A long-acting preparation of a locally injectable progesterone reversible temperature-sensitive gel and a preparation method thereof

Abstract

The application discloses a long-acting preparation of a reversible temperature-sensitive gel of a locally injected progesterone and a preparation method of the long-acting preparation. The gel long-acting preparation is prepared from the progesterone, a gel matrix poloxamer 407, a solubilizer polysorbate 80, a suspending agent polyethylene glycol 400, an analgesic and a preservative benzyl alcohol by using water for injection. The preparation has reversibility, can realize gelation under a body temperature condition and keeps a non-Newtonian fluid state when being lower than a gelation temperature. The preparation still keeps the temperature-sensitive gelation performance after being boiled and heat-press sterilized. The preparation can be rapidly gelled under a body temperature after being subcutaneously injected, forms a drug reservoir to realize slow release, can be slowly released in a rat body for 14 days and the in-vivo residence time is prolonged by 6 times compared with a reference preparation according to an animal PK experiment. In addition, an aqueous medium can significantly reduce pain caused by injection of an oily solvent, thereby effectively solving the problems of injection site pain and high injection frequency and providing a better progesterone medication guarantee for a pregnant population.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a long-acting reversible thermosensitive gel formulation of progesterone for local injection and its preparation method. Background Technology

[0002] Progesterone is a steroid hormone synthesized by the placenta, ovaries, and adrenal glands. Common clinical indications include threatened miscarriage, prevention of premature labor, dysfunctional uterine bleeding, and luteal insufficiency. Currently available progesterone products have various routes of administration, commonly including intramuscular injection, oral administration, and vaginal administration. Intramuscular injection is the most common method for maintaining normal pregnancy. However, progesterone injections use soybean oil as a solvent, and intramuscular injection can easily cause injection site pain, induration, and allergic reactions, even leading to local inflammation such as sterile cysts. Furthermore, progesterone requires continuous injections for several days during pregnancy maintenance, resulting in low patient compliance and prolonged pain. Oral administration also suffers from the first-pass effect in the liver, resulting in a small amount entering systemic circulation and low bioavailability. Vaginal administration often leads to increased discharge, breast tenderness, and other side effects; additionally, this type of dosage form is relatively expensive and has low patient accessibility.

[0003] Temperature-sensitive hydrogels (THCs) are a novel type of injectable formulation. They are flowable liquids at low or room temperature, but upon injection into the body, they rapidly gel, transforming from a liquid to a semi-solid state. This forms a local drug reservoir at the injection site, slowly releasing the drug for a long-lasting effect. Of the four injectable gel products marketed in the US between 2004 and 2018, three utilize the PLGA and N-2-methylpyrrolidone systems, specifically for the treatment of periodontitis. Used to treat prostate cancer And for drug rehabilitation Because N-2-methylpyrrolidone has reproductive toxicity, the instructions for use of drugs using this system all state that pregnant women should use it with caution. Summary of the Invention

[0004] The main objective of this invention is to provide a long-acting, reversible, thermosensitive progesterone gel formulation for local injection and its preparation method, to overcome the problems of injection site pain and poor compliance caused by frequent injections of oily progesterone injections during early pregnancy pregnancy maintenance treatment. Furthermore, the thermosensitive gel of this invention differs from ordinary irreversible thermosensitive gels; it can withstand high-temperature sterilization and retains thermosensitive gelation after cooling. Key quality attributes such as gelation time and gelation temperature remain unchanged after moist heat sterilization, thus achieving a long-term effect of 1-2 weeks with a single injection, and maintaining effective thermosensitive gelation even after terminal sterilization.

[0005] The aforementioned long-acting, locally injectable reversible thermosensitive gel formulation of progesterone is prepared with water for injection. The mass concentrations of each component are as follows: progesterone 0.06-0.1 g / mL, gel matrix poloxamer 407 0.15-0.20 g / mL, solubilizer polysorbate 80 0.001-0.005 g / mL, suspending agent polyethylene glycol 400 0.03-0.05 g / mL, and analgesic and preservative benzyl alcohol 0.005-0.01 g / mL.

[0006] Preferably, the mass concentrations of each component are as follows: progesterone 0.06 g / mL, gel matrix poloxamer 407 0.17 g / mL, solubilizer polysorbate 80 0.001 g / mL, suspending agent polyethylene glycol 400 0.03 g / mL, and analgesic and preservative benzyl alcohol 0.01 g / mL.

[0007] One method for preparing the local injection of reversible thermosensitive progesterone gel long-acting formulation is as follows: Poloxamer 407 is added to water for injection and dissolved by shaking in a shaker at 4-20℃; then polysorbate 80 and benzyl alcohol are added, and after shaking to dissolve, progesterone micro powder is added in portions and ground and dispersed until there are no obvious particulate powders on the container wall and in the solution; then polyethylene glycol 400 is added, and after further grinding and dispersion, the mixture is sealed and placed in a refrigerator at 2-8℃ for 5-20 minutes. After filling, it is placed in an autoclave at 120-125℃ for 10-20 minutes to sterilize, thus obtaining the local injection of reversible thermosensitive progesterone gel long-acting formulation.

