Long-acting sustained-release pramipexole preparation and method for preparing the same

Abstract

There are provided a sustained-release pramipexole preparation with a long-acting effect and a method for preparing the same. The sustained-release pramipexole preparation with a long-acting effect contains pramipexole pamoate or pramipexole palmitate and a polylactic acid-glycolic acid copolymer or polylactic acid. The drug loading capacity of the preparation is 10% to 50%. The molar ratio of lactic acid to glycolic acid in the polylactic acid-glycolic acid copolymer is 85:15 to 95:5. This microsphere is round in shape, has a smooth surface, is porous, can effectively reduce the early burst release of the drug, and can solve the problem of high burst release of the existing pramipexole pamoate microspheres. Further, the present invention is characterized by a smaller blood concentration fluctuation, which brings about an extended sustained-release period that effectively solves the problem of the short release period of the existing pramipexole pamoate microspheres and more stable release.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a long-acting sustained-release pramipexole preparation and a method for preparing the same.

Background Art

[0002] According to relevant research, the prevalence of Parkinson's disease (PD) in the population aged 60 and above is 1.37%. With the aging of the Chinese population, the care and treatment of a large-scale PD patient community is a social welfare issue that cannot be ignored.

[0003] Pramipexole is a second-generation potent selective non-ergot dopamine D2 receptor agonist, which is used in the treatment of idiopathic Parkinson's disease and can cover all stages of disease treatment up to the advanced stage. It can significantly improve the motor symptoms of early and advanced Parkinson's disease patients and also relieve the depressive symptoms associated with the disease. Pramipexole is a pharmaceutical recommended in Parkinson's disease treatment guidelines at home and abroad. However, in the dosage form of currently commercially available pramipexole hydrochloride tablets, administration three times a day is required. Due to the large number of administrations, Parkinson's disease patients are often troubled by clinical symptoms such as memory decline, limb tremors, and dysphagia. Therefore, among patients, forgetting to take the medicine often occurs, which may lead to the deterioration of the disease condition and even life-threatening situations such as suffocation and suffocation death. Long-acting sustained-release preparations can avoid the first-pass effect, enhance bioavailability, extend the dosing cycle, reduce the number of administrations, significantly reduce the occurrence of non-compliance, and bring real clinical benefits to patients.

[0004] The biodegradable polymers, poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), are suitable as carriers for pramipexole sustained-release formulations because their excellent biocompatibility has been certified by the US Food and Drug Administration (FDA) and they are included in the US Pharmacopeia as pharmaceutical excipients. PLGA (or PLA) capsule-encapsulated long-acting sustained-release formulations, including microspheres, in situ gels, etc., can achieve drug administration every one week to six months. However, existing PLGA sustained-release formulations often face the problems of high initial burst release and unstable drug release (large fluctuations in blood drug concentration), and the peak-trough fluctuation (PTF) can even exceed that of oral formulations, failing to meet the basic requirements in China for formulation innovation to reduce toxicity and improve efficacy. Therefore, the development of pramipexole / PLGA or PLA sustained-release formulations with stable drug release and a long sustained-release period (more than one week) is important for the treatment of PD and holds great potential in clinical applications.

[0005] Pramipexole is a reagent with certain nucleophilicity. During the preparation process of microspheres, it supplies electrons, acts as a Lewis base, and causes the degradation of polymer materials. Such degradation often occurs unintentionally and uncontrollably, so the degradation of PLGA is irregular and uncontrollable. When the molecular weight of PLGA (weight-average molecular weight Mw, the same hereinafter) decreases regularly as a whole, the viscosity of the oil phase decreases, affecting the particle size, drug loading capacity, and release cycle of the final product. Furthermore, in many cases, the molecular weight of PLGA does not decrease uniformly, specifically manifested as an increase in the molecular weight distribution (PDI), the generation of low-molecular polymers and oligomers, and an increase in monomer residues. This affects the batch-to-batch stability of the product (equivalent to low process stability) and the generation of process-related impurities (API that reacts with monomers and oligomers). Additionally, the increase in low molecules, oligomers, and monomers that affects the compactness and apparent porosity of the microsphere structure impairs the encapsulation rate and burst release state of the product.

