Novel long-acting preparation and preparation method thereof

Abstract

The invention discloses a novel long-acting preparation and a preparation method thereof, belongs to the field of pharmaceutical preparations, and finds that a certain amount of glyceryl monolinoleate (GMLO) and soybean lecithin (SPC) can be fully and uniformly mixed in a certain amount of ethanol (ETOH) or N-methyl pyrrolidone (NMP) to form a clear liquid with good fluidity, and the liquid has a good effect on hydrophobic drugs ZL006-05 (code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name Y-3, code name The compound has a good dissolving effect. The formula (1) is shown in the description. When the liquid preparation is exposed to a water-containing component such as body fluid, gel is formed, so that a long-acting drug release effect is achieved. The liquid preparation can also be used for slow-release carriers of drugs with other properties. The invention also relates to a delivery method using the liquid formulation.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a novel long-acting preparation and a preparation method thereof. Background Art

[0002] Y-3 is a small molecule PSD-95 inhibitor that is poorly soluble in water and has the activity of dissociating the coupling of PSD-95 and nNOS. Preclinical efficacy and toxicology studies have shown that the efficacy of Y-32mg / kg is equivalent to the same dose of edaravone and dextroborneol (a neuroprotectant launched in 2020). It is also safe and has no obvious dependence, and has potential application value in the treatment of pathological neuralgia. However, due to its poor solubility in water, strong photosensitivity, and reduced stability at high temperatures, it is mostly used clinically for indications requiring long-term administration. Therefore, it is of great significance to prepare a long-acting sustained-release preparation.

[0003] The present invention has discovered that a certain amount of glyceryl monolinoleate (GMLO) and soybean lecithin (SPC) can be thoroughly mixed in a certain amount of ethanol (ETOH) or N-methylpyrrolidone (NMP) to form a clear, fluid liquid that effectively dissolves the hydrophobic drug ZL006-05 (codenamed Y-3, hereinafter referred to as Y-3). When exposed to aqueous components, such as body fluids, the liquid formulation forms a gel, thereby achieving sustained drug release. After administration via subcutaneous, intramuscular, or adipose injection, the gel forms in vivo, continuously releasing the active substance, thereby reducing the number of dosing cycles. Summary of the Invention

[0004] Technical problem solved: The present invention provides a new long-acting preparation and its preparation method, which solves the technical problems that Y-3 has poor solubility in water, strong photosensitivity, reduced stability at high temperatures, and is mostly used in clinical practice for long-term administration.

[0005] Technical solution: A long-acting preparation carrier comprising one or more of the following components:

[0006] a) at least an amount of glyceryl monolinoleate;

[0007] b) at least a certain amount of soybean lecithin;

[0008] c) at least a certain amount of one or both of ethanol and N-methylpyrrolidone as a solvent;

[0009] The mass ratio of monolinoleyl glyceride is 20% to 90%; the mass ratio of soybean lecithin is 10% to 80%; and the mass ratio of the solvent is 5% to 50%.

[0010] A long-acting preparation comprising one or more of the following components:

[0011] a) at least an amount of glyceryl monolinoleate;

[0012] b) at least a certain amount of soybean lecithin;

[0013] c) at least a certain amount of one or both of ethanol and N-methylpyrrolidone as a solvent;

[0014] d) at least a certain amount of Y-3;

[0015] The mass ratio of monolinoleyl glyceride is 20% to 90%; the mass ratio of soybean lecithin is 10% to 80%; and the mass ratio of the solvent is 5% to 50%.

[0016] Preferably, the viscosity of the long-acting preparation is less than or equal to 18 mPas at 25 degrees.

[0017] Preferably, the drug loading amount of Y-3 is 0.1 to 150 mg / g.

[0018] Preferably, the long-acting preparation transforms from a liquid into a liquid crystal when in contact with water, and the liquid crystal phase structure is one or more of a lamellar phase, a cubic phase or a hexagonal phase, and the phase structure does not change after loading with Y-3.

[0019] Preferably, the administration route of the long-acting preparation includes subcutaneous injection, intramuscular injection or fat injection.

[0020] Preferably, the preparation method is:

[0021] Step a: Weigh soybean lecithin (SPC), add one or both of ethanol and N-methylpyrrolidone to completely dissolve the soybean lecithin;

[0022] Step b: adding glyceryl monolinoleate (GMLO) and mixing thoroughly to prepare a blank long-acting preparation;

[0023] Step c: Weigh Y-3 and add it to the blank long-acting preparation. Shake thoroughly until Y-3 dissolves. Pre-filter through a 0.45 μm filter membrane. Sterilize the filtrate through a 0.22 μm + 0.22 μm filter membrane. Dispense into ampoules or pre-filled syringes.

