CN113616594A - Preparation of progesterone nanocrystalline injection - Google Patents

Preparation of progesterone nanocrystalline injection Download PDF

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CN113616594A
CN113616594A CN202111036966.7A CN202111036966A CN113616594A CN 113616594 A CN113616594 A CN 113616594A CN 202111036966 A CN202111036966 A CN 202111036966A CN 113616594 A CN113616594 A CN 113616594A
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injection
progesterone
water
sodium chloride
nanocrystalline
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郭倩倩
徐成
邢珍珍
胡雄林
朱亚芳
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NANJING ZEHENG PHARMACEUTICAL SCIENCE & TECHNOLOGY CO LTD
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Abstract

The invention belongs to the field of biological pharmacy, and particularly discloses a preparation method of progesterone nanocrystalline injection. By the preparation technology of a nano crystal suspension of Top-Down, a stabilizing agent is prepared into a solution and stirred with progesterone to form a suspension, and the liquid medicine is poured into a grinding cavity of a wet grinder (containing crosslinked polystyrene resin) for grinding at 4000r for 45 min. The method not only effectively solves the problem that the progesterone API is difficult to dissolve in water, but also has good stability and simple preparation process, and is suitable for large-scale production and manufacturing.

Description

Preparation of progesterone nanocrystalline injection
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a preparation method of progesterone nano-crystalline injection.
Background
Progesterone (Progesterone), also known as Progesterone, gestagen, pregnenedione, chemically designated D-pregn-4-ene-3, 20-dione, with molecular formula C21H3O2Which is very soluble in chloroform, in ethylAlcohol, ether or vegetable oil, and is insoluble in water. The melting point of the progesterone is 128-131 ℃, the specific rotation degree is +186 to +198 degrees, and the structural formula is shown in figure 1.
With the comprehensive three-birth policy of China, the average number of newly-added pregnant mothers in the future is estimated to be close to 250 thousands of pregnant mothers every year. Obviously, this policy tends to emerge more and more in the elderly, and studies have shown that age is one of the factors that cause an increase in natural miscarriage rates. The pregnant women of advanced age have correspondingly declined ovarian function due to the older age, so the pregnancy abortion rate is higher. The current market for pregnant women to protect their fetus, prevent threatened abortion and supplement progesterone is the administration of progesterone. In the future, the demand for progesterone will also be increasing or decreasing.
Progesterone has wide clinical application, can be used for preventing spontaneous premature birth, treating luteal phase insufficiency, secondary amenorrhea and premenstrual syndrome, and also plays an important role in egg presentation, in vitro fertilization, hormone replacement treatment and the like. However, progesterone has low solubility and bioavailability, liver first-pass effect, and the injection prepared from the progesterone has high irritation and poor patient compliance. The preparation product with high efficiency and low toxicity can not be solved by the conventional preparation technology.
In recent years, scholars adopt various methods to improve the solubility of drugs, such as cyclodextrin inclusion, cosolvent solubilization and the like, but the methods have certain limitations, such as that the drug prepared into the cyclodextrin inclusion compound can increase the kidney burden of patients, and the cosolvent has the problems of drug precipitation, toxic and side effects of organic solvents and the like during compatibility. Progesterone oil injection is the most commonly used progesterone formulation. Intramuscular injection of oil can achieve effective blood concentration after being completely absorbed for 2-8h, has high bioavailability and no liver clearance mechanism, and is the most effective luteal phase supporting medicament at home and abroad at present. However, the progesterone injection on the market adopts an oil solvent, and the surface tension of oil molecules is large, so that the tissue absorption is slow, and the accumulation of liquid medicine in the tissue is easy to cause. After long-time administration by large-dose injection, the skin of the injection part is easily red and swollen, the pain is easy to cause, and the compliance of the patient is poor. The national food and drug administration (CFDA) issued article 178 in 2016, requiring all progesterone injection manufacturers to revise their drug specifications. The specific requirements include: one, adverse reactions, increase 'rash, pruritus, pain, irritation, red swelling at injection site, local induration, local aseptic abscess in severe patients, and artificial panniculitis case report'. Secondly, the attention points increase that if the product is applied in large dose for a long time, the risk of local induration is increased occasionally; severe local reactions such as local aseptic abscess, artificial panniculitis and the like occur; often the resulting local induration, absorption recovery in the sterile pus month takes a longer time ".
In conclusion, the development of a progesterone injection using water as a dispersion medium is clinically needed, and the problem of solubility is a difficult problem in the field.
The nanometer science and technology is a new technology rising at the end of the 20 s and is widely applied to the aspects of pharmacy, biology, material synthesis and the like. In recent years, the rapid development of nanocrystal technology has become an important research hotspot in the pharmaceutical field. The nano crystal drug adopts a small amount of surfactant to form a submicron colloidal dispersion system with pure drug particles, does not need carrier materials, is not limited by encapsulation efficiency, and has wide drug dosage adjustable range. There are generally two methods for preparing nanocrystals, i.e., the Bottom up method and the Top down method. The nanocrystalline injection can avoid the first pass action of the liver and the inactivation of the gastrointestinal tract caused by oral administration, and reduce the side effect of the gastrointestinal administration; compared with oil injection, the injection can reduce adverse reaction to injection part after administration, improve administration safety, and improve patient tolerance.
Disclosure of Invention
In order to solve the problem of the clinical preparation of the hydrophobic medicament, the invention adopts a Top down method, namely, the medicament powder with large particle size is crushed into small medicament particles by certain mechanical force, some stabilizing agents are added to maintain the stability of the preparation, and the nanocrystal technology not only can increase the solubility and dissolution of the medicament and improve the stability of the medicament, but also can improve the curative effect and bioavailability of the medicament and simultaneously reduce the toxic and side effect.
