CN111346054A - Progesterone emulsion type injection and its preparing method - Google Patents
Progesterone emulsion type injection and its preparing method Download PDFInfo
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Abstract
A progesterone emulsion injection comprises progesterone, an oily solvent and water for injection, wherein the oily solvent is a mixture of oil for injection and benzyl benzoate, and the mass ratio of the oil for injection to the benzyl benzoate is 1: 5-5: 1. In the progesterone emulsion injection, the progesterone is extremely good in solubility, the dosage of the oleaginous solvent can be greatly reduced, and adverse reactions caused by oil needle injection are greatly relieved. Meanwhile, the progesterone emulsion injection has high drug encapsulation rate, and the drug is not separated out after long-term placement.
Description
Technical Field
The invention relates to the field of pharmacy, and in particular relates to a progesterone emulsion injection.
Background
Progesterone (also called Progesterone and lutein) is a natural progestogen secreted by ovary corpus luteum, and has chemical name of pregnane-4-ene-3, 20-dione and molecular formula of C21H30O2Molecular weight 314.47, CAS number 57-83-0. Progesterone is white or off-white crystalline powder, and is odorless and tasteless; it is very soluble in chloroform, soluble in ethanol, diethyl ether or vegetable oil, and insoluble in water.
The pharmacological actions of progesterone are mainly: (1) the later period of the menstrual cycle promotes the secretion of endometrium and the thickening of endometrium, so as to facilitate the implantation of fertilized eggs, reduce the excitability of uterine muscle and ensure the safe implementation of pregnancy; (2) the compound preparation can be used together with estrogen to promote the growth of mammary gland acinus and prepare for milk production; (3) inhibit the release of luteinizing hormone from anterior pituitary, prevent follicle from mature, and inhibit ovulation. Progesterone is clinically used for hormone replacement therapy in menstrual disorder, amenorrhea, threatened abortion, habitual abortion, dysfunctional uterine bleeding, corpus luteum insufficiency, premenstrual syndrome, perimenopause, and the like.
The progesterone single preparation and specification on the market at present are as follows: injections (5, 10, 20mg/1mL, 50mg/2mL), capsules (100mg), soft capsules (50, 100, 200mg), pessaries (25mg) and vaginal sustained release gels (8%/90 mg). These marketed formulations involve routes of administration: intramuscular injection, oral administration and vaginal mucosal administration. The progesterone intramuscular injection has definite curative effect and low price, and is a traditional medicine for luteal support of human assisted reproductive technology. Oral administration of progesterone has severe hepatic first pass effects with low bioavailability (< 10%) and is not recommended for use in assisted reproductive technologies. The drug effect of the vaginal drug delivery is the same as that of intramuscular injection, the local drug concentration of the uterus is high, the adverse reaction of the whole body is less, but the incidence rate of the vaginal bleeding in the luteal phase is high, and the price is high. From this, it can be seen that intramuscular injection is still the ideal route for administration of progesterone from the viewpoint of efficacy and economy.
However, the existing progesterone intramuscular injection also has some defects, such as: (1) pain and stimulation of injection parts are easy to form local induration, local aseptic abscess happens, and the formed local induration and the absorption and the subsidence of the aseptic abscess need a long time; (2) the injection has higher viscosity, has certain resistance when being sucked and injected by an injector, and is easy to seep back; (3) needs to be injected in hospitals, and has poor patient compliance. The defects of the progesterone intramuscular injection are greatly related to the formula of the product. Progesterone is a fat-soluble substance, and the existing injection is an oil solution type injection (commonly called as an oil needle) prepared by taking soybean oil as a solvent, so the problems of injection pain, induration, inconvenience for injection and the like are frequently caused when the injection is used.
In order to overcome the deficiencies of the existing intramuscular injection of progesterone, researchers have made various attempts. Published journal papers and patents relating to new varieties or new technologies of progesterone injections include: submicron emulsion injection (CN101152186B), lipid microsphere injection (CN106074383A), aqueous solution type injection of cyclodextrin (or hydroxypropyl cyclodextrin) inclusion compound (CN109381424A, CN106727288A, CN1517091 and CN104857522A), suspension type injection (CN107198677A and CN107441039A), nanocrystalline injection (CN109223722A), polymer nanoparticle or microsphere injection (CN107441061A and CN 107157956A). Wherein, the prescription and the process of the nanoparticle or microsphere injection are complex, and the production difficulty is high; in the nanocrystalline or suspension injection, due to the fact that the water solubility of progesterone is too low, drugs cannot be effectively released from an injection part, and adverse reactions can be caused due to long-term accumulation of insoluble drugs; cyclodextrin or hydroxypropyl cyclodextrin used in cyclodextrin inclusion compound has certain renal toxicity and may cause cancer, and it should be used with caution. In contrast, emulsion injection such as microemulsion or liposphere may be an ideal substitute.
Progesterone is a fat-soluble drug, but its solubility in oily solvents commonly used in emulsion injections (e.g., vegetable oil for injection, medium-chain fatty acid triglycerides, etc.) is not great. The two patents (CN101152186B, CN106074383A) related to progesterone emulsion injection that have been disclosed so far do not consider this problem, and the oily solvent and the amount thereof used may not be enough to ensure that the clinically used progesterone can be dissolved in these oily solvents for a long time, and the solubility of progesterone in water is very low (about 20 μ g/ml), so there is a possibility of drug precipitation during storage of the progesterone submicron emulsion or lipid microsphere injection prepared by the related art. Because the emulsion injection is a non-clear emulsion, once the precipitation of the medicament is difficult to observe, the clinically used medicament-carrying emulsion injection with the risk of medicament precipitation has great potential safety hazard.