[0006] Existing microsphere products do not control the degradation of polymer materials during preparation. Taking the microspheres of risperidone as an example, during preparation, a polymer material with a high molecular weight is selected, and the microspheres are prepared when it degrades to the required molecular weight. In this method, the degradation of the polymer material cannot be controlled, and the microspheres can only be prepared when it degrades to an appropriate molecular weight. This method is neither economical nor reliable, and it is a forced measure when the mechanism is not clear.

Summary of the Invention

[0007] An object of the present invention is to develop a sustained-release pramipexole drug having stable drug release and a long release cycle; another object is to control the compatibility between pramipexole and excipients to improve the quality of the product.

[0008] In a first aspect of the present invention, a long-acting sustained-release pramipexole preparation is provided, which contains pramipexole pamoate or pramipexole palmitate and a polylactic acid-glycolic acid copolymer or polylactic acid. The drug loading capacity of the preparation is 10% - 55%, preferably 10% - 50%, more preferably 15% - 45%; and the molar ratio of lactic acid to glycolic acid of the polylactic acid-glycolic acid copolymer is 85:15 - 95:5.

[0009] In some embodiments of the first aspect of the present invention, the molecular weight of the polylactic acid-glycolic acid copolymer is 10000 Da - 100000 Da; and the molecular weight of the polylactic acid is 10000 Da - 100000 Da.

[0010] In some embodiments of the first aspect of the present invention, the molar ratio of pamoic acid to pramipexole of pramipexole pamoate is 1:2 or 1:1.

[0011] In some embodiments of the first aspect of the present invention, the molar ratio of palmitic acid to pramipexole of pramipexole palmitate is 1:1.

[0012] In some embodiments of the first aspect of the present invention, the dosage form of the long-acting sustained-release pramipexole formulation is selected from microspheres, long-acting sustained-release particles, or subcutaneous implants.

[0013] In some embodiments of the first aspect of the present invention, the dosage form of the long-acting sustained-release pramipexole formulation is microspheres having a drug loading capacity of 15 to 45%; preferably 30 to 45%, more preferably 35 to 40%.

[0014] In some embodiments of the first aspect of the present invention, the dosage form of the long-acting sustained-release pramipexole formulation is long-acting sustained-release particles or subcutaneous implants having a drug loading capacity of 15 to 55%; preferably 30 to 55%, more preferably 40 to 55%.

[0015] The second aspect of the present invention provides a method for preparing pramipexole microspheres, comprising the following steps: Preparation of the oil phase: Dissolving pramipexole pamoate or pramipexole palmitate in a first solvent to obtain a first oil phase, dissolving a poly(lactic acid-glycolic acid) copolymer or polylactic acid in a second solvent to obtain a second oil phase, and then mixing the first oil phase and the second oil phase to obtain an oil phase; Preparing an aqueous solution of polyvinyl alcohol as the aqueous phase; Mixing the oil phase and the aqueous phase, emulsifying by high-speed shearing; solidifying the emulsified microspheres, evaporating the solvent, washing with water, and freeze-drying.

[0016] In some embodiments of the second aspect of the present invention, the first solvent is selected from the group consisting of dimethyl sulfoxide, methanol, ethanol, isopropanol, tert-butanol, or N,N-dimethylformamide, preferably dimethyl sulfoxide or methanol; and the second solvent is selected from the group consisting of dichloromethane, chloroform, or ethyl acetate, preferably dichloromethane.

[0017] In some embodiments of the second aspect of the present invention, the weight ratio of pramipexole pamoate or pramipexole palmitate to polylactic acid-glycolic acid copolymer or polylactic acid is 1:1 to 1:5, preferably 1:1 to 1:3.

[0018] In some embodiments of the second aspect of the present invention, the weight-to-volume ratio (g / mL) of pramipexole pamoate or pramipexole palmitate to the first solvent is 1:1 to 1:10, preferably 1:3 to 1:8.

