric acid. The chemical name of progesterone is: pregn-4-ene-3, 20-dione, molecular formula: c21H30O2Molecular weight: 314.47, the structural formula is as follows:
progesterone is a natural progestogen secreted by the ovarian corpus luteum and is an important hormone for maintaining pregnancy. Progesterone has many functions during pregnancy, including: promote and help the endometrium to accept early embryo more easily by inducing secretory change, which is necessary for the successful implantation of fertilized egg and maintaining normal pregnancy, and inhibit the contraction of myometrium by negative transcription regulation of nitric oxide synthase to cause the uterus calm. Progesterone can significantly increase the concentration of progestogen in the blood, and improve various symptoms and diseases caused by the lack of progestogen or the insufficient function of corpus luteum, including: (1) can be used for treating premenstrual syndrome and abortion caused by luteal insufficiency; (2) functional uterine bleeding or amenorrhea due to anovulation; (3) supplementing various diseases caused by corpus luteum deficiency; (4) cycling with estrogen counteracts the effects of simple estrogen on the intima.
The existing progesterone preparation in China at present mainly comprises: capsule, pill, gel, sustained release gel, soft capsule, transdermal absorption cream, injection, etc. Progesterone is mainly available in two dosage forms, oral and injection, according to the classification of administration route.
The oral preparation is convenient and quick to administer and is easily accepted by patients, but the oral progesterone can be quickly damaged in gastrointestinal tracts and livers, and the supplement and treatment effects are difficult to achieve. Since progesterone solubility is very low and the first pass effect is severe, oral bioavailability is only 10%. The oral preparation improves the solubility of the progesterone by increasing the concentration of the surfactant, and cannot fundamentally solve the problems of strong first pass effect and low bioavailability of the progesterone; the daily dosage still needs to be large to achieve the curative effect, so the problems of fast metabolism and low bioavailability of progesterone in vivo cannot be fundamentally solved.
For the reasons mentioned above, the route of administration by injection is still the main route of administration of progesterone in china. In the assisted reproductive process, the existing preparation for providing luteal support is mainly a progesterone oil solution injection. Since the preparation is intramuscular oil solution, and is injected daily for a long period of time (about 12 weeks). When the oil solution is injected, discomfort such as pain, local inflammation, allergy and other symptoms of a patient is easily caused, and the individual pathological reports even indicate that progesterone is injected intramuscularly to induce acute eosinophilic pneumonia. And the half-life of the oil agent progesterone is long, and the oil agent progesterone can be recovered usually within a plurality of weeks. The long-term high-frequency injection can also cause other symptoms such as induration and the like at the injection part, which is not favorable for the health of the tissue of the injection part. Patients are pregnant women, progesterone injection is very inconvenient every day, and the progesterone injection has the problems of muscle hardening, pain and the like caused by an oil solvent.
Disclosure of Invention
In view of the above, the present invention provides a progesterone suspension type long-acting injection and a preparation method thereof, and the present invention can achieve a sustained release effect for one week or more by intramuscular injection of the suspension, so that the drug is stably released, the bioavailability is improved, the biocompatibility is good, the irritation is small, and the compliance of patients is improved.
The invention provides a progesterone suspension type long-acting injection, which comprises the following components in percentage by weight:
2.5 to 15 percent of progesterone;
0.1-2% of primary stabilizer, wherein the primary stabilizer is selected from one or more of polyethylene glycol, povidone, hypromellose, sodium carboxymethylcellulose and lecithin;
0.01-1% of secondary stabilizer, wherein the secondary stabilizer is selected from one or more of polyoxyethylene sorbitan fatty acid ester, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil and sodium deoxycholate;
0-1% of a pH regulator;
0-2% of an osmotic pressure regulator;
the rest is water for injection.
The invention also provides a progesterone suspension freeze-dried powder injection which is prepared by freeze-drying progesterone suspension, wherein the progesterone suspension comprises the following components in percentage by weight:
2.5 to 15 percent of progesterone;
0.1-2% of primary stabilizer, wherein the primary stabilizer is selected from one or more of polyethylene glycol, povidone, hypromellose, sodium carboxymethylcellulose and lecithin;
0.01-1% of secondary stabilizer, wherein the secondary stabilizer is selected from one or more of polyoxyethylene sorbitan fatty acid ester, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil and sodium deoxycholate;
0-1% of a pH regulator;
0-2% of an osmotic pressure regulator;
the rest is water for injection.