Therefore, there is a need to provide a new progesterone emulsion injection to solve the above technical problems.
Disclosure of Invention
The invention aims to provide a progesterone emulsion injection, in particular to an emulsion injection for intramuscular injection, and the progesterone injection with excellent solubility is obtained through the specific selection of the oleaginous solvent, so that the dosage of the oleaginous solvent can be greatly reduced, and the adverse reaction caused by oil needle injection can be greatly relieved. Meanwhile, the progesterone emulsion injection has high drug encapsulation rate, and the drug is not separated out after long-term placement.
In order to achieve the above object, according to one aspect of the present invention, there is provided a progesterone emulsion injection comprising progesterone, an oleaginous solvent and water for injection, wherein the oleaginous solvent is a mixture of oil for injection and benzyl benzoate, and the mass ratio of the oil for injection to the benzyl benzoate is 1:5 to 5: 1. It will be understood by those skilled in the art that the mass ratio of the oil for injection to the benzyl benzoate falls within the range of 1:5 to 5:1, i.e., the ratio of the mass ratio of the oil for injection to the benzyl benzoate may be any one of 0.2 to 5. For example, the mass ratio of the oil for injection to the benzyl benzoate is 1:3, 1:2.5, 1:2, 2:1, 2.5:1, 3:1, and the like.
In a preferred embodiment, the mass ratio of the oil for injection to the benzyl benzoate is 2: 3.
In some embodiments, the injectable oil is selected from at least one of injectable vegetable oil and injectable medium chain fatty acid triglyceride. That is, the oil for injection may be a vegetable oil for injection, may be a medium-chain fatty acid triglyceride for injection, or may be a mixture of one (or more) vegetable oil for injection (e.g., soybean oil for injection) and one (or more) medium-chain fatty acid triglyceride (e.g., a saturated straight-chain fatty acid triglyceride having 8 carbon atoms).
In some embodiments, the injectable vegetable oil is selected from at least one of injectable soybean oil, injectable castor oil, injectable corn oil, injectable rape oil, injectable sesame oil, injectable olive oil, injectable peanut oil and injectable sunflower oil.
In some embodiments, the medium chain fatty acid triglyceride for injection is a saturated straight chain fatty acid triglyceride having 6 to 12 carbon atoms.
In some embodiments, the mass ratio of the progesterone to the oleaginous solvent is 5:100 to 30: 100. It will be understood by those skilled in the art that the mass ratio of the progesterone to the oleaginous solvent falls within the range of 5:100 to 30:100, i.e., the ratio of the mass ratio of the progesterone to the oleaginous solvent may be any one of 0.05 to 0.3. For example, the mass ratio of the progesterone to the oleaginous solvent is 10:100, 15:100, 25:100, 30:100, and the like.
In some embodiments, the oily solvent is contained in an amount of 5 to 40g per 100 ml of the progesterone emulsion injection.
In some embodiments, the progesterone emulsion injection further comprises an emulsifier, glycerol and water for injection, wherein the mass ratio of the emulsifier to the oleaginous solvent is 5: 100-50: 100, and in some embodiments, 0.5-3 g of the glycerol is contained in each 100 ml of the progesterone emulsion injection.
It will be understood by those skilled in the art that the amount of the water for injection should meet the dosage specification of the progesterone emulsion injection, in addition to the specific ratio requirements of the oleaginous solvent, the emulsifier and the glycerin as described above. For example, in the present application, the dosage specification of the progesterone emulsion injection may be 5mg/0.5ml, 10mg/0.5ml, 20mg/0.5ml, 5mg/1.0ml, 10mg/1.0ml, 20mg/1.0ml, 50mg/1.0ml, 50mg/2.0 ml. After the dosage of each component in the progesterone emulsion injection meets the requirements recorded above, the dosage of the water for injection meets the requirements of dosage specification.
In some embodiments, the emulsifier is selected from at least one of soybean lecithin for injection, egg lecithin for injection, polysorbate 80, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer 188.
In some embodiments, the emulsifier is soybean lecithin for injection, egg yolk lecithin for injection, polysorbate 80, polyoxyethylene castor oil, or polyethylene glycol 15-hydroxystearate. That is, in these examples, the emulsifier is a single component emulsifier, and is one of soybean lecithin for injection, egg lecithin for injection, polysorbate 80, polyoxyethylene castor oil, and polyethylene glycol 15-hydroxystearate.
When the emulsifier is the soybean lecithin or egg yolk lecithin for injection, the mass ratio of the soybean lecithin or egg yolk lecithin for injection to the oleaginous solvent is 5: 100-30: 100;
when the emulsifier is the polysorbate 80, the mass ratio of the polysorbate 80 to the oleaginous solvent is 5: 100-30: 100;
when the emulsifier is the polyoxyethylene castor oil, the mass ratio of the polyoxyethylene castor oil to the oleaginous solvent is 10: 100-40: 100;
when the emulsifier is the polyethylene glycol 15-hydroxystearate, the mass ratio of the polyethylene glycol 15-hydroxystearate to the oleaginous solvent is 10: 100-50: 100.