[0019] In some embodiments of the second aspect of the present invention, the weight-to-volume ratio (g / mL) of polylactic acid-glycolic acid copolymer or polylactic acid to the second solvent is 1:1 to 1:10, preferably 1:2 to 1:8.

[0020] In some embodiments of the second aspect of the present invention, the mixing of the first oil phase and the second oil phase is carried out under stirring at a temperature of ≤25°C, preferably at a temperature of ≤10°C, more preferably at a temperature of ≤4°C, and the stirring time is ≤10 hours, preferably ≤2 hours, more preferably ≤1 hour, and even more preferably ≤0.5 hour.

[0021] The third aspect of the present invention provides a method for preparing a pramipexole subcutaneous implant or pramipexole long-acting sustained-release particles, comprising the following steps: crushing and mixing pramipexole pamoate or pramipexole palmitate with a polylactic acid-glycolic acid copolymer or polylactic acid, performing hot melt extrusion, and then stretching the extruded product to form short rods, thereby obtaining a pramipexole subcutaneous implant; stretching the extruded product, pelletizing it using a pelletizer, and then crushing it to the desired particle size to obtain pramipexole sustained-release particles.

[0022] In some embodiments of the third aspect of the present invention, the weight ratio of pramipexole pamoate or pramipexole palmitate to polylactic acid-glycolic acid copolymer or polylactic acid is 5:1 to 1:1, preferably 3:1 to 1:1.

[0023] In some embodiments of the third aspect of the present invention, the extrusion temperature of hot melt extrusion is 30 to 200 °C, preferably 40 to 160 °C, more preferably 80 to 120 °C.

[0024] Compared with the prior art, the present invention achieves the following beneficial effects.

[0025] The microspheres of the present invention have a smooth and porous surface, are rounded, can effectively reduce the initial burst release of drugs, and can solve the problem of high burst release seen in existing pramipexole pamoate microspheres. On the other hand, the sustained release period can be effectively extended, addressing the problem of short release cycles of existing pramipexole pamoate microspheres, reducing the fluctuations in blood drug concentration, and achieving more stable release.

[0026] In the method for preparing the microspheres of the present invention, the raw materials and auxiliary agents are prepared separately and then mixed to obtain an oil phase. By controlling the mixing time of the raw materials and auxiliary agents, the mixing temperature of the oil phase, and selecting the type of excipient, the decomposition rate of the excipient during preparation is controlled. This control restricts the generation of low molecular weight polymers and oligomers during the decomposition process of the excipient, improving the batch-to-batch stability of the product and reducing the generation of process-related impurities.

Brief Description of the Drawings

[0027]

Figure 1

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Figure 5

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Figure 7

Figure 8

Figure 9

Figure 10

[0028] The following specific embodiments are provided to explain the above content of the present invention in more detail. However, the scope of the subject matter of the present invention should not be construed as being limited to the following examples. Any technical solutions achieved based on the above content of the present invention belong to the scope of the present invention. Unless otherwise specified, the tests in the following examples can be carried out according to the methods described in the Pharmacopoeia of the People's Republic of China (2020 Edition).

[0029] Unless otherwise specified, in the "pramipexole pamoate" described in the examples, the molar ratio of pamoic acid to pramipexole is 1:2, and in the "pramipexole palmitate" described in the examples, the molar ratio of palmitic acid to pramipexole is 1:1.

[0030] Detection of particle size: An appropriate amount of microsphere powder was dispersed in purified water, and the particle size of the microspheres was measured using a Mastersizer 3000 laser particle size distribution measuring device.

[0031] Detection or calculation of drug loading capacity: First, a sustained-release preparation (for example, microspheres, long-acting sustained-release particles, or a subcutaneous implant) was disrupted with acetonitrile or dimethyl sulfoxide to release pramipexole into the solution. Then, PLGA was precipitated with water, the solution was centrifuged, and the pramipexole content in the supernatant was measured. The drug loading capacity was calculated based on the weight ratio of the active ingredient, pramipexole salt, to the sustained-release preparation (for example, microspheres, long-acting sustained-release particles, or a subcutaneous implant).