[0024] Preferably, the preparation method is:

[0025] Step a: Weigh soybean lecithin (SPC), add one or both of ethanol and N-methylpyrrolidone to completely dissolve the soybean lecithin;

[0026] Step b: adding glyceryl monolinoleate (GMLO) and mixing thoroughly to prepare a blank long-acting preparation;

[0027] Step c: Weigh Y-3 and add it to the blank long-acting preparation. Shake thoroughly until the Y-3 dissolves. Pre-filter through a 0.45 μm filter membrane. Sterilize the filtrate through a 0.22 μm + 0.22 μm filter membrane. Dispense into ampoules or pre-filled syringes.

[0028] Step d: After the subpackaging is completed, the product is sterilized by moist heat sterilization at 121 degrees Celsius for 30 minutes to obtain a long-acting preparation.

[0029] Preferably, the long-acting preparation is sterilized by filtration or terminal sterilization.

[0030] A long-acting preparation and its application, wherein the long-acting preparation is used to prepare a drug for treating chronic neurological diseases, including retinal ischemia, pathological neuralgia, vascular dementia and indications requiring long-term administration.

[0031] Beneficial effects:

[0032] Molecules with amphiphilic groups can associate in water to form semisolid gels. Their internal structure includes hydrophilic regions, hydrophobic regions, and lipid layers. Therefore, they can encapsulate drug molecules with different activities, such as hydrophilic, hydrophobic, and amphiphilic. In this study, soybean lecithin (SPC) and monolinoleylglycerol (GMLO) were thoroughly mixed in the presence of a certain amount of ethanol or N-methylpyrrolidone to form a light yellow clear liquid preparation with good fluidity. Propylene glycol can be appropriately added to adjust the viscosity of the system. The preparation structure was observed under a polarized light microscope, the preparation characterization was evaluated, and in vitro and in vivo drug release experiments were conducted to verify the long-term sustained-release performance.

[0033] The further significant advantage of above-mentioned Y-3 long-acting preparation is that medicine is discharged gradually through long time, and and do not need repeated administration.Therefore this dosage form is particularly suitable for the very important situation of object compliance difficulty, unreliable or dosage level.

[0034] Another advantage of the present invention is that after contact with water, a mixed phase with multiple phase structures coexisting is formed, which has a good solubilization effect and structural protection effect on Y-3, and can be stored for a long time without phase separation and Y-3 structural transformation.

[0035] The present invention can be used for multiple administration methods such as subcutaneous, intramuscular, and fat administration, and the injection sites may include the gluteus maximus, deltoid muscle, abdominal fat layer, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The present invention will now be further illustrated with reference to the following non-limiting examples and accompanying drawings, in which:

[0037] Figure 1 The structure of the long-acting preparation under polarized light microscopy is illustrated;

[0038] Figure 2 The dissolution of Y-3 in the long-acting preparation was described;

[0039] Figure 3 This indicates that the addition of Y-3 does not change the phase structure of the long-acting preparation;

[0040] Figure 4 The figure shows the Y-3 concentration in rats after subcutaneous injection of a long-acting formulation containing 80 mg / g of Y-3.

[0041] Figure 5 The figure shows the Y-3 concentration in rats after intramuscular injection of different doses of a long-acting formulation containing 80 mg / g of Y-3.

[0042] Figure 6 The in vitro release of 80 mg / g Y-3 depot in excess aqueous phase is shown. DETAILED DESCRIPTION

[0043] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0044] Example 1: Effect of Component Dosage on the Long-Acting Formulation

[0045] Injectable formulations containing different ratios of soybean phospholipids (SPC) and monolinoleylglycerol (GMLO) and ethanol (EtOH) as solvent were prepared, and different phase structures were formed after adding excess water.

[0046] Step a: Weigh the prescribed amount of soybean lecithin (SPC), add a certain amount of ethanol to completely dissolve the soybean lecithin,

[0047] Step b: Add glyceryl monolinoleate (GMLO) and mix thoroughly to obtain a blank long-acting preparation.

[0048] Step c: Add appropriate amount of propylene glycol (PG) to adjust the viscosity.

[0049] Step d: Each preparation was dropped into a beaker of water and the phase behavior was observed at 25°C using a polarized light microscope.

[0050] The results are listed in Table 1.

[0051] Table 1 Phase difference of long-acting preparations with different component dosages

[0052]

[0053]

[0054] Q Ⅱ = reverse cubic phase

[0055] H II = Reverse hexagonal phase

[0056] Lα=Lamellar phase

[0057] Example 2: Solubility experiment of Y-3 in the long-acting preparation

[0058] Prepare a blank long-acting preparation according to the following steps: Step a: Weigh 2.947 g of soybean lecithin (SPC), add 1 g of ethanol to completely dissolve the soybean lecithin,

[0059] Step b: Add 5.473 g of glyceryl monolinoleate (GMLO) and mix thoroughly to obtain a blank long-acting preparation.