[0008] The second method for preparing the local injection reversible thermosensitive gel long-acting formulation is as follows: Polyethylene glycol 400 is added to water for injection, followed by poloxamer 407, and the mixture is shaken and dissolved at 4-20℃; then polysorbate 80 and benzyl alcohol are added, and after shaking and dissolving, progesterone micro powder is added in portions and ground and dispersed until there are no obvious particulate powder particles on the container wall and in the solution; the mixture is sealed and refrigerated at 2-8℃ for 5-20 minutes, then filled and sterilized in an autoclave at 120-125℃ for 10-20 minutes to obtain the local injection reversible thermosensitive gel long-acting formulation.

[0009] The reversible, temperature-sensitive, long-acting progesterone gel formulation prepared in this invention is reversible, capable of gelling at body temperature and exhibiting a pseudoplastic fluid state, while maintaining a non-Newtonian fluid state below the gelation temperature. Furthermore, this formulation possesses high-temperature resistance, retaining its temperature-sensitive gelling properties even after boiling and autoclaving, with a gelation temperature of 31°C, a gelation time of 0.5-1 min, and a pH of 7.0-9.6. This long-acting gel formulation undergoes a reversible phase transition in vitro with changes in ambient temperature. Subcutaneous injection results in rapid gelation at body temperature, forming a drug reservoir for sustained release. In rats, this formulation provides sustained release for 14 days, with a 6-fold longer average residence time and a relative bioavailability of 60.23% compared to oil-based progesterone injections. Moreover, the aqueous medium significantly reduces pain associated with oil-based injections, effectively addressing the issues of injection site pain and high injection frequency, thus providing better progesterone administration for pregnant women. Attached Figure Description

[0010] Figure 1 The left image shows the side view of the long-acting, locally injected reversible thermosensitive gel formulation of progesterone prepared in Example 1 after gelation and when placed at an angle; the right image shows the surface state when placed at an angle.

[0011] Figure 2 The left image shows the gelation state of the long-acting, locally injectable progesterone reversible thermosensitive gel formulation prepared in Example 2 before terminal sterilization; the right image shows the gelation state of the formulation after re-gelling following sterilization, placed horizontally.

[0012] Figure 3 : An upright microscope image of the long-acting, locally injected progesterone reversible thermosensitive gel formulation prepared in Example 1.

[0013] Figure 4 Scanning electron microscope image of the long-acting, locally injected progesterone reversible thermosensitive gel formulation prepared in Example 1.

[0014] Figure 5 Example 1: Shear stress versus shear rate curve of the local injection reversible thermosensitive gel long-acting formulation of progesterone.

[0015] Figure 6 Example 1: Viscosity of the long-acting, locally injected progesterone reversible thermosensitive gel formulation as a function of shear rate.

[0016] Figure 7 Rheological temperature scanning results of the long-acting, locally injected progesterone reversible thermosensitive gel formulation prepared in Example 1.

[0017] Figure 8The in vivo formation image observed half an hour after subcutaneous injection of 0.3 mL of the long-acting local progesterone reversible thermosensitive gel formulation prepared in Example 1 into the back of an SD rat.

[0018] Figure 9 Bar chart showing the percentage of residual progesterone in the subcutaneous gel after subcutaneous injection of 0.3 mL / rat of the long-acting, locally injected progesterone reversible thermosensitive gel formulation prepared in Example 1 on days 1, 2, 3, 7, and 14.

[0019] Figure 10 Example 1: Finished product of the local injection reversible thermosensitive gel long-acting formulation of progesterone.

[0020] Figure 11 Comparison of blood concentration curves between subcutaneous injection of 0.3 mL / rat of the long-acting, locally injected progesterone reversible thermosensitive gel formulation prepared in Example 1 and subcutaneous injection of 0.36 mL of the commercially available oily injection solution. Detailed Implementation

[0021] Example 1

[0022] Add 1.70g of poloxamer 407 to 10mL of water for injection and dissolve by shaking in a shaker at 15℃ for 2 hours. Then add 0.01g of polysorbate 80 and 0.1g of benzyl alcohol, shake to dissolve, and transfer to a grinder. Add 0.6g of progesterone micro powder in 5 portions and grind to disperse until there are no obvious particulate powders on the container wall and in the solution. Then add 0.3g of polyethylene glycol 400 and continue to grind and disperse evenly. Seal and refrigerate at 4℃ for 10 minutes until it no longer sticks to the container wall. Remove and fill into single pre-filled syringes, 2mL / syringe. Finally, sterilize in an autoclave at 121℃ for 15 minutes to obtain a long-acting, reversible, temperature-sensitive progesterone gel for local injection.