In some embodiments, the emulsifier is a mixed emulsifier of one of soybean lecithin for injection and egg yolk lecithin for injection and at least one of polysorbate 80, polyoxyethylated castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer 188. That is, in these examples, the emulsifier is a multi-component emulsifier, wherein one component is one of soybean lecithin for injection and egg yolk lecithin for injection, and the other component is one or more of polysorbate 80, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer 188. For example, the emulsifier may be any one of the following mixtures: a mixture of soybean lecithin for injection and polysorbate 80, a mixture of soybean lecithin for injection and polyoxyethylene castor oil, a mixture of soybean lecithin for injection and polyethylene glycol 15-hydroxystearate, a mixture of egg yolk lecithin for injection and polysorbate 80, a mixture of egg yolk lecithin for injection and polyoxyethylene castor oil, a mixture of egg yolk lecithin for injection and polyethylene glycol 15-hydroxystearate, a mixture of soybean lecithin for injection and polysorbate 80 and polyoxyethylene castor oil, a mixture of soybean lecithin for injection and polysorbate 80 and polyethylene glycol 15-hydroxystearate, and the like.
In the above embodiment, the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection to the mixed emulsifier is 1:2 to 10: 11. That is, in the mixed emulsifier, the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection to other emulsifiers is 1:1 to 10:1, so that the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection to the mixed emulsifier satisfies 1:2 to 10: 11.
In the embodiment, the mass ratio of the mixed emulsifier to the oleaginous solvent is 5: 100-20: 100.
In some embodiments, the progesterone emulsion injection further comprises at least one of a stabilizer, a bacteriostatic agent, an analgesic, and a pH adjuster. One or more of the auxiliary agents can be specifically selected and added according to actual needs by the technical personnel in the field.
In the above embodiment, the stabilizer may be at least one of oleic acid and sodium oleate; the bacteriostatic agent can be at least one of benzyl alcohol, hydroxypropyl butyl ester (methyl ester), phenol, chlorobutanol and thimerosal; the analgesic agent can be at least one of benzyl alcohol, chlorobutanol, lidocaine or procaine hydrochloride; the pH regulator can be at least one of hydrochloric acid, sodium hydroxide, citric acid and sodium citrate.
In the present application, the progesterone emulsion injection can be obtained by a conventional preparation method.
Of course, according to another aspect of the present application, there is also provided a preparation method of the progesterone emulsion type injection, the preparation method comprising: respectively and uniformly mixing the oil phase and the water phase in the formula under a heating state to obtain a mixed oil phase and a mixed water phase; mixing the mixed oil phase and the mixed water phase, and then carrying out high-speed shearing emulsification and high-pressure homogenization to obtain an emulsion with the average particle size and the particle size distribution meeting the requirements; a step of filtering the emulsion with a 0.45 μm microfiltration membrane; and subpackaging, sealing and sterilizing.
In the preparation method, in the step of obtaining the mixed oil phase, the benzyl benzoate and the oil for injection are mixed in proportion, and then the progesterone and other oil phases in the formula are added in a heating state and are completely dissolved to obtain the mixed oil phase.
In the above preparation method, in the step of obtaining the mixed aqueous phase, an emulsifier and other water-soluble agents in the formulation are added to the heated water for injection, and completely dissolved to obtain the mixed aqueous phase.
In the above preparation method, in the step of obtaining an emulsion, the mixed oil phase and the mixed water phase are first mixed under high-speed stirring, and emulsified under high-speed shearing under a protective gas to obtain a primary emulsion; then, after the injection water is added until the requirement of dosage specification is met, high-pressure homogenization is carried out under the protective gas until the emulsion meets the requirement.
In the above-mentioned production method, sterilization is performed by a flow-through steam sterilization method or an autoclave sterilization method.
In the above preparation method, the progesterone emulsion type injection satisfies at least one of the following criteria: (i) the average particle size is 100-250 nm, (ii) the polydispersity index is less than 0.20, and (iii) the Zeta potential range is-20 mV to-40 mV.
The verification shows that after the progesterone emulsion injection is filtered by a microporous filter membrane of 0.45 mu m, the content of progesterone falls in the range of 95-105% of the marked amount, and the encapsulation rate of the progesterone is more than 90%.
Compared with the existing progesterone injection, the progesterone emulsion injection has the following advantages:
(1) in the progesterone emulsion injection, the oily solvent has good solubility to progesterone by introducing benzyl benzoate, so that the dosage of the oily solvent can be greatly reduced, and adverse reaction caused by oil needle injection is greatly relieved;
(2) the verification shows that the progesterone emulsion injection has high drug encapsulation rate, and the drug is not separated out after long-term placement;
(3) the progesterone emulsion injection simultaneously conforms to all the provisions of the Chinese pharmacopoeia preparation general rule injection item.
Drawings
Fig. 1A and 1C are graphs showing fluorescence images of an intramuscular injection of the progesterone emulsion injection formulation of the present invention containing a fluorescent dye in verification example 2 for 30 minutes and 12 hours;
FIGS. 1B and 1D are graphs of fluorescence images of 30 minutes and 12 hours after intramuscular injection of a commercially available progesterone injection containing a fluorescent dye in verification example 2.
Detailed Description
Hereinafter, the technique of the present invention will be described in detail with reference to specific embodiments. It should be understood that the following detailed description is only for the purpose of assisting those skilled in the art in understanding the present invention, and is not intended to limit the present invention.
EXAMPLE 1 oleaginous solvent
In this example, the oleaginous solvent in the progesterone emulsion injection of the present invention is provided.
The greasy solvent is a mixture of oil for injection and benzyl benzoate, and the mass ratio of the oil for injection to the benzyl benzoate is 1: 5-5: 1. It will be understood by those skilled in the art that the mass ratio of the oil for injection to the benzyl benzoate falls within the range of 1:5 to 5:1, i.e., the ratio of the mass ratio of the oil for injection to the benzyl benzoate may be any one of 0.2 to 5. For example, the mass ratio of the oil for injection to the benzyl benzoate is 1:3, 1:2.5, 1:2, 2:1, 2.5:1, 3:1, and the like.