[0032] Calculation of encapsulation efficiency: Encapsulation efficiency = drug loading capacity ÷ theoretical drug loading capacity × 100%.

[0033] Calculation of solvent residue: Solvent residue = weight of solvent ÷ total weight of microspheres × 100%.

[0034] Viscosity measurement: The well-dissolved oil phase was accurately taken at 500 μl using a Brookfield DV2T rotational viscometer with a No. 40 spindle, and the viscosity (cp) of the oil phase at 20 °C and 4.0 rpm after standing for different times was measured.

[0035] Molecular weight measurement: Gel filtration chromatography (GPC) was used, dichloromethane was used as the mobile phase, and the weight-average molecular weight (Mw) of PLGA or PLA was detected at a flow rate of 1 mL / min and a sample size of 100 μl through three Aglient PLgel (5 μm, 300 mm * 7.5 mm) chromatography columns.

[0036] As the polymer material related to the present invention, for example, PLGA 7525 3A is abbreviated as 7525 3A. Here, "7525" indicates that the LA:GA block ratio is 75:25, "3" indicates that the intrinsic viscosity (IV) of the product is about 0.3 dL / g, and "A" indicates carboxyl end capping. PLA 2A indicates PLA having an IV of about 0.2 dL / g and carboxyl end capping.

[0037] Example 1 2 g of pramipexole pamolate and 5 g of PLGA (7525 3A) were uniformly mixed. At 25 °C, they were dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL) and stirred for 0.5 hour until uniform (used as oil phase sample (1)).

[0038] 2.2 g of pramipexole palmitate and 5 g of PLGA (7525 3A) were uniformly mixed. At 25 °C, they were dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL) and stirred for 0.5 hour until uniform (used as oil phase sample (2)).

[0039] 2.2 g of pramipexole palmitate and 5 g of PLGA (7525 3A) were uniformly mixed. At 10 °C, they were dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL) and stirred for 0.5 hour until homogeneous (designated as oil phase sample (3)).

[0040] 2.2 g of pramipexole palmitate and 5 g of PLGA (7525 3A) were uniformly mixed. At 4 °C, they were dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL) and stirred for 0.5 hour until homogeneous (designated as oil phase sample (4)).

[0041] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to obtain oil phase 1, and 5 g of PLGA (7525 3A) was dissolved in 25 mL of dichloromethane to obtain oil phase 2. They were stirred at 25 °C for 0.5 hour, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (5)).

[0042] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to obtain oil phase 1, and 5 g of PLGA (7525 3A) was dissolved in 25 mL of dichloromethane to obtain oil phase 2. They were stirred at 25 °C for 1 hour, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (6)).

[0043] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to obtain oil phase 1, and 5 g of PLGA (7525 3A) was dissolved in 25 mL of dichloromethane to obtain oil phase 2. They were stirred at 25 °C for 2 hours, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (7)).

[0044] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to obtain oil phase 1, and 5 g of PLGA (5050, 4.5A) was dissolved in 25 mL of dichloromethane to obtain oil phase 2. They were stirred at 25 °C for 0.5 hour, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (8)).

[0045] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to prepare oil phase 1, and 5 g of PLGA (8515, 4A) was dissolved in 25 mL of dichloromethane to prepare oil phase 2. The mixture was stirred at 25 °C for 0.5 hour, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (9)).

[0046] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to prepare oil phase 1, and 5 g of PLA (2A) was dissolved in 25 mL of dichloromethane to prepare oil phase 2. The mixture was stirred at 25 °C for 0.5 hour, and oil phase 1 and oil phase 2 were uniformly mixed (designated as oil phase sample (10)).

[0047] At various standing times, the weight average molecular weight (Mw) of PLGA or PLA in the above oil phase samples (1) to (10) was measured. The results are shown in the following table.