[0023] Depend on Figure 3 and Figure 4 As shown in the upright microscope and scanning electron microscope images, when the above-mentioned gel matrix cannot be rapidly dissolved and dispersed, it presents a state of encapsulating progesterone drug particles. After gelation, the progesterone particles are encapsulated in the dense structure formed by the gel matrix.

[0024] Depend on Figure 5 and Figure 6 As shown, at low and room temperatures, its shear stress (τ) increases linearly with the shear rate (γ') and its viscosity (η) does not change with the increase of the shear rate (γ'), exhibiting the properties of a Newtonian fluid. At body temperature, the overall trend of the formulation with γ' tends to be stable, and the sample η decreases with the increase of γ', exhibiting the state of a pseudoplastic fluid.

[0025] Depend on Figure 8 and Figure 9 As shown, the gel formulation can gel in animals and achieve long-term sustained release in SD rats. The local drug dosage shows a decreasing trend over time, decreasing by 15% on the second day, 5% on the third day, and a total reduction of 85% over two weeks.

[0026] Depend on Figure 11 Animal studies comparing the gel formulation with marketed oil-based injectable solutions showed that the gel formulation had a significantly longer average residence time (6 times longer) and a relative bioavailability of 60.23% compared to the oil-based injectable solution.

[0027] Example 2

[0028] Add 0.5g of polyethylene glycol 400 to 10mL of water for injection, then add 2.00g of poloxamer 407, and shake to dissolve for 2 hours at 15℃. Then add 0.01g of polysorbate 80 and 0.1g of benzyl alcohol, shake to dissolve, and transfer to a grinder. Add 0.6g of progesterone micro powder in 5 portions and grind to disperse until there are no obvious particulate powder particles on the container wall and in the solution. Seal and refrigerate at 4℃ for 10 minutes until it no longer sticks to the container wall. Remove and fill into single pre-filled syringes, 2mL / syringe. Finally, sterilize in an autoclave at 121℃ for 15 minutes to obtain a long-acting, reversible, temperature-sensitive progesterone gel for local injection.

[0029] Example 3

[0030] Same as Example 2, except that the amount of poloxamer 407 used is 1.70g.

[0031] Example 4

[0032] Same as Example 2, except that the amount of poloxamer 407 used is 1.60g.

Claims

1. A long-acting, locally injectable, reversible, temperature-sensitive progesterone gel formulation, characterized in that... The long-acting gel formulation is prepared with water for injection, and the mass concentrations of each component are as follows: progesterone 0.06-0.1 g / mL, gel matrix poloxamer 407 0.15-0.20 g / mL, solubilizer polysorbate 80 0.001-0.005 g / mL, suspending agent polyethylene glycol 400 0.03-0.05 g / mL, and analgesic and preservative benzyl alcohol 0.005-0.01 g / mL.

2. The long-acting, locally injectable progesterone reversible thermosensitive gel formulation according to claim 1, characterized in that, The mass concentrations of each component are as follows: progesterone 0.06 g / mL, gel matrix poloxamer 407 0.17 g / mL, solubilizer polysorbate 80 0.001 g / mL, suspending agent polyethylene glycol 400 0.03 g / mL, and analgesic and preservative benzyl alcohol 0.01 g / mL.

3. The method for preparing the long-acting, locally injectable progesterone reversible thermosensitive gel formulation according to claim 1, characterized in that, The specific steps of the preparation method are as follows: Poloxamer 407 is added to water for injection and dissolved by shaking in a shaker at 4-20℃; then polysorbate 80 and benzyl alcohol are added, and after shaking to dissolve, progesterone micro powder is added in portions and ground and dispersed until there are no obvious particulate powders on the container wall and in the solution; then polyethylene glycol 400 is added, and after further grinding and dispersion, the mixture is sealed and placed in a refrigerator at 2-8℃ for 5-20 minutes. After filling, it is placed in an autoclave at 120-125℃ for 10-20 minutes to sterilize, thus obtaining a long-acting reversible thermosensitive progesterone gel for local injection.

4. The method for preparing the long-acting, locally injectable progesterone reversible thermosensitive gel formulation according to claim 1, characterized in that, The specific operation of the preparation method is as follows: polyethylene glycol 400 is added to water for injection, then poloxamer 407 is added, and the mixture is shaken and dissolved in a shaker at 4-20℃; then polysorbate 80 and benzyl alcohol are added, and after shaking and dissolving, progesterone micro powder is added in portions, and the mixture is ground and dispersed until there are no obvious particulate powders on the container wall and in the solution; the mixture is sealed and placed in a refrigerator at 2-8℃ for 5-20 minutes, and after filling, it is placed in an autoclave at 120-125℃ for 10-20 minutes to sterilize, thus obtaining a long-acting reversible thermosensitive progesterone gel for local injection.

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