The purpose of the invention is realized by the following modes:
a progesterone nanocrystalline injection is characterized in that every 20000mL of the injection comprises the following components: 20g of progesterone, 30g of sodium chloride, 100 g of stabilizing agent and 300g of water for injection, wherein the volume of the water for injection is 20000 mL.
Preferably, the prescription of each 20000mL injection comprises the following components: 20g of progesterone, 30g of sodium chloride, 200g of stabilizing agent and 300g of water for injection, wherein the volume of the water for injection is 20000 mL.
Most preferably, the formulation of the injection per 20000mL is as follows: 20g of progesterone, 30g of sodium chloride, 200g of stabilizer and 20000mL of water for injection.
The stabilizer is Tween 80.
The preparation method of the progesterone nano-crystalline injection comprises the following steps:
adding stabilizer into sodium chloride water solution, stirring overnight on magnetic stirrer, adding 20g progesterone, stirring to obtain uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
It is worth mentioning that the preparation process of the invention requires common injection production equipment in the industry, and has high practicability. And the progesterone, sodium chloride and tween 80 used are commercially available.
The following is a brief description of the idea of the present invention and the process of searching for the kind and amount of the stabilizer.
1. Screening of stabilizer species
In view of the problem that progesterone API is hardly soluble in water, the inventors considered soybean lecithin, egg yolk lecithin, tween 80, docusate sodium, poloxamer 188 and the like as stabilizers, and screened out auxiliary materials that can be used for intramuscular injection from these stabilizers, followed by making a combination of prescriptions with reference to the usage amount of the auxiliary materials specified by FDA, and compared the dispersion coefficients of the particle diameters of the prepared samples. Brief description of the experiments the results are shown in table 1.
TABLE 1 particle size examination of five stabilizer samples
Stabilizer Particle size (nm) PDI RSD％
Soybean lecithin 7125 0.884 100
Egg yolk lecithin 1402 0.987 21.4
Tween 80 284.2 0.213 3.04
Docusate sodium 6521 0.721 15.8
Poloxamer 188 745.1 0.453 4.52
As can be seen from Table 1, the particle size of Tween 80 can reach nanoscale, which is 284.2nm, and PDI is 0.213 when the Tween 80 is ground under the same conditions, so that the Tween 80 has the characteristics of a nanosuspension, and the grinding effect of other auxiliary materials is not ideal and is mostly greater than the nanoscale, so that Tween 80 is selected as a stabilizer in the formula.
2. Screening of dosage
After the stabilizer is determined, the dosage of the stabilizer is further optimized, and since the maximum dosage of tween 80 for intramuscular injection is 12% (w/v) specified by FDA, five concentrations of 0.5%, 0.75%, 1%, 1.25% and 1.5% are selected for quality inspection respectively to determine suitable concentrations, and the results are shown in table 2.
TABLE 2 quality investigation results of samples prepared with different amounts of Tween 80
Figure BDA0003247589650000031
As can be seen from Table 2, the particle size gradually decreased as the content of Tween 80 increased, whereas the particle size was about 300nm as the content of Tween 80 was 1%, and the particle size did not decrease significantly as the content of Tween 80 was increased. Because tween 80 has slight hemolytic effect, the content should be selected to be lower by 1% in order to reduce the irritation as much as possible according to the characteristics of the injection.
Drawings
Figure 1 structural formula of progesterone.
Detailed Description
The present invention will be further illustrated by the following examples of the present invention, which are not intended to limit the scope of the present invention.
Example 1
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 200g
Water for injection 20000mL
Adding 200g Tween 80 into 30g sodium chloride water solution, stirring overnight on a magnetic stirrer, adding 20g progesterone, stirring to obtain uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
Example 2
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 210g
Water for injection 20000mL
Adding 210g Tween 80 into 30g sodium chloride water solution, stirring overnight on a magnetic stirrer, adding 20g progesterone, stirring to obtain uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
Example 3
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 220g
Water for injection 20000mL
Adding 220g Tween 80 into 30g sodium chloride water solution, stirring overnight on a magnetic stirrer, adding 20g progesterone, stirring to obtain a uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
Example 4
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 230g
Water for injection 20000mL
Adding 230g of Tween 80 into 30g of sodium chloride aqueous solution, stirring overnight on a magnetic stirrer, adding 20g of progesterone, stirring to obtain a uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
Example 5
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 240g
Water for injection 20000mL
Adding 240g of Tween 80 into 30g of sodium chloride aqueous solution, stirring overnight on a magnetic stirrer, then adding 20g of progesterone, stirring into a uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
Example 6
Per 20000mL progesterone nanocrystalline injection:
progesterone 20g
Sodium chloride 30g
Tween 80 250g
Water for injection 20000mL
Adding 250g of Tween 80 into 30g of sodium chloride aqueous solution, stirring overnight on a magnetic stirrer, adding 20g of progesterone, stirring to obtain a uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber (containing crosslinked polystyrene resin) of wet grinder at 4000r45min, adding water for injection to 20000mL to get final product.
By adopting the prescription process of the technical scheme of the embodiment 1-6, all quality indexes of the prepared product meet the regulations, and the detailed measurement results are shown in table 3.
Table 3 quality examination results of samples prepared in each example
Figure BDA0003247589650000061
Example 6
To investigate the stability of the prescription process, particle size stability for 60 days was investigated for the three lots of example 1. The results are shown in Table 4.
TABLE 4 stability test results of progesterone nanocrystalline injection
Figure BDA0003247589650000062
Figure BDA0003247589650000071
3 batches of the embodiment added with Tween 80 are tested for 2 months for a long time, all the quality accords with the specification, the particle size of the progesterone is controlled to be 300nm, and the PDI is about 0.2-0.3.

