Pramipexole-containing long-acting sustained-release preparation and method for preparing the same

Abstract

Disclosed is a pramipexole-containing long-acting sustained-release pharmaceutical composition containing a pharmaceutically acceptable salt of pramipexole and a pharmaceutical polymer material. The formulation is selected from microspheres, sustained-release particles, and subcutaneous implants. The pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, α-linolenate, heptadecanoate, pamoate, and palmitate. The polymer material is selected from PLGA, PLA, mPEG-PLA, and PEG-PLA-PEG. The present invention belongs to the technical field of pharmaceutical preparations and solves the problems of the short release period and low release effect of pramipexole in the prior art.

Description

Technical Field

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

Background Art

[0002] According to the study by Qi S, Yin P, Wang L, et al. Prevalence of Parkinson’s Disease: A Community‐Based Study in China. Mov Disord. Published online August 14, 2021:mds.28762. doi:10.1002 / mds.28762, during the past few decades, China has undergone great social and economic as well as demographic changes and has entered a stage of deep aging. The prevalence of Parkinson's disease (PD) in the population aged 60 years or older is 1.37% (95% confidence interval 1.02% - 1.73%), and the total number of PD patients in China is estimated to reach 3.62 million.

[0003] Pramipexole is a second-generation potent selective non-ergot D2 receptor agonist, which is used clinically for the treatment of idiopathic Parkinson's disease and can cover all stages of disease treatment up to the late stage. It can significantly improve the motor symptoms of early and late Parkinson's disease patients and can also improve the depressive symptoms of Parkinson's disease patients. Pramipexole is the first-choice drug recommended in Parkinson's disease treatment guidelines at home and abroad.

[0004] Parkinson's disease patients are often troubled by symptoms such as memory decline, tremors in hands and feet, and difficulty swallowing, which frequently lead to forgetting to take medicine and result in the deterioration of the disease condition. The currently commercially available pramipexole hydrochloride tablets require administration three times a day due to their short release period, with a large number of administrations, causing great inconvenience to Parkinson's disease patients. Therefore, researching and developing a sustained-release formulation of pramipexole that can be stably released once a week, once every two weeks, once a month, or once every three months, etc., is of great significance in improving patient compliance and enhancing the clinical treatment effect.

Summary of the Invention

[0005] In view of the above problems, the present invention aims to provide a sustained-release formulation containing pramipexole that has a stable drug load, a high encapsulation efficiency, can achieve stable drug release over a long period of time, and can suppress burst release to an extremely low level, which is beneficial to the clinical effect and the safety of medication, and is beneficial to the clinical effect and drug safety.

[0006] In one aspect, the present invention provides a sustained-release formulation containing pramipexole that contains a pharmaceutically acceptable salt of pramipexole and a pharmaceutical polymer material; The formulation is selected from microspheres, sustained-release particles, and subcutaneous implants; The pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, α-linolenate, heptadecanoate, pamoate, and palmitate; preferably, the pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, α-linolenate, heptadecanoate, and palmitate; more preferably, the pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, heptadecanoate, and palmitate; The polymer material is selected from PLGA, PLA, mPEG-PLA, and PEG-PLA-PEG.

[0007] In one embodiment, in the pharmaceutically acceptable salt of pramipexole provided by the present invention, the molar ratio of pramipexole to elaidic acid, stearic acid, oleic acid, α-linolenic acid, heptadecanoic acid, or palmitic acid is 1:1.

[0008] In one embodiment, in the pharmaceutically acceptable salt of pramipexole provided by the present invention, the molar ratio of pramipexole to pamoic acid is 1:1 or 2:1; preferably, the molar ratio of pramipexole to pamoic acid is 2:1.

[0009] In one embodiment, in the sustained-release formulation provided by the present invention, the content of pramipexole (calculated as the free compound) constitutes 10-55% of the total weight of the formulation; and the content of the polymer material constitutes 90-45% of the total weight of the formulation.

[0010] In one embodiment, in the sustained-release formulation provided by the present invention, the polymer material is PLGA with a molecular weight of 10,000-100,000 Da, and the LA:GA block ratio of PLGA is 5:95-95:5.

[0011] In a preferred embodiment, in the sustained-release formulation provided by the present invention, the polymer material is PLGA with a molecular weight of 25,000-100,000 Da, and the LA:GA block ratio of PLGA is 50:50-85:15.

[0012] In a preferred embodiment, in the sustained-release formulation provided by the present invention, the type of PLGA used is 2.5A, 3A, 5A, 4.5A, 4.5E, 5E, 7A, 7E, or 8E.

[0013] In one embodiment, in the sustained-release formulation provided by the present invention, the polymer material is PLA with a molecular weight of 10,000-100,000 Da.

[0014] In one embodiment, in the sustained-release formulation provided by the present invention, the polymer material is mPEG-PLA, the molecular weight of mPEG in mPEG-PLA is 1000-4000 Da, and the molecular weight of PLA is 10000-100000 Da.

[0015] In one embodiment, in the sustained-release formulation provided by the present invention, the polymer material is PEG-PLA-PEG, the molecular weight of PEG is 1000-4000 Da, and the molecular weight of PLA is 10000-100000 Da.