The suspension type long-acting injection is a preparation for intramuscular or intravenous injection, which is prepared by dispersing insoluble or difficultly soluble solid medicines in a liquid dispersion medium. After the medicine is injected, a reservoir structure is formed at the injection site, so that the medicine is slowly released, and the aim of long-acting effect is fulfilled. The currently common preparation methods are divided into the following two main categories: the Top-down method including a grinding method, a high-pressure homogenization method, etc., and the Bottom-up method including an anti-solvent method. The powder injection is a powdery object formed by mixing the medicine and the reagent and sterilizing and drying, and is convenient to transport and store.
The invention aims to provide a stable long-acting progesterone injection, which can be prepared into suspension, freeze-dried powder injection or common powder injection by micronization and nanocrystallization and addition of a stabilizer, and can be used for intramuscular or subcutaneous injection administration. The suspension can solve the problem of difficult drug administration, uses few auxiliary materials and has large drug-loading rate, thereby obviously improving the bioavailability and reducing the administration times.
The invention discloses a progesterone suspension type long-acting injection for threatened abortion and assisted reproductive corpus luteum support and a method for preparing the suspension. The preparation, including general suspension, freeze-dried powder injection and the like, can be used for subcutaneous or intramuscular injection. The invention can achieve the sustained release effect of one week or more by intramuscular injection of the suspension, so that the medicine is stably released, the bioavailability is improved, and the compliance of patients is improved. Moreover, the preparation process is simple and controllable, and industrial production can be realized. Experimental data show that after intramuscular injection, the progesterone preparation can achieve the sustained-release effect of at least one week.
The progesterone suspension provided by the embodiment of the invention is a suspension in the common sense, can be prepared into a prefilled injection, and comprises the following components in percentage by weight:
the progesterone suspension freeze-dried powder injection provided by the embodiment of the invention can be dispersed into a suspension by adding water and shaking when in use, and the progesterone suspension freeze-dried powder injection comprises the following components in percentage by weight:
in the progesterone suspension injection and the freeze-dried powder injection, the primary stabilizer is selected from one or more of polyethylene glycol, povidone, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and lecithin. As the polyethylene glycol, commercially available products such as polyethylene glycol 4000 can be used.
In the progesterone suspension injection and the freeze-dried powder injection, the secondary stabilizer is selected from one or more of polyoxyethylene sorbitan fatty acid ester, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil and sodium deoxycholate. Wherein, the polyoxyethylene sorbitan fatty acid ester is a commercial product such as Tween 80.
In the present invention, the primary stabilizer is used in combination with the secondary stabilizer to obtain a good effect. In the embodiment of the invention, the stabilizing effect of hypromellose, vitamin E polyethylene glycol succinate and sodium carboxymethylcellulose is relatively good; povidone, polyvinyl alcohol, lecithin, etc. have poor effects. In a preferred embodiment of the invention, the primary stabilizer is selected from polyethylene glycol, hypromellose or sodium carboxymethylcellulose; the secondary stabilizer is selected from polyoxyethylene sorbitan fatty acid ester or vitamin E polyethylene glycol succinate.
In the embodiment of the invention, the progesterone suspension type long-acting injection comprises 2.5-15% of progesterone, and preferably 3-10%. In the progesterone suspension injection and the freeze-dried powder injection, the progesterone is selected from a progesterone crystal form 1, a progesterone crystal form 2 or a mixture of the progesterone crystal form 1 and the progesterone crystal form 2. In the embodiment of the invention, the progesterone suspension type long-acting injection comprises 0.1-2% of primary stabilizer, preferably 0.3-1.5%, and the stabilizing effect can be achieved by using 0.3% of hydroxypropyl methylcellulose in terms of dosage. The progesterone suspension type long-acting injection comprises 0.01-1% of secondary stabilizer, preferably 0.02-0.5%.
In the progesterone suspension injection and the lyophilized powder injection, the pH regulator is selected from one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, hydrochloric acid, lactic acid, sodium hydroxide, citrate and tartrate. The osmotic pressure regulator is preferably selected from one or more of sodium chloride, glucose and glycerol, and more preferably sodium chloride. The progesterone suspension type long-acting injection comprises 0-1% of pH regulator; according to the embodiment of the invention, a pH regulator is not used, and 0.1-0.5% of the pH regulator can be used. The progesterone suspension type long-acting injection comprises 0-2% of osmotic pressure regulator, and preferably comprises 0.05% -1%.