[0060] Step c: Add 0.5 g of propylene glycol (PG) to adjust the viscosity.

[0061] Weigh 30mg, 60mg, 90mg, 120mg, 150mg, 180mg and 210mg respectively into 1g of blank long-acting preparation and shake thoroughly to dissolve Y-3. The dissolution of Y-3 in lyotropic liquid crystal is shown in Fig. Figure 2 .

[0062] Example 3: Subcutaneous administration of Y-3 long-acting formulation to study in vivo release

[0063] Prepare the Y-3 long-acting preparation as follows:

[0064] Step a: Weigh 2.947 g of soybean lecithin (SPC) and add 1 g of ethanol to completely dissolve the soybean lecithin;

[0065] Step b: Add 5.473 g of glyceryl monolinoleate (GMLO) and mix thoroughly to obtain a blank long-acting preparation;

[0066] Step c: Add 0.5 g of propylene glycol (PG) to adjust the viscosity;

[0067] Step d: Weigh 800 mg of Y-3 and add it to a blank long-acting preparation. Shake thoroughly until Y-3 dissolves to prepare an 80 mg / g Y-3 long-acting preparation. Pre-filter through a 0.45 μm filter membrane.

[0068] In vivo drug release studies were conducted in SD rats. The formulation was administered subcutaneously between the shoulder blades using a 21G syringe (0.6 mm x 30 mm) at a dose of 30 mg / kg. Release profiles were monitored over 14 days. LC-MS was used to analyze Y-3 concentrations in rat plasma samples. The Y-3 plasma concentration curves for the long-acting formulation in SD rats are shown in Figure 2. Figure 4 .

[0069] Y-3 can still be detected in the 80mg / g Y-3 long-acting preparation within 14 days, and the sustained-release effect of the long-acting preparation is fully demonstrated.

[0070] Example 4: Intramuscular injection of Y-3 long-acting formulation to study in vivo release

[0071] The long-acting preparation is prepared according to the following steps:

[0072] Step a: Weigh 2.947 g of soybean lecithin (SPC) and add 1 g of ethanol to completely dissolve the soybean lecithin;

[0073] Step b: Add 5.473 g of glyceryl monolinoleate (GMLO) and mix thoroughly to obtain a blank long-acting preparation;

[0074] Step c: Add 0.5 g of propylene glycol (PG) to adjust the viscosity;

[0075] Step d: Weigh 800 mg of Y-3 and add it to a blank long-acting preparation. Shake thoroughly until Y-3 dissolves to prepare an 80 mg / g Y-3 long-acting preparation. Pre-filter through a 0.45 μm filter membrane.

[0076] In vivo drug release studies were conducted in SD rats. The formulation was injected into the left hind limb muscle of the SD rats using a 21G syringe (0.6 mm x 30 mm) at doses of 30 mg / kg, 60 mg / kg, and 120 mg / kg. Release profiles were monitored over 14 days. LC-MS was used to analyze Y-3 concentrations in rat plasma samples. The Y-3 plasma concentration curves for the long-acting formulation in SD rats are shown in Figure 2. Figure 5At a formulation concentration of 80 mg / g and a 30 mg / kg dose, the Cmax was 77.4 ng / mL, Tmax was 76 hours, and AUC was 13075 h*ng / mL when injected intramuscularly in rats. At a formulation concentration of 80 mg / g and a 60 mg / kg dose, the Cmax was 329 ng / mL, Tmax was 108 hours, and AUC was 24434 h*ng / mL when injected intramuscularly in rats. At a formulation concentration of 80 mg / g and a 120 mg / kg dose, the Cmax was 184 ng / mL, Tmax was 92 hours, and AUC was 32854 h*ng / mL when injected intramuscularly in rats. These Y-3 exposures required for analgesic effects were achieved. The experimental PK parameters described in Examples 3 and 4 are shown in Table 2.

[0077] Table 2 Experimental PK parameters in Example 4

[0078]

[0079] A = 80 mg / g formulation concentration, 30 mg / kg administered subcutaneously in rats;

[0080] B = 80 mg / g formulation concentration, 30 mg / kg administered intramuscularly in rats;

[0081] C = 80 mg / g formulation concentration, 60 mg / kg administered intramuscularly in rats;

[0082] D = 80 mg / g of the preparation concentration, 120 mg / kg of the administration dose was injected intramuscularly in rats.