[0048]

Table 1

[0049] From the above table, it is understood that reducing the GA ratio in PLGA, reducing the mixing temperature of pramipexole and PLGA, and reducing the mixing time can all mitigate the decrease in the molecular weight of PLGA in the oil phase. The preferred mixing temperature is ≤25 °C, more preferably ≤10 °C, and most preferably ≤4 °C. By dissolving pramipexole and PLGA separately before mixing, the mixing time of pramipexole and PLGA can be reduced, and the purpose of suppressing the degradation of PLGA in the oil phase preparation process can also be achieved.

[0050] Example 2 To prepare the aqueous phase, 30 g of polyvinyl alcohol was dissolved in 3 L of purified water and set aside for later use.

[0051] For the oil phase, 5 g of PLGA (5050 4.5A) was dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL). At 25°C, the rotation speed of the high-speed shearing machine was adjusted to 1000 rpm, and the oil phase was injected into the aqueous phase (1 L) at a rate of 5 mL / min using a syringe for shear emulsification. After emulsification was completed, the microsphere suspension was mechanically stirred at a speed of 300 rpm and solidified for 4 hours. The microspheres were collected, washed with 1 L of deionized water, and after lyophilization, powdered microspheres were obtained (designated as microsphere sample (1)).

[0052] 2.2 g of pramipexole palmitate and 5 g of PLGA (5050 4.5A) were mixed and dissolved in a mixed solvent of methanol and dichloromethane (15 mL, 25 mL) to form an oil phase. At 25°C, the rotation speed of the high-speed shearing machine was adjusted to 1000 rpm, and the oil phase was injected into the aqueous phase (1 L) at a rate of 5 mL / min using a syringe for shear emulsification. After emulsification was completed, the microsphere suspension was mechanically stirred at a speed of 300 rpm and solidified for 4 hours. The microspheres were collected, washed with 1 L of deionized water, and after lyophilization, powdered microspheres were obtained (designated as microsphere sample (2)).

[0053] 2.2 g of pramipexole palmitate was dissolved in 15 mL of methanol to obtain oil phase 1; 5 g of PLGA (5050 4.5A) was dissolved in 25 mL of dichloromethane to obtain oil phase 2. The mixture was stirred at 4°C for 0.5 hour, and oil phase 1 and oil phase 2 were uniformly mixed to form an oil phase. Under low-temperature conditions of 4°C, the rotation speed of the high-speed shearing machine was adjusted to 1000 rpm, and the oil phase was injected into the aqueous phase (1 L) at a rate of 5 mL / min using a syringe for shear emulsification. After emulsification was completed, the microsphere suspension was mechanically stirred at a speed of 300 rpm, the solvent was evaporated, and it was solidified for 4 hours. The microspheres were collected, washed with 1 L of deionized water, and after lyophilization, powdered microspheres were obtained (designated as microsphere sample (3)).

[0054] The test results of the particle size, drug loading capacity, encapsulation efficiency, and PLGA molecular weight of the above microsphere samples (1) to (3) are shown in the following table:

Table 2

[0055] From the above table, it is clear that the microspheres prepared by the method of dissolving the mixture of pramipexole and PLGA in a solvent to obtain an oil phase result in significant degradation of the polymer material. This leads to a decrease in the viscosity of the oil phase, a decrease in the particle size of the microspheres, and a significant decrease in the encapsulation efficiency. However, the microspheres prepared by the method of dissolving pramipexole and PLGA separately in a solvent and mixing them to obtain an oil phase showed only a slight decrease in the molecular weight of the polymer material, and these microspheres showed high drug loading capacity and encapsulation efficiency.

[0056] Example 3 4.0 g of pramipexole pamoate (molar ratio of pamoic acid residue to pramipexole is 1:2) was dissolved in 17.5 mL of DMSO to form Oil Phase 1; 6 g of PLGA (8515, 5A) was dissolved in 17.5 mL of dichloromethane to form Oil Phase 2. Oil Phase 1 and Oil Phase 2 were mixed and stirred at a temperature of 4°C for 0.5 hour to obtain an oil phase.