In the progesterone suspension injection freeze-dried powder injection provided by the embodiment of the invention, the freeze-drying protective agent can be one or more selected from lactose, maltose, glucose, trehalose, glycerol, mannitol, sorbitol, sodium chloride, phosphate, polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose (CMC-Na), polyethylene glycol and albumin, and preferably mannitol.
In the progesterone suspension injection and the freeze-dried powder injection, the average particle size of progesterone particles is selected from the group consisting of less than 20 microns, less than 10 microns, less than 5 microns and less than 1 micron; specifically, the particle size can be about 1 to 3 micrometers and about 2 micrometers.
After the progesterone suspension injection and the lyophilized powder injection are injected through muscles or subcutaneous tissues, the suspension can achieve the sustained release effect of one week or more, the bioavailability can be obviously improved, and the compliance of patients can be improved.
The preparation method of the progesterone suspension type long-acting injection comprises the following steps:
the progesterone is prepared into the progesterone suspension type long-acting injection by adopting a wet grinding method, an anti-solvent-high pressure homogenization method or a micro-jet method.
The first progesterone suspension injection can be prepared by the following method, which comprises the following steps: wet milling, anti-solvent-high pressure homogenization, microfluidization, or a combination thereof.
Wherein, the wet grinding method comprises the following steps: mixing progesterone, water and auxiliary materials according to a certain proportion, stirring to uniformly disperse, and grinding by using a wet grinding machine to obtain the progesterone suspension. In the preferred embodiment of the present invention, when the wet grinding method is used, the grinding beads used are zirconia beads and polystyrene beads. Specifically, the progesterone suspension can be obtained by cyclic milling at 1500rpm for 10 min.
The anti-solvent-high pressure homogenization method comprises the following steps: dispersing progesterone in organic solvent such as methanol, heating and ultrasonic treating to dissolve progesterone completely, adding the solution into water containing stabilizer or organic solution to precipitate progesterone to obtain progesterone suspension, homogenizing under high pressure to obtain progesterone suspension with particle size less than 220nm, and optionally filtering with membrane to remove bacteria. High pressure homogenization may include: after 6 cycles at 300bar at low pressure, 10 cycles at 900bar at high pressure. In an anti-solvent-high pressure homogenization method, the problem of sterility can be solved through membrane sterilization, and the whole-process sterile operation is not needed, so that the production cost is reduced; the preparation with proper particle size and shape can be obtained by adding some stabilizing agents.
The micro-fluidic method comprises the following steps: dispersing progesterone in water, adding auxiliary materials, adding into a micro-jet machine, circulating for 1 time under 10000psi pressure and circulating for 3 times under 20000psi pressure, and completing ultramicro treatment to obtain the progesterone suspension.
The second progesterone suspension freeze-dried powder injection can be prepared by adding a certain amount of freeze-drying protective agent into the first suspension, subpackaging and freeze-drying. The method for preparing the progesterone suspension freeze-dried powder injection can comprise the following steps: adding 1-20% of freeze-drying protective agent into the progesterone suspension, and freeze-drying to obtain the progesterone suspension freeze-dried powder injection. In the freeze-drying process of the embodiment of the invention, under the conditions of a suitable freeze-drying protective agent and a suitable freeze-drying process, crystals aggregate and grow, and the progesterone freeze-dried powder injection with a suitable particle size is prepared. Specifically, the lyophilization process may comprise: prefreezing at-40 deg.C for four hours, vacuumizing, maintaining at-40 deg.C for two hours, raising to-20 deg.C for three hours, raising to-10 deg.C for two hours, raising to 0 deg.C for two hours, and raising to 20 deg.C for two hours.
Or, the suspension is sprayed and dried to prepare the common progesterone suspension injection powder.
In the invention, the progesterone suspension injection can be used for providing luteal support in threatened abortion and assisted reproduction. The suspension can be prepared into suspensions or freeze-dried powder injection and the like by micronization and nanocrystallization and adding a plurality of stabilizing agents, and can be used for intramuscular or subcutaneous injection administration. The suspension solves the problem of difficult drug administration, uses few auxiliary materials and has large drug-loading rate, can obviously improve the bioavailability, achieves the sustained-release effect for one week or more, and reduces the administration frequency. Moreover, the preparation process of the preparation is simple and controllable, and industrial production can be realized.