[0083] Example 5: In vitro cumulative release of Y-3 long-acting preparation

[0084] The long-acting preparation is prepared according to the following steps:

[0085] Step a: Weigh 2.947 g of soybean lecithin (SPC) and add 1 g of ethanol to completely dissolve the soybean lecithin;

[0086] Step b: Add 5.473 g of glyceryl monolinoleate (GMLO) and mix thoroughly to obtain a blank long-acting preparation;

[0087] Step c: Add 0.5 g of propylene glycol (PG) to adjust the viscosity;

[0088] Step d: Weigh 800 mg of Y-3 and add it to the blank long-acting preparation. Shake thoroughly until the Y-3 dissolves to prepare an 80 mg / g Y-3 long-acting preparation. Pre-filter through a 0.45 μm filter membrane.

[0089] Step e: Select 30mg / kg, 60mg / kg, and 120mg / kg doses and place them in dialysis bags. Place them in the dissolution medium and stir at constant temperature. Take out a certain amount of release medium at regular intervals and add the same volume of fresh dissolution medium. The in vitro release curves are shown in Figure 6 .

[0090] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be encompassed therein. Any reference in a claim should not be construed as limiting the claim to which it relates.

Claims

1. A long-acting preparation carrier, characterized in that Contains one or more of the following components: a) at least an amount of glyceryl monolinoleate; b) at least a certain amount of soybean lecithin; c) at least a certain amount of one or both of ethanol and N-methylpyrrolidone as a solvent; The mass ratio of monolinoleyl glyceride is 20% to 90%; the mass ratio of soybean lecithin is 10% to 80%; and the mass ratio of the solvent is 5% to 50%.

2. A long-acting preparation, characterized in that Contains one or more of the following components: a) at least an amount of glyceryl monolinoleate; b) at least a certain amount of soybean lecithin; c) at least a certain amount of one or both of ethanol and N-methylpyrrolidone as a solvent; d) at least a certain amount of Y-3; The mass ratio of monolinoleyl glyceride is 20% to 90%; the mass ratio of soybean lecithin is 10% to 80%; and the mass ratio of the solvent is 5% to 50%.

3. The long-acting preparation according to claim 2, characterized in that The viscosity of the long-acting preparation is less than or equal to 18 mPas at 25 degrees.

4. The long-acting preparation according to claim 2, characterized in that The drug loading amount of the Y-3 is 0.1 to 150 mg / g.

5. The long-acting preparation according to claims 2 to 4, characterized in that The long-acting preparation changes from liquid to liquid crystal when it comes into contact with water. The liquid crystal phase structure is one or more of a lamellar phase, a cubic phase or a hexagonal phase. The phase structure does not change after loading with Y-3.

6. The long-acting preparation according to claims 2 to 4, characterized in that The administration routes of the long-acting preparation include subcutaneous injection, intramuscular injection or fat injection.

7. The long-acting preparation according to claims 2 to 4, characterized in that The preparation method is: Step a: Weigh soybean lecithin (SPC), add one or both of ethanol and N-methylpyrrolidone to completely dissolve the soybean lecithin; Step b: adding glyceryl monolinoleate (GMLO) and mixing thoroughly to prepare a blank long-acting preparation; Step c: Weigh Y-3 and add it to the blank long-acting preparation. Shake thoroughly until Y-3 dissolves. Pre-filter through a 0.45 μm filter membrane. Sterilize the filtrate through a 0.22 μm + 0.22 μm filter membrane. Dispense into ampoules or pre-filled syringes.

8. The long-acting preparation according to claim 7, characterized in that The preparation method is: Step a: Weigh soybean lecithin (SPC), add one or both of ethanol and N-methylpyrrolidone to completely dissolve the soybean lecithin; Step b: adding glyceryl monolinoleate (GMLO) and mixing thoroughly to prepare a blank long-acting preparation; Step c: Weigh Y-3 and add it to the blank long-acting preparation. Shake thoroughly until the Y-3 dissolves. Pre-filter through a 0.45 μm filter membrane. Sterilize the filtrate through a 0.22 μm + 0.22 μm filter membrane. Dispense into ampoules or pre-filled syringes. Step d: After the subpackaging is completed, the product is sterilized by moist heat sterilization at 121 degrees Celsius for 30 minutes to obtain a long-acting preparation.

9. The long-acting preparation according to claim 2, characterized in that The long-acting preparation is sterilized by filtration or terminal sterilization.

10. A long-acting preparation and its application, characterized in that: The long-acting preparation is used as a drug for the preparation of a drug for treating chronic nervous system diseases, wherein the chronic nervous system diseases include retinal ischemia, pathological neuralgia, vascular dementia and indications requiring long-term administration.

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