[0057] 30 g of PVA was dissolved in 3 L of water to form an aqueous phase.

[0058] Under shear conditions of 8000 rpm, the oil phase and the aqueous phase were mixed and shear-emulsified. Then, the emulsified microsphere solution was stirred and solidified at a temperature of 4°C for 1 hour, the temperature was gradually raised to 25°C, and further solidified for 2 hours to evaporate the solvent from the solution.

[0059] Recovery: The solidified microspheres were sieved, the target microspheres were selected, and washed 2 - 3 times with purified water.

[0060] Lyophilization: The microspheres were dried using a lyophilizer or a three-in-one dryer to obtain the final product.

[0061] As a result of observing the prepared microspheres with a scanning electron microscope, the image shown in Figure 1 was obtained.

[0062] Example 4 4.0 g of pramipexole pamoate (molar ratio of pamoic acid residue to pramipexole is 1:2) was dissolved in 17.5 mL of DMSO to form Oil Phase 1; 6 g of PLA 2A was dissolved in 17.5 mL of dichloromethane to form Oil Phase 2. Oil Phase 1 and Oil Phase 2 were mixed and stirred at 4 °C for 0.5 hour to form an oil phase.

[0063] 30 g of PVA was dissolved in 3 L of water to form an aqueous phase.

[0064] Under the shearing condition of 8000 rpm, the oil phase and the aqueous phase were mixed and shear-emulsified. The emulsified microsphere solution was stirred and solidified at 4 °C for 1 hour, then the temperature was gradually raised to 25 °C and further solidified for 2 hours to evaporate the solvent from the solution.

[0065] Recovery: The solidified microspheres were sieved, the target microspheres were selected, and washed 2 - 3 times with purified water.

[0066] Lyophilization: The microspheres were dried using a lyophilizer or a three-in-one dryer to obtain the final product.

[0067] Example 5 40 g of pramipexole pamoate (molar ratio of pamoic acid residue to pramipexole is 1:2) and 25 g of PLA 5A were pulverized and uniformly mixed, then subjected to hot melt extrusion. The extruded product was drawn into a short rod of 3 × 30 mm and sterilized by irradiation under the condition of 8 kGy to obtain a subcutaneous implant of pramipexole.

[0068] Hot melt extrusion parameters: Thermo Fisher Pharma 11 and a co-rotating twin screw were used. The hot melt extruder was started with the following settings: feed temperature was room temperature, pressure temperature was 35 - 40 °C, mixing temperature was 80 - 100 °C, degassing temperature was 100 °C, extrusion temperature was 80 °C, die temperature was 60 °C. The pressure was set at 60 bar, the extrusion speed was 100 rpm, and the torque was 7 - 8 N·cm.

[0069] Example 6 The extrudate of Example 5 was drawn and pelletized using a pelletizer, and then pulverized into particles with a particle size of 60 - 100 μm. Subsequently, it was sterilized by irradiation under the condition of 8 kGy to obtain long-acting sustained-release pramipexole particles.

[0070] Comparative Example 1 4.0 g of pramipexole pamoate (molar ratio of pamoate residue to pramipexole was 1:2) was dissolved in 17.5 mL of DMSO to form Oil Phase 1; 6 g of PLGA (5050, 4.5A) was dissolved in 17.5 mL of dichloromethane to form Oil Phase 2. Oil Phase 1 and Oil Phase 2 were mixed and stirred at a temperature of 4 °C for 0.5 hour to form an oil phase.

[0071] 30 g of PVA was dissolved in 3 L of water to form an aqueous phase.

[0072] Under the shearing condition of 8000 rpm, the oil phase and the aqueous phase were mixed and shear-emulsified. Then, the emulsified microsphere solution was stirred at a temperature of 4 °C for 1 hour to solidify, the temperature was gradually raised to 25 °C, and it was further solidified for 2 hours to evaporate the solvent from the solution.

[0073] Recovery: The solidified microspheres were sieved, the target microspheres were selected, and washed 2 - 3 times with purified water.