The oil for injection is at least one selected from vegetable oil for injection and triglyceride of medium chain fatty acid for injection. That is, the oil for injection may be a vegetable oil for injection, may be a medium-chain fatty acid triglyceride for injection, or may be a mixture of one (or more) vegetable oil for injection (e.g., soybean oil for injection) and one (or more) medium-chain fatty acid triglyceride (e.g., a saturated straight-chain fatty acid triglyceride having 8 carbon atoms).
The vegetable oil for injection is at least one selected from soybean oil for injection, castor oil for injection, corn oil for injection, rape oil for injection, sesame oil for injection, olive oil for injection, peanut oil for injection and sunflower oil for injection. The medium-chain fatty acid triglyceride for injection is saturated straight-chain fatty acid triglyceride containing 6-12 carbon atoms.
In the present embodiment, the following oleaginous solvents are provided as examples.
Oleaginous solvent 1: comprises soybean oil for injection and benzyl benzoate, wherein the mass ratio of the soybean oil for injection to the benzyl benzoate is 2: 3;
greasy solvent 2: comprises olive oil for injection and benzyl benzoate, wherein the mass ratio of the olive oil for injection to the benzyl benzoate is 2: 3;
greasy solvent 3: comprises castor oil for injection and benzyl benzoate, wherein the mass ratio of the castor oil for injection to the benzyl benzoate is 2: 3;
oleaginous solvent 4: comprises peanut oil for injection and benzyl benzoate, wherein the mass ratio of the peanut oil for injection to the benzyl benzoate is 2: 3;
oleaginous solvent 5: comprises medium-chain fatty acid triglyceride and benzyl benzoate for injection, wherein the mass ratio of the medium-chain fatty acid triglyceride to the benzyl benzoate for injection is 2: 3;
greasy solvent 6: the injection-use medium-chain fatty acid triglyceride and soybean oil for injection comprise benzyl benzoate, wherein the mass ratio of the medium-chain fatty acid triglyceride for injection to the soybean oil for injection is 1:1, and the mass ratio of the sum of the medium-chain fatty acid triglyceride for injection and the soybean oil for injection to the benzyl benzoate is 2: 3.
In order to verify the solubility of the oleaginous solvent of the present invention for progesterone, the applicant further removed benzyl benzoate from the oleaginous solvent 1-6 to form oleaginous solvent comparative examples 1-6. Namely:
greasy solvent comparative example 1: soybean oil for injection;
greasy solvent comparative example 2: contains oleum Olivarum for injection;
greasy solvent comparative example 3: castor oil for injection and benzyl benzoate;
greasy solvent comparative example 4: peanut oil for injection;
greasy solvent comparative example 5: medium chain fatty acid triglycerides for injection;
greasy solvent comparative example 6: comprises medium-chain fatty acid triglyceride for injection and soybean oil for injection, wherein the mass ratio of the medium-chain fatty acid triglyceride for injection to the soybean oil for injection is 1: 1.
5ml of the above-mentioned oleaginous solvents 1 to 6 and oleaginous solvents comparative examples 1 to 6 were taken, respectively, an excess amount of progesterone was added, shaken at 25 ℃ for 24 hours, centrifuged to obtain a supernatant, filtered, and the subsequent filtrate was diluted with absolute ethanol, and then the concentration of progesterone was measured by an HPLC method (HPLC method under the term of progesterone in the second pharmacopoeia of China, 2015) to calculate the solubility in each solvent, as shown in Table 1.
TABLE 1 solubility of progesterone in oily solvents 1-6 and oily solvent comparative examples 1-6
| Solvent(s) | Composition of | Solubility of Progesterone (mg/ml) |
| Oleaginous solvent 1 | Soybean oil-benzyl benzoate for injection | 300.3 |
| Oleaginous solvent 2 | Olive oil-benzyl benzoate for injection | 298.8 |
| Oleaginous solvent 3 | Castor oil-benzyl benzoate for injection | 303.2 |
| Oleaginous solvent 4 | Peanut oil-benzyl benzoate for injection | 259.7 |
| Oleaginous solvent 5 | Middle-chain fatty acid triglyceride-benzyl benzoate for injection | 320.6 |
| Oleaginous solvent 6 | Medium chain fatty acid triglyceride-soybean oil-benzyl benzoate | 310.0 |
| Oleaginous solvent comparative example 1 | Soybean oil for injection | 18.0 |
| Oleaginous solvent comparative example 2 | Olive oil for injection | 17.7 |
| Oleaginous solvent comparative example 3 | Castor oil for injection | 19.0 |
| Oleaginous solvent comparative example 4 | Peanut oil for injection | 15.5 |
| Oleaginous solvent comparative example 5 | Medium-chain fatty acid triglyceride for injection | 32.8 |
| Oleaginous solvent comparative example 6 | Medium chain fatty acid triglyceride-soybean oil | 25.1 |
As is clear from the data in table 1, the solubility of the medium-chain fatty acid triglyceride for injection for progesterone is greater than that of the vegetable oil for injection for progesterone; the solubility of the mixture of the medium-chain fatty acid triglyceride for injection and the oil for injection on the progesterone is obviously superior to that of the single vegetable oil for injection. The oily solvent containing benzyl benzoate provided by the invention can be used for remarkably increasing the solubility of progesterone.