Drawings
FIG. 1 is a graph showing the particle size distribution of a progesterone suspension obtained in example 2 of the present invention;
FIG. 2 is a photomicrograph of progesterone microparticles in progesterone suspension obtained in example 2 of the present invention;
FIG. 3 shows the pathological sections of rats injected intramuscularly with progesterone suspension obtained in example 2 and with the commercial preparation SD;
figure 4 is a graph of the intramuscular plasma injection profile of progesterone suspension obtained in example 2 of the present invention and commercial SD rat formulation.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In order to further understand the present application, the long-acting progesterone suspension injection, the preparation method thereof, and the progesterone suspension powder injection provided by the present application are specifically described below with reference to the examples.
In the following examples, the crystal form of progesterone used was crystal form 1, the particle size of the progesterone bulk drug was 60 μm, and the average particle size of the resulting suspension was 2 μm; the CMC-Na and the polyvidone are both medicinal grade.
Example 1
Preparation of progesterone suspension injection (wet grinding method)
Prescription (100):
the preparation process comprises the following steps:
(1) grinding media were prepared by dissolving 3g of polyethylene glycol 4000, 0.3g of tween 80 and 2.7g of sodium chloride in 300mL of water for injection, and stirring until completely dissolved, as grinding media.
(2) 200mL of zirconia milling beads were poured into the milling chamber, 15g of progesterone was dispersed in 150mL of milling media, poured into the chamber, and the residual drug was transferred with the remaining media.
(3) Grinding at 1500rpm for 10min to obtain progesterone suspension, and packaging into prefilled syringe under aseptic condition to obtain 100-count prefilled injection.
Example 2
Preparation of progesterone suspension injection (wet grinding method)
Prescription (100):
the preparation process comprises the following steps:
(1) grinding media were prepared by dissolving 1.35g of sodium carboxymethylcellulose, 0.15g of tween 80 and 2.7g of sodium chloride in 300mL of water for injection, and stirring until completely dissolved as grinding media.
(2) 200mL of zirconia milling beads were poured into the milling chamber, 7.5g of progesterone was dispersed in 150mL of milling media, poured into the chamber, and the residual drug was transferred with the remaining media.
(3) Grinding at 1500rpm for 10min to obtain progesterone suspension, and packaging into prefilled syringe under aseptic condition to obtain 100-count prefilled injection.
Example 3
Preparation of progesterone suspension injection (micro-jet method)
Prescription (100):
the preparation process comprises the following steps:
(1) weighing 15g of progesterone, adding 3g of povidone and 800.3 g of tween, adding 300mL of water for injection, and uniformly stirring to obtain a primary suspension.
(2) And (3) adding the primary suspension into a microfluidizer, circulating for 1 time under 10000psi pressure, and circulating for 3 times under 20000psi pressure, and micronizing to obtain progesterone suspension with uniform particle size.
(3) And subpackaging the obtained progesterone suspension into prefilled syringes under aseptic condition to obtain 100-branch prefilled injection.
Example 4
Preparation of progesterone suspension freeze-dried powder injection (anti-solvent-high pressure homogenization method)
Prescription (100):
the preparation process comprises the following steps:
(1) weighing 10g of progesterone, adding 100mL of methanol, heating to dissolve, slowly adding into 5000mL of distilled water containing 0.3g of Tween 80, adding while stirring at the rotation speed of 500rpm, and continuously stirring for 30min after the addition is finished to obtain a primary suspension.
(2) Adding the primary suspension into a high-pressure homogenizer, circulating at low pressure of 300bar for 6 times, and circulating at high pressure of 900bar for 10 times to obtain uniform progesterone suspension with particle size less than 220nm, and sterilizing with a 220nm filter membrane.
(3) Adding 15g of mannitol serving as a freeze-drying protective agent into the suspension, uniformly stirring, subpackaging in penicillin bottles with each bottle being 3mL and 100 bottles in total, and freeze-drying, wherein the process comprises the following steps: prefreezing at-40 deg.C for four hours, vacuumizing, maintaining at-40 deg.C for two hours, maintaining at-20 deg.C for three hours, maintaining at-10 deg.C for two hours, maintaining at 0 deg.C for two hours, and maintaining at 20 deg.C for two hours to obtain progesterone suspension lyophilized powder for injection.