[0074] Freeze-drying: The microspheres were dried using a freeze-dryer or a three-in-one dryer to obtain the final product.

[0075] Comparative Example 2 4.0 g of pramipexole pamoate (molar ratio of pamoic acid residue to pramipexole is 1:2) was dissolved in 17.5 mL of DMSO to form Oil Phase 1; 6 g of PLGA (7525, 5A) was dissolved in 17.5 mL of dichloromethane to form Oil Phase 2. Oil Phase 1 and Oil Phase 2 were mixed and stirred at 4 °C for 0.5 hour to form an oil phase.

[0076] 30 g of PVA was dissolved in 3 L of water to form an aqueous phase.

[0077] Under the shearing condition of 8000 rpm, the oil phase and the aqueous phase were mixed and shear-emulsified. Then, the emulsified microsphere solution was stirred and solidified at 4 °C for 1 hour, the temperature was gradually raised to 25 °C, and further solidified for 2 hours to evaporate the solvent from the solution.

[0078] Recovery: The solidified microspheres were sieved and the target microspheres were selected.

[0079] Freeze-drying: The microspheres were dried using a freeze-dryer or a three-in-one dryer to obtain the final product.

[0080] Experimental Example 1 The drug loading capacity, encapsulation efficiency, particle size, burst release, solvent residue, and molecular weight of the pramipexole microspheres from Examples 3 to 4 and Comparative Examples 1 to 2, the pramipexole subcutaneous implants from Example 5, and the long-acting sustained-release pramipexole particles from Example 6 were tested. The results are shown in the following table.

[0081]

Table 3

[0082] Experimental Example 2 Samples of Examples 3 to 5 and Comparative Examples 1 and 2, as well as an oral solid preparation (pramipexole hydrochloride tablets), were selected and animal tests were conducted. Twenty-five male rats weighing around 250 g were screened, randomly divided into groups (5 rats per group), and a sample uniformly mixed with a solvent (0.5% CMC-Na, 0.1% Tween-20, 0.9% NaCl) was intramuscularly injected at a drug dosage of 4 mg / kg for single administration. Blood was collected from the vein before and after administration, and the pramipexole concentration in plasma after administration was measured.

[0083] According to FIGS. 2-1, 3-1, 4-1, and 5-1, it is clear that the burst release of Examples 3 to 4 is significantly reduced compared to Comparative Examples 1 and 2. By increasing the LA ratio in PLGA (LA:GA ≧ 85:15), the present invention effectively reduces the early burst release of the drug and solves the problem of large burst release in existing pramipexole pamolate microspheres.

[0084] On the other hand, according to FIGS. 2-2, 3-2, 4-2, and 5-2, it can be seen that Examples 3 to 4 can effectively extend the sustained release period of the preparation compared to Comparative Examples 1 and 2. This indicates that by increasing the LA ratio in PLGA (LA:GA ≧ 85:15), the present invention can effectively extend the sustained release period and solve the problem of short release period in existing pramipexole pamolate microspheres.

[0085] According to FIG. 6, the pramipexole pamolate subcutaneous implant prepared in Example 5 has less burst release, stable drug release, and can achieve administration once every three months.

[0086] Based on the single-dose blood drug concentration curve, fitting for multiple doses was performed using Phoenix WinNonlin [2] software, and for the above Examples 3 to 4 and Comparative Examples 1 and 2, the fluctuations in blood drug concentration after reaching the steady state in the body were evaluated. The results are shown in the following table and FIGS. 7 to 10. Note [2]: Phoenix WinNonlin is an industry standard for analyzing pharmacokinetic and pharmacodynamic data and is suitable for analytical platforms for non-clinical and clinical PK / PD studies from early non-clinical research to large-scale clinical trials.

[0087]

Table 4

[0088] According to the above table and Figures 7 to 10, it can be concluded that the microspheres of the present invention provide a longer drug administration cycle, smaller fluctuations in blood drug concentration, and more stable release.