Example 2 Progesterone emulsion injection 1-3
In this example, 1 to 3 emulsion injections of progesterone, each of which was 5mg:1ml, 10mg:1ml and 20mg:1ml, were provided. The oily solvent contained in the progesterone emulsion injection comprises medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of the medium-chain fatty acid triglyceride to the benzyl benzoate is 2: 3. The progesterone emulsion injection also comprises egg yolk lecithin for injection and glycerin as an emulsifier; wherein the mass ratio of the yolk lecithin for injection to the oleaginous solvent is 12:100, and each 100 ml of the progesterone emulsion injection contains 2.5 g of glycerin.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 1: the specification is 5mg:1ml, and the formula comprises: 5g of progesterone, 60g of benzyl benzoate, 40g of triglyceride of medium-chain fatty acid, 12g of egg yolk lecithin, 25g of glycerol and 1000ml of water for injection.
Progesterone emulsion injection 2: the specification is 10mg:1ml, and the formula comprises: 10g of progesterone, 60g of benzyl benzoate, 40g of triglyceride of medium-chain fatty acid, 12g of egg yolk lecithin, 25g of glycerol and 1000ml of water for injection.
Progesterone emulsion injection 3: the specification is 20mg:1ml, and the formula comprises: 20g of progesterone, 60g of benzyl benzoate, 40g of triglyceride of medium-chain fatty acid, 12g of egg yolk lecithin, 25g of glycerol and 1000ml of water for injection.
The preparation method of the progesterone emulsion injection is as follows, the specific formula of each injection is different, but the steps of the preparation method are the same.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and medium-chain fatty acid triglyceride, heating to 65 deg.C, adding progesterone and egg yolk lecithin, stirring to dissolve, and making into mixed oil phase;
(2) dissolving glycerol in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection 1-3 of the embodiment has milky white appearance, the pH value of 6.5, the average particle size (Zeta average) of emulsion droplets of 182nm, the PDI of 0.15, the Zeta potential of-22.6 mV, the drug content of 95-105% of the labeled amount and the drug encapsulation rate of more than 90%.
Example 3 emulsion injection of Progesterone 4
In this example, 50mg:1ml of progesterone emulsion injection 4 is provided.
The oily solvent contained in the progesterone emulsion injection 4 contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of the medium-chain fatty acid triglyceride to the benzyl benzoate is 2: 3. The progesterone emulsion injection also comprises yolk lecithin for injection as an emulsifier, sodium oleate as a stabilizer and glycerol; wherein the mass ratio of the yolk lecithin for injection to the oleaginous solvent is 12.5:100, and each 100 ml of the progesterone emulsion injection contains 2.5 g of glycerin.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 4: the specification is 50mg:1ml, and the formula comprises: 50g of progesterone, 120g of benzyl benzoate, 80g of triglyceride of medium-chain fatty acid, 25g of egg yolk lecithin, 0.3g of sodium oleate, 25g of glycerol and 1000ml of water for injection.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and medium-chain fatty acid triglyceride, heating to 65 deg.C, adding progesterone and egg yolk lecithin, stirring to dissolve, and making into mixed oil phase;
(2) dissolving glycerol and sodium oleate in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion type injection 4 of the embodiment has the advantages of milky white appearance, 6.6 pH value, 195nm average particle size (Zeta average), 0.16 PDI, -32.2mV Zeta potential, 95-105% marking amount of drug content and more than 90% of drug encapsulation rate.
Example 4 emulsion injection of Progesterone 5
In this example, a 10mg:1ml emulsion injection 5 of progesterone was provided.
The oily solvent contained in the progesterone emulsion injection 5 contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of the medium-chain fatty acid triglyceride to the benzyl benzoate is 5: 4. The progesterone emulsion injection also comprises polysorbate 80 (also called tween 80) as an emulsifier, and glycerol; wherein the mass ratio of the polysorbate 80 to the oleaginous solvent is 23.1:100, and each 100 ml of the progesterone emulsion injection contains 2.0 g of glycerin.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 5: the specification is 10mg:1ml, and the formula comprises: 10g of progesterone, 48g of benzyl benzoate, 60g of triglyceride of medium-chain fatty acid, 25g of polysorbate 80, 20g of glycerol and 1000ml of water for injection.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and medium-chain fatty acid triglyceride, heating to 65 deg.C, adding progesterone, stirring to dissolve, and collecting mixed oil phase;
(2) dissolving glycerol and polysorbate 80 in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection 5 of the embodiment has the advantages of milk white appearance, pH value of 6.5, average particle size of emulsion droplets (Zeta average) of 163nm, PDI of 0.08, Zeta potential of-24.4 mV, drug content falling within the range of the labeled amount of 95-105%, and drug encapsulation rate of more than 90%.
Example 5 emulsion injection of Progesterone 6
In this example, a 50mg:1ml emulsion injection of progesterone 6 is provided.
The oily solvent contained in the progesterone emulsion injection 6 comprises castor oil for injection and benzyl benzoate, wherein the mass ratio of the castor oil for injection to the benzyl benzoate is 1: 3. The progesterone emulsion injection also comprises a mixture of soybean lecithin for injection and poloxamer 188 as an emulsifier, oleic acid as a stabilizer and glycerol; wherein the mass ratio of the emulsifier to the oleaginous solvent is 12:100, and each 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerol. And in the emulsifier, the mass ratio of the soybean lecithin for injection to the poloxamer 188 is 5: 1.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 6: the specification is 50mg:1ml, and the formula comprises: 50g of progesterone, 150g of benzyl benzoate, 50g of castor oil for injection, 20g of soybean lecithin for injection, 4g of poloxamer 188, 0.5g of oleic acid, 25g of glycerol and 1000ml of water for injection.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and castor oil for injection, heating to 65 deg.C, adding progesterone, oleic acid and soybean lecithin for injection, stirring to dissolve, and using as mixed oil phase;
(2) dissolving glycerol and poloxamer 188 in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection 6 of the embodiment has the advantages of milk white appearance, pH value of 6.5, average particle size of emulsion droplets (Zeta average) of 171nm, PDI of 0.08, Zeta potential of-28.7 mV, drug content falling within the range of the labeled amount of 95-105%, and drug encapsulation rate of more than 90%.