Example 5
Preparation of progesterone suspension freeze-dried powder injection
Prescription (100):
the preparation process comprises the following steps:
(1) grinding media were prepared by dissolving 3g of polyethylene glycol 4000, 0.3g of tween 80 and 2.7g of sodium chloride in 300mL of water for injection, and stirring until completely dissolved, as grinding media.
(2) Pouring 200mL of zirconium oxide grinding beads into a grinding cavity, dispersing 15g of progesterone into 150mL of grinding medium, pouring into the cavity, transferring residual medicine by using the residual medium, and circularly grinding at 1500rpm for 10min to obtain progesterone suspension.
(3) Adding 15g of mannitol serving as a freeze-drying protective agent into the suspension, uniformly stirring, subpackaging in penicillin bottles with each bottle being 3mL, and freeze-drying by the same process as example 5 to obtain the progesterone suspension freeze-dried powder injection.
Example 6
Test 1 particle size and particle size distribution
The suspension obtained in example 2 of the present invention was diluted with water for injection, and the particle size and particle size distribution were measured using a laser particle size analyzer, and the results are shown in fig. 1, where fig. 1 is a particle size distribution diagram of the progesterone suspension obtained in example 2 of the present invention. As can be seen from FIG. 1, in example 2 of the present invention, sodium carboxymethylcellulose and Tween 80 are adopted for matching, and the particle size of the suspension sample is about 2 μm, and the particle size distribution is relatively uniform.
In the embodiment of the invention, the stabilizing effect of hypromellose, vitamin E polyethylene glycol succinate and sodium carboxymethylcellulose is relatively good; povidone, polyvinyl alcohol, lecithin, etc. have relatively poor effects. Relatively good stabilizer, narrow particle size distribution and span controlled within 2; the stabilizer with poor effect has serious sedimentation in the grinding process, wide particle size distribution and span more than 3.
Experiment 2 micrographic image of microparticles
The suspension obtained in example 2 of the present invention was diluted with water for injection, and the morphology and aggregation thereof were observed with a microscope, and the results are shown in FIG. 2, which is a photomicrograph of progesterone microparticles in the progesterone suspension obtained in example 2 of the present invention. As can be seen from FIG. 2, the particle size of the suspension sample is about 2 μm, which is consistent with the results of laser particle size measurement, indicating that the suspension is relatively stable and uniform in particle size.
Example 7
Intramuscular injection progesterone suspension and progesterone oil solution foot licking test for SD rats
Test animals: SD male rats weighing 190 g-210 g and 24 rats were randomly divided into four groups of 6 rats.
Progesterone suspension a, prepared as in example 2, diluted to a concentration of 20 mg/mL;
progesterone injection B, commercially available (zhejiang juju pharmaceutical products gmbh, progesterone oil solution), 1 mL: 20 mg;
positive control: 50% glucose;
negative control: physiological saline.
Test methods and results:
0.1mL of the solution was injected subcutaneously into the footpad of the right hind paw of each rat; following injection, the time to first paw lick was recorded, along with cumulative paw lick times at 3, 6, 9, 12, 15, and 30 minutes, and the results are shown in Table 1.
TABLE 1 results of foot licking test within 30min after administration to SD rats
The following conclusions can be drawn from table 1: the progesterone suspension and the oil solution have significant difference (P1<0.05) with the positive control group, but have no significant difference (P2>0.05) with the negative control group. The two results show that the two have less irritation to the underfoot tissue after the subcutaneous injection of rats. However, compared to the incidence, onset, duration and lifting behavior of foot licking, progesterone oil solutions cause significant irritation; the time for the progesterone suspension to lick feet is shorter and is similar to that of a negative control group (physiological saline), which shows that the progesterone suspension disclosed by the invention is very weak in local irritation and has obvious advantages.
Example 8
Evaluation of irritation of intramuscular injection of progesterone suspension and progesterone oil solution in SD rats
Test animals: SD male rats weighing 190 g-210 g, 6 rats were randomly divided into two groups of 3 rats each.
A progesterone suspension, prepared as in example 2, diluted to a concentration of 20 mg/mL;
progesterone injection, commercially available (zhejiang juju pharmaceutical products ltd., progesterone oil solution), 1 mL: 20 mg.
Test methods and results:
rats were given intramuscularly and sacrificed at 1d, 7d, and 14d of administration, pathological sections were prepared, and inflammatory responses were observed.