[0089] The technical features outlined in the previous examples can be integrated in various configurations. For the sake of brevity, not all possible combinations of the various technical features in the previous examples have been described. However, as long as these combinations of technical features do not present contradictions, they should be considered within the scope disclosed by this specification.

[0090] The above examples merely illustrate some embodiments of the present invention and facilitate a specific and detailed understanding of the technical solution of the present invention, but should not be construed as limiting the protection scope of the present invention patent. It should be noted that those skilled in the art can make some changes and improvements without departing from the concept of the present invention, and all of these are included in the protection scope of the present invention. It should also be understood that the technical solutions obtained by those skilled in the art based on the technical solution provided by the present invention through logical analysis, inference, or limited experiments are also within the protection scope of the appended claims of the present invention. Therefore, the protection scope of the patent right of the present invention should be defined by the content of the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A long-acting, sustained-release pramipexole formulation characterized by containing pramipexole pamoate or pramipexole palmitate and polylactic acid-glycolic acid copolymer or polylactic acid, wherein the drug loading volume of the formulation is 10% to 55%, preferably 10% to 50%, more preferably 15% to 45%, and the molar ratio of lactic acid to glycolic acid of the polylactic acid-glycol copolymer is 85:15 to 95:

5.

2. The long-acting, sustained-release pramipexole formulation according to claim 1, characterized in that the molecular weight of the polylactic acid-glycolic acid copolymer is 10,000 Da to 100,000 Da, and the molecular weight of the polylactic acid is 10,000 Da to 100,000 Da.

3. A long-acting, sustained-release pramipexole preparation according to claim 1 or 2, characterized in that the molar ratio of pamoic acid to pramipexole in pramipexole pamoate is 1:2 or 1:

1.

4. The long-acting sustained-release pramipexole preparation according to claim 1 or 2, characterized in that the dosage form of the long-acting sustained-release pramipexole preparation is selected from microspheres, long-acting sustained-release particles, or subcutaneous implants.

5. A method for preparing pramipexole microspheres, comprising the following steps: Preparation of the oil phase: Dissolve pramipexole pamoate or pramipexole palmitate in the first solvent to obtain the first oil phase, dissolve polylactic acid-glycolic acid copolymer or polylactic acid in the second solvent to obtain the second oil phase, and then mix the first oil phase and the second oil phase to obtain the oil phase; Prepare an aqueous solution of polyvinyl alcohol as the aqueous phase; The oil phase and aqueous phase are mixed and emulsified by high-speed shearing; the emulsified microspheres are solidified, the solvent is evaporated, washed with water, and freeze-dried.

6. The method for preparing pramipexole microspheres according to claim 5, characterized in that the first solvent is selected from the group consisting of dimethyl sulfoxide, methanol, ethanol, isopropanol, tert-butanol, or N,N-dimethylformamide, preferably dimethyl sulfoxide or methanol; and the second solvent is selected from the group consisting of dichloromethane, chloroform, or ethyl acetate, preferably dichloromethane.

7. A method for preparing pramipexole microspheres according to claim 5 or 6, characterized in that the mixing of the first oil phase and the second oil phase is carried out under stirring at a temperature of ≤25°C, preferably ≤10°C, more preferably ≤4°C, and the stirring time is ≤10 hours, preferably ≤2 hours, more preferably ≤1 hour, and even more preferably ≤0.5 hours.

8. A method for preparing a pramipexole subcutaneous implant or pramipexole long-acting sustained-release particles, comprising the following steps: grinding and mixing pramipexole pamoate or pramipexole palmitate with a polylactic acid-glycolic acid copolymer or polylactic acid, performing hot-melt extrusion, then drawing the extruded product to form short rods, thereby obtaining a pramipexole subcutaneous implant; drawing the extruded product, pelletizing it using a pelletizer, then grinding it to a desired particle size, thereby obtaining pramipexole sustained-release particles.

9. A method for preparing a subcutaneous implant or sustained-release particles of pramipexole according to claim 8, characterized in that the extrusion temperature of the hot melt extruder is 30°C to 200°C, preferably 40°C to 160°C, and more preferably 80°C to 120°C.

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