Example 6 emulsion injection of Progesterone 7
In this example, a 10mg:0.5ml emulsion injection 7 of progesterone was provided.
The oily solvent contained in the progesterone emulsion injection 7 comprises soybean oil for injection and benzyl benzoate, wherein the mass ratio of the soybean oil for injection to the benzyl benzoate is 2: 3. The progesterone emulsion injection also comprises a mixture of soybean lecithin for injection and polyoxyethylene 35 castor oil as an emulsifier, and glycerol; wherein the mass ratio of the emulsifier to the oleaginous solvent is 12:100, and each 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerol. In the emulsifier, the mass ratio of the soybean lecithin for injection to the polyoxyethylene 35 castor oil is 5: 1.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 7: the specification is 10mg:0.5ml, and the formula comprises: 20g of progesterone, 60g of benzyl benzoate, 40g of soybean oil for injection, 10g of soybean lecithin for injection, 2g of polyoxyethylene 35 castor oil, 25g of glycerol and 1000ml of water for injection.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and soybean oil for injection, heating to 65 deg.C, adding progesterone and soybean lecithin for injection, and stirring to dissolve to obtain mixed oil phase;
(2) dissolving glycerol and polyoxyethylene 35 castor oil in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection 7 of the embodiment has the advantages of milky white appearance, 6.6 pH value, 160nm average particle size (Zeta average), 0.10 PDI, 23.2mV Zeta potential, 95-105% of labeled amount of drug content and more than 90% of drug encapsulation rate.
Example 7 emulsion injection of Progesterone 8
In this example, a 50mg:2ml emulsion injection 8 of progesterone was provided.
The oily solvent contained in the progesterone emulsion injection 8 contains medium-chain fatty acid triglyceride and benzyl benzoate, wherein the mass ratio of the medium-chain fatty acid triglyceride to the benzyl benzoate is 3: 7. The progesterone emulsion injection also comprises a mixture of yolk lecithin for injection and poloxamer 188 as an emulsifier, benzyl alcohol as a bacteriostatic agent, and glycerol; wherein the mass ratio of the emulsifier to the oleaginous solvent is 12:100, and each 100 ml of the progesterone emulsion injection contains 2.5 g of the glycerol. And in the emulsifier, the mass ratio of the yolk lecithin for injection to the poloxamer 188 is 5: 1.
As an example, the specific formulation of the progesterone emulsion injection of the present embodiment is as follows.
Progesterone emulsion injection 8: the specification is 20mg:2ml, and the formula comprises: 25g of progesterone, 70g of benzyl benzoate, 30g of triglyceride of medium-chain fatty acid, 10g of egg yolk lecithin for injection, 1882 g of poloxamer, 10g of benzyl alcohol, 25g of glycerol and 1000ml of water for injection.
The preparation method comprises the following steps:
(1) mixing benzyl benzoate and medium-chain fatty acid triglyceride, heating to 65 deg.C, adding progesterone, injectable egg yolk lecithin and benzyl alcohol, stirring to dissolve, and making into mixed oil phase;
(2) dissolving glycerol and poloxamer 188 in water for injection, heating to 65 deg.C to obtain mixed water phase;
(3) slowly adding the mixed oil phase into the mixed water phase under high-speed stirring (15000rpm), continuously stirring at high speed for 10 minutes under the protection of nitrogen flow to obtain primary emulsion, and diluting to 1000ml with water for injection;
(4) under the protection of nitrogen flow, repeatedly homogenizing the primary emulsion by using a high-pressure homogenizer until the average particle size (Zeta average) is less than 250nm and PDI is less than 0.2;
(5) filtering with 0.45 μm microporous membrane, packaging (1 ml per bag), charging nitrogen, and sealing; and the number of the first and second groups,
(6) autoclaving at 121 deg.C for 15 min.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection 8 of the embodiment has the advantages of milk white appearance, pH value of 6.8, average particle size of emulsion droplets (Zeta average) of 168nm, PDI of 0.09, Zeta potential of-24.4 mV, drug content falling within the range of the labeled amount of 95-105%, and drug encapsulation rate of more than 90%.
Comparative example 1 emulsion injection of progesterone without benzyl benzoate (1 ml per injection containing 20mg of progesterone)
In this comparative example 1, a progesterone emulsion injection containing no benzyl benzoate was provided in a size of 20mg:1 ml. The specific formula is as follows: 20g of progesterone, 50g of soybean oil for injection, 50g of triglyceride of medium-chain fatty acid, 12g of egg yolk lecithin for injection, 25g of glycerol and 1000ml of water for injection. The preparation method of the progesterone is the same as that of example 2, and is not described herein again.
The prepared progesterone emulsion injection is taken, and the average particle size (Zetaaverage), the polydispersity index PDI and the Zeta potential of emulsion droplets are measured by a laser particle sizer. Filtering with 0.45 μm microporous membrane, diluting the filtrate with anhydrous ethanol to obtain progesterone concentration of about 100 μ g/ml, analyzing by HPLC method according to progesterone of 2015 th Chinese pharmacopoeia, and calculating the content of the medicinal materials in the injection. Centrifuging the injection in 100nm sieve filter, collecting the filtrate, diluting with ethanol, and measuring the concentration by HPLC to calculate the encapsulation rate of progesterone in the emulsion.