Results referring to fig. 3, fig. 3 shows the pathological sections of intramuscular injection of progesterone suspension obtained in example 2 of the present invention and commercial preparation SD rat. In fig. 3, the upper row "a" is the results of muscle tissue sections 1 day, 7 days and 14 days after administration of the progesterone suspension of the present invention; the lower row "B" is the results of muscle tissue sections 1 day, 7 days, and 14 days after administration of the oil solution.
As can be seen from fig. 3, under microscope, muscle cells were infiltrated by a large number of inflammatory cells after injection of 7d and 14d of progesterone oil solution, i.e., an acute inflammatory response was generated; in contrast, for the progesterone suspension of the present invention, a small amount of inflammatory cells were present around the muscle cells after 7 days of administration. After 14 days, the muscle tissue has no inflammatory cell infiltration, which shows that the progesterone suspension causes slight inflammatory reaction after being injected into the muscle tissue, and the muscle cells are restored to a normal state after two weeks.
The results of the lick foot test and the pathological research are consistent, and compared with the progesterone oil solution, the progesterone suspension provided by the invention has good biocompatibility and low muscle irritation.
Example 9
Plasma pharmacokinetics comparison test of intramuscular injection of progesterone suspension and progesterone oil solution in SD (Sprague Dawley) rats
Progesterone suspension, prepared as in example 2;
progesterone injection, commercially available (zhejiang juju pharmaceutical products ltd., progesterone oil solution), 1 mL: 20 mg.
Test animals: SD male rats weighing 190 g-210 g and 12 animals were randomly divided into two groups of 6 animals each.
Administration dose: progesterone suspension: 44.1mg/kg, once a week;
progesterone injection (oil solution): 6.3mg/kg, daily injection;
the administration mode comprises the following steps: and (4) carrying out intramuscular injection.
The test instrument: a Waters liquid chromatogram-mass spectrum combined instrument comprises a quaternary gradient pump, an automatic sample injector, a column temperature box, an electrospray ionization interface, a triple quadrupole mass spectrum detector, a Waters system chromatographic workstation and an ACQUITYTM Ultra Performance LC Ultra-high phase liquid phase system which is a product of Waters company in America.
Test methods and results:
progesterone suspension group: 3 rats were each injected intramuscularly with a progesterone suspension at a dose of 44.1mg/kg, and 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 1d, 1n (bright), 2d, 2n, 3d, 3n, 4d, 4n, 5d, 5n, 6d, 6n, 7d, 7n after administration, blood was taken from the canthus of the rat eye, placed in a heparin-treated centrifuge tube, plasma was separated by centrifugation, and stored in a freezer at-20 ℃. The plasma concentration of progesterone in plasma was measured, and the time-dependent plasma concentration profile of progesterone obtained is shown in fig. 4, and fig. 4 is a plasma intramuscular injection profile of the progesterone suspension obtained in example 2 of the present invention and a commercial preparation SD rat.
Progesterone injection group: injecting progesterone injection into 3 rats, respectively, diluting with oil for injection to appropriate concentration, with the dosage of 6.3mg/kg, and collecting blood 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, and 12h after the first administration; administering once daily, taking blood before and 12h after administration, and measuring blood plasma drug concentration for 7 days; and after reaching stable blood concentration on the eighth day, taking blood after 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 12h of administration, placing the blood in a centrifugal tube treated by heparin, centrifugally separating the blood plasma, and storing the blood plasma in a refrigerator at the temperature of minus 20 ℃. The plasma drug concentration of progesterone in the plasma was measured, and the resulting plasma drug concentration change curve of progesterone with time is shown in fig. 4, and the specific data are respectively shown in table 2 and table 3. The AUC calculation results of the progesterone suspension group and the oil solution group are shown in table 4.
TABLE 2 progesterone suspension SD rat intramuscular injection time-blood concentration Table
TABLE 3 multiple dosing time-plasma concentration schedule for progesterone injection group
TABLE 4 AUC calculation results for progesterone suspension group and oil solution group
From the above results, it can be concluded that: after single intramuscular injection of the progesterone suspension, the progesterone suspension has a curve trend basically consistent with that of a common commercially available preparation when the progesterone suspension is taken once a day, the relative bioavailability of the progesterone suspension can reach 94.20%, the suspension is released slowly after intramuscular injection, and the blood concentration is in a stable release state for a long time. Therefore, the progesterone suspension injection can achieve a slow release effect, greatly reduce the administration times, improve the compliance of patients and have development value.