Claims (5)

1. A progesterone nanocrystalline injection is characterized in that every 20000mL of the injection comprises the following components: 20g of progesterone, 30g of sodium chloride, 100 g of stabilizing agent and 300g of water for injection, wherein the volume of the water for injection is 20000 mL.
2. The progesterone nano-crystalline injection of claim 1, wherein the formulation per 20000mL of injection is: 20g of progesterone, 30g of sodium chloride, 200g of stabilizing agent and 300g of water for injection, wherein the volume of the water for injection is 20000 mL.
3. The progesterone nano-crystalline injection of claim 1, wherein the formulation per 20000mL of injection is: 20g of progesterone, 30g of sodium chloride, 200g of stabilizer and 20000mL of water for injection.
4. The progesterone nanoparticle injection of claim 1 wherein the stabilizer is tween 80.
5. The progesterone nanocrystalline injection according to claim 1, wherein the complete preparation process comprises the following steps: adding stabilizer into sodium chloride water solution, stirring overnight on magnetic stirrer, adding 20g progesterone, stirring to obtain uniform suspension, and adding C25Stirring with dispersing emulsifying homogenizer, and grinding the medicinal liquid in grinding chamber of wet grinder (containing crosslinked polystyrene resin) for 4000r 45min, and adding water for injection to 20000 mL.
CN202111036966.7A 2021-09-06 2021-09-06 Preparation of progesterone nanocrystalline injection Pending CN113616594A (en)

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