The verification shows that the progesterone emulsion injection of the comparative example 1 has milky white appearance, the pH value is 6.5, the average particle size (Zeta average) of emulsion droplets is 178nm, the PDI is 0.14, the Zeta potential is-25.0 mV, the drug content falls to 88.7 percent of the marked amount, and the drug encapsulation rate is more than 90 percent.
It can be seen that in the emulsion injection of progesterone of comparative example 1, which does not contain benzyl benzoate, the content of the drug is low due to insufficient solubility of progesterone in the oil phase (mixture of soybean oil for injection and medium-chain fatty acid triglyceride), and the precipitated drug is trapped during filtration.
Verification example 1 content of dissolved progesterone in progesterone emulsion injection after leaving the same
The progesterone emulsion injection of comparative example 1 and examples 2, 3 and 4 was taken and left at 25 ℃ and 60% relative humidity for 3 months. Filtering the emulsion with 0.45 μm microporous membrane, collecting the filtrate, diluting with anhydrous ethanol to obtain a labeled concentration of progesterone of about 100 μ g/ml, analyzing by HPLC method under the item of progesterone of the 2015 edition Chinese pharmacopoeia, and calculating the content of progesterone in the injection in dissolved state, the result is shown in Table 2.
TABLE 2 Progesterone content in the dissolved state after 3 months at room temperature
| Comparative example 1 | Example 2 | Example 3 | Example 4 | |
| Amount of progesterone in dissolved state (indicated%) | 75.2％ | 98.8％ | 98.0％ | 98.6％ |
As shown by the results in Table 2, in comparative example 1 containing no benzyl benzoate, the amount of progesterone in the dissolved state was only 75.2% of the total amount, indicating precipitation of progesterone. In a turbid emulsion system, the precipitated solid cannot be seen with the naked eye, and injection administration has a great risk. In the progesterone emulsion injection containing benzyl benzoate (examples 2, 3 and 4), progesterone still exists in a dissolved state, and obvious advantages are shown.
Verification example 2 diffusion of emulsion injection of Progesterone at injection site after intramuscular injection
In this test example, the dispersion of the progesterone emulsion injection of the present invention at the injection site after intramuscular injection was tested. Specifically, in this verification example, the progesterone emulsion injection described in example 5 was taken, and the oil-soluble fluorescent dye IR780 was added thereto, and sufficient sonication was performed to dissolve the IR 780.
In addition, as a control, a commercially available general progesterone oil solution type injection was also taken, and an oil-soluble fluorescent dye IR780 was added thereto for ultrasonic dissolution.
Commercially available SD rats were anesthetized with pentobarbital, the right thigh injection site was shaved, sterilized with 75% ethanol, and injected intramuscularly. 0.2ml of commercially available progesterone oil solution containing IR780 and 0.5ml of progesterone emulsion injection containing IR780 are injected respectively, and the volumes of oil-soluble solvents in the two samples to be tested are the same and are 0.2ml respectively.
Fluorescence at the injection site was observed on a small animal whole fluorescence imager 30 minutes and 12 hours after dosing, and the observation conditions were: the IR780 excitation wavelength was 770nm, the emission wavelength was 830nm, and the exposure time was 10 s. The fluorescence imaging images are shown in fig. 1A to 1D.
Wherein, fig. 1A is a fluorescence imaging graph after 30 minutes of injection of the progesterone emulsion injection of the invention, and fig. 1B is a fluorescence imaging graph after 30 minutes of injection of a commercially available progesterone injection; fig. 1C is a photograph showing fluorescence images of the progesterone emulsion injection of the present invention after 12 hours of injection, and fig. 1D is a photograph showing fluorescence images of the progesterone emulsion injection commercially available after 12 hours of injection.
As shown in fig. 1A and 1B, the difference between the fluorescence regions of the progesterone emulsion injection of the present invention and the commercially available progesterone injection after 30 minutes of intramuscular injection was not large, indicating that the oleaginous solvent in the progesterone emulsion injection of the present invention was concentrated in the vicinity of the injection region. Over time, as shown in fig. 1A and 1C, the fluorescence area of the progesterone emulsion injection provided by the invention is greatly expanded, while as shown in fig. 1B and 1D, the fluorescence area of the commercially available progesterone injection is not obviously changed, which indicates that the oily solvent of the progesterone emulsion injection provided by the invention is obviously diffused in muscle tissues after intramuscular injection, so that adverse reactions such as induration and the like at the injection site can be reduced.
Verification example 3 test of local induration and fat deposition after intramuscular injection of progesterone emulsion injection of the present invention
In this test example, the test of local induration and fat deposition after intramuscular injection of the progesterone emulsion injection of the present invention was examined. Specifically, in this verification example, the progesterone emulsion injection described in example 5 was used as an experimental group, and a commercially available progesterone injection was used as a control group.
Experimental animals: female New Zealand rabbits weigh 2.5-3.0 kg.
The experimental method comprises the following steps: new Zealand rabbits were randomly divided into 2 groups of 3 rabbits each. Using the progesterone emulsion injection of example 5 as a test group and a commercially available progesterone injection as a control group, 1ml was intramuscularly injected into the hind leg of a rabbit for 10 days, and the induration of the injection site was examined. The animals were sacrificed 24 hours after the last injection, and the skin at the injection site was cut open to observe the deposition of fat.
As a result: the injection site of the control group was able to feel a distinct induration when touched with a hand, whereas the injection site of the test group did not feel a induration. The skin at the injection site was cut open and observed, and the control group had macroscopic fat deposition around the injection site, while the test group had no fat deposition. The result proves that the progesterone emulsion injection can obviously reduce the adverse reaction of the injection part.