Claims (10)
1. A progesterone suspension type long-acting injection comprises the following components in percentage by weight:
2.5 to 15 percent of progesterone;
0.1-2% of primary stabilizer, wherein the primary stabilizer is selected from one or more of polyethylene glycol, povidone, hypromellose, sodium carboxymethylcellulose and lecithin;
0.01-1% of secondary stabilizer, wherein the secondary stabilizer is selected from one or more of polyoxyethylene sorbitan fatty acid ester, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil and sodium deoxycholate;
0-1% of a pH regulator;
0.05 to 1 percent of osmotic pressure regulator;
the rest is water for injection.
2. The long-acting injectable formulation of claim 1, wherein said primary stabilizer is selected from the group consisting of polyethylene glycol, hypromellose or sodium carboxymethylcellulose; the secondary stabilizer is selected from polyoxyethylene sorbitan fatty acid ester or vitamin E polyethylene glycol succinate.
3. The long-acting injection of progesterone suspension of claim 1 wherein the progesterone is selected from one or more of crystalline form 1 progesterone and crystalline form 2 progesterone.
4. The long-acting injection of progesterone suspension type of claim 1, wherein the pH regulator is one or more selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen carbonate, hydrochloric acid, lactic acid, sodium hydroxide, citrate and tartrate.
5. The long-acting injection of progesterone suspension type according to claim 1, wherein the osmotic pressure regulator is one or more selected from the group consisting of sodium chloride, glucose and glycerol.
6. The method for preparing a progesterone suspension type long acting injection of claim 1 comprising:
the progesterone is prepared into the progesterone suspension type long-acting injection by adopting a wet grinding method, an anti-solvent-high pressure homogenization method or a micro-jet method.
7. The method according to claim 6, wherein the wet grinding method is used, and the grinding beads used are zirconia beads and polystyrene beads.
8. A progesterone suspension injection powder is prepared by freeze drying or spray drying progesterone suspension, wherein the progesterone suspension comprises the following components in percentage by weight:
2.5 to 15 percent of progesterone;
0.1-2% of primary stabilizer, wherein the primary stabilizer is selected from one or more of polyethylene glycol, povidone, hypromellose, sodium carboxymethylcellulose and lecithin;
0.01-1% of secondary stabilizer, wherein the secondary stabilizer is selected from one or more of polyoxyethylene sorbitan fatty acid ester, vitamin E polyethylene glycol succinate, polyoxyethylene castor oil and sodium deoxycholate;
0-1% of a pH regulator;
0.05 to 1 percent of osmotic pressure regulator;
the rest is water for injection.
9. The progesterone suspension injectable powder of claim 8, wherein the process for preparing the progesterone suspension injectable powder comprises: adding 1-20% of freeze-drying protective agent into the progesterone suspension, and freeze-drying to obtain the progesterone suspension freeze-dried powder injection.
10. The progesterone suspension injectable powder of claim 9, wherein the lyoprotectant is one or more selected from lactose, maltose, glucose, trehalose, glycerol, mannitol, sorbitol, sodium chloride, phosphate, PVP, CMC-Na, polyethylene glycol and albumin.
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| WO2020135352A1 (en) * | 2018-12-28 | 2020-07-02 | 四川科伦药物研究院有限公司 | Method for preparing progesterone particulate, prepared progesterone particulate and injection thereof |
| CN113633611B (en) * | 2020-05-11 | 2024-08-27 | 鲁南制药集团股份有限公司 | Medroxyprogesterone caproate suspension injection and preparation method thereof |
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| CN1901885A (en) * | 2003-11-13 | 2007-01-24 | 阿尔扎公司 | Melt blend dispersions comprising a low water solubility drug and an ethylene oxide-propylene oxide block copolymer |
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| CN105147605A (en) * | 2015-06-24 | 2015-12-16 | 中国人民解放军军事医学科学院毒物药物研究所 | Progestin nano composition and preparation method thereof |
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| CN1441704A (en) * | 2000-05-10 | 2003-09-10 | 斯凯伊药品加拿大公司 | Medium milling |
| CN1901885A (en) * | 2003-11-13 | 2007-01-24 | 阿尔扎公司 | Melt blend dispersions comprising a low water solubility drug and an ethylene oxide-propylene oxide block copolymer |
| WO2010121320A1 (en) * | 2009-04-24 | 2010-10-28 | Iceutica Pty Ltd | Production of encapsulated nanoparticles at high volume fractions |
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