The present invention has been described in relation to the above embodiments, which are only exemplary of the implementation of the present invention. It must be noted that the disclosed embodiments do not limit the scope of the invention. Rather, modifications and equivalent arrangements included within the spirit and scope of the claims are included within the scope of the invention.
Claims (15)
1. A progesterone emulsion injection comprises progesterone, an oily solvent and water for injection, and is characterized in that the oily solvent is a mixture of oil for injection and benzyl benzoate, and the mass ratio of the oil for injection to the benzyl benzoate is 1: 5-5: 1.
2. The progesterone emulsion-type injection according to claim 1, wherein the oil for injection is at least one selected from the group consisting of vegetable oil for injection and medium-chain fatty acid triglyceride for injection.
3. The progesterone emulsion injection of claim 2, wherein the injectable vegetable oil is selected from at least one of injectable soybean oil, injectable castor oil, injectable corn oil, injectable rape oil, injectable sesame oil, injectable olive oil, injectable peanut oil and injectable sunflower oil.
4. The progesterone emulsion injection of claim 2, wherein the medium-chain triglyceride for injection is a saturated straight-chain triglyceride containing 6 to 12 carbon atoms.
5. The progesterone emulsion injection according to claim 1, wherein the mass ratio of progesterone to the oleaginous solvent is 5:100 to 30: 100.
6. The progesterone emulsion injection of claim 1, wherein the oleaginous solvent is contained in an amount of 5 to 40g per 100 ml of the progesterone emulsion injection.
7. The progesterone emulsion injection of any one of claims 1-6, further comprising an emulsifier and glycerol; wherein the mass ratio of the emulsifier to the oleaginous solvent is 5: 100-50: 100, and 0.5-3 g of glycerol is contained in each 100 ml of the progesterone emulsion injection.
8. The progesterone emulsion-type injection of claim 7, wherein the emulsifier is at least one selected from the group consisting of soybean lecithin for injection, egg lecithin for injection, polysorbate 80, polyoxyethylene castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer 188.
9. The progesterone emulsion-type injection of claim 8, wherein the emulsifier is soybean lecithin for injection, egg lecithin for injection, polysorbate 80, polyoxyethylene castor oil, or polyethylene glycol 15-hydroxystearate; wherein the mass ratio of the soybean lecithin or egg yolk lecithin for injection to the oleaginous solvent is 5: 100-30: 100;
the mass ratio of the polysorbate 80 to the oleaginous solvent is 5: 100-30: 100;
the mass ratio of the polyoxyethylene castor oil to the oleaginous solvent is 10: 100-40: 100;
the mass ratio of the polyethylene glycol 15-hydroxystearate to the oleaginous solvent is 10: 100-50: 100.
10. The progesterone emulsion-type injection of claim 8, wherein the emulsifier is a mixed emulsifier of one of soybean lecithin for injection and egg yolk lecithin for injection and at least one of polysorbate 80, polyoxyethylated castor oil, polyethylene glycol 15-hydroxystearate, and poloxamer 188; wherein the mass ratio of the soybean lecithin for injection or the egg yolk lecithin for injection to the mixed emulsifier is 1: 2-10: 11.
11. The progesterone emulsion injection of claim 10, wherein the mass ratio of the mixed emulsifier to the oleaginous solvent is 5:100 to 20: 100.
12. The emulsion injection of progesterone of claim 1 further comprising at least one of a stabilizer, a bacteriostatic agent, an analgesic and a pH adjuster.
13. The emulsion dosage form injection of progesterone of claim 12, wherein the stabilizer is selected from at least one of oleic acid and sodium oleate; the bacteriostatic agent is selected from at least one of benzyl alcohol, hydroxypropyl butyl ester (methyl ester), phenol, chlorobutanol and thimerosal; the analgesic is at least one selected from benzyl alcohol, chlorobutanol, lidocaine or procaine hydrochloride; the pH regulator is at least one selected from hydrochloric acid, sodium hydroxide, citric acid and sodium citrate.
14. The progesterone emulsion injection of claim 1, wherein the progesterone emulsion injection meets at least one of the following criteria: (i) the average particle size is 100-250 nm, (ii) the polydispersity index is less than 0.20, and (iii) the Zeta potential range is-20 mV to-40 mV.
15. A method for preparing the progesterone emulsion injection of claim 1, comprising: respectively and uniformly mixing the oil phase and the water phase in the formula under a heating state to obtain a mixed oil phase and a mixed water phase;
mixing the mixed oil phase and the mixed water phase, and then carrying out high-speed shearing emulsification and high-pressure homogenization to obtain an emulsion with the average particle size and the particle size distribution meeting the requirements;
a step of filtering the emulsion with a 0.45 μm microporous filter membrane; and the number of the first and second groups,
subpackaging, sealing by melting and sterilizing.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113730339A (en) * | 2021-09-17 | 2021-12-03 | 中国药科大学 | Progesterone sustained release composition and its application |
| CN113730339B (en) * | 2021-09-17 | 2023-08-22 | 中国药科大学 | Progesterone sustained-release composition and application thereof |
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| Publication number | Publication date |
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| WO2021179817A1 (en) | 2021-09-16 |
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Effective date of registration: 20200723 Address after: No.302, Hu Zhuangtou, sanhuangmiao village committee, Zhenglu Town, Changzhou City, Jiangsu Province Applicant after: Jiangsu Jiaerke Pharmaceutical Group Co.,Ltd. Address before: 201102 room q1022, floor 1, no.258, Pingyang Road, Minhang District, Shanghai Applicant before: Shanghai tufa Pharmaceutical Technology Co.,Ltd. |