[0016] In a second aspect, the present invention provides a pramipexole-containing long-acting sustained-release formulation in which the formulation is in the form of microspheres and the active ingredient is the heptadecanoate, palmitate, erucate, stearate, or oleate of pramipexole.

[0017] In a second aspect, the present invention provides a pramipexole-containing long-acting sustained-release formulation in which the formulation is in the form of microspheres and the active ingredient is the heptadecanoate or palmitate of pramipexole; each unit formulation contains 1-3 parts of pramipexole and 9-7 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50, and the theoretical drug loading is 10%-30%, preferably, the theoretical drug loading is 15%-25%.

[0018] In one embodiment, in the pramipexole-containing microspheres provided by the present invention, PLGA is 50:50 3A or 50:50 4.5E.

[0019] In a third aspect, the present invention provides a sustained-release formulation containing pramipexole in which the formulation is in the form of microspheres and the active ingredient is the erucate, stearate or oleate of pramipexole; each unit formulation contains 2 to 4 parts of pramipexole and 8 to 6 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 75:25 to 85:15, and the theoretical drug loading is 20% to 40%, preferably, the theoretical drug loading is 25% to 35%.

[0020] In one embodiment, in the pramipexole-containing microspheres provided by the present invention, PLGA is 2.5A, 5A, 5E, or 7E; preferably, PLGA is 2.5A, 5A, or 7E.

[0021] In one embodiment, in the pramipexole-containing macrospheres provided by the present invention, PLGA is 85:15 2.5A, 75:25 5E, 75:25 5A, or 75:25 7E; preferably, PLGA is 85:15 2.5A, 75:25 5A, or 75:25 7E.

[0022] In a fourth aspect, the present invention provides a sustained-release formulation containing pramipexole in which the formulation is in the form of microspheres and the active ingredient is the erucate, palmitate or oleate of pramipexole; each unit formulation contains 3 to 5.5 parts of pramipexole and 7 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 75:25 to 85:15, and the theoretical drug loading is 30% to 55%, preferably, the theoretical drug loading is 35% to 50%, more preferably, the theoretical drug loading is 35% to 45%.

[0023] In one embodiment, in the pramipexole-containing microspheres provided by the present invention, PLGA is 4.5A, 7A, 5E, or 8E; preferably, PLGA is 4.5A, 7A, or 8E.

[0024] In one embodiment, in the PLAMIPEXOLE-containing microspheres provided by the present invention, PLGA is 85:15 4.5A, 85:15 5E, 75:25 7A, or 75:25 8E; preferably, PLGA is 85:15 4.5A, 75:25 7A, or 75:25 8E.

[0025] In a fifth aspect, the present invention provides a sustained-release formulation containing pramipexole in which the formulation is in the form of sustained-release particles and the active ingredient is an erucate, pamoate, stearate, oleate, palmitate, or heptadecanoate of pramipexole; each unit formulation contains 1 to 5.5 parts of pramipexole and 9 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50 to 85:15, and the theoretical drug loading is 20% to 55%.

[0026] In one embodiment, in the sustained-release particles containing pramipexole provided by the present invention, PLGA is 2.5A, 3A, 5A, 4.5A, 4.5E, 5E, 7A, or 7E.

[0027] In a sixth aspect, the present invention provides a sustained-release formulation containing pramipexole in which the formulation is in the form of a subcutaneous implant and the active ingredient is an erucate, pamoate, stearate, oleate, or palmitate of pramipexole; each unit formulation contains 2 to 5.5 parts of pramipexole and 8 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50 to 85:15 (preferably 75:25 to 85:15), and the theoretical drug loading is 20% to 55%.

[0028] In one embodiment, in the subcutaneous implant containing pramipexole provided by the present invention, PLGA is 2.5A, 4.5A, 5A, 5E, 7A, or 7E.

[0029] In a seventh aspect, the present invention provides a method for preparing the above microsphere formulation, comprising the following steps: Preparation of the oil phase: Dissolving a pharmaceutically acceptable salt of pramipexole in a first solvent to obtain a first oil phase; dissolving PLGA in a second solvent to obtain a second oil phase; Preparation of the external aqueous phase: Dissolving PVA in water for later use; Mixing of the oil phases: Stirring and mixing the first oil phase and the second oil phase to obtain a mixed oil phase; Emulsification: Filling the external aqueous phase into an in-line shear mixer and mixing it with the mixed oil phase at a speed of 5000 - 13000 rpm for shear emulsification; Solidification: Evaporating the solvent from the sheared solution under stirring, heating it according to a temperature rising curve for solidification, and then freeze-drying to form microspheres.

[0030] In a preferred embodiment, during the solidification step, the solvent is evaporated from the sheared solution under stirring, heated according to a temperature rising curve for solidification, sieved, and then freeze-dried to form microspheres.

[0031] In an embodiment, in the method for preparing microspheres provided by the present invention, the first solvent is selected from one or more of dichloromethane, benzyl alcohol, methanol, ethanol, isopropanol, tert-butanol, NMP, DMSO, and DMF; preferably, it is dichloromethane or benzyl alcohol.

[0032] In an embodiment, in the method for preparing microspheres provided by the present invention, the second solvent is selected from one or more of dichloromethane, chloroform, and ethyl acetate; preferably, it is dichloromethane or chloroform.

[0033] In an embodiment, in the method for preparing microspheres provided by the present invention, the mass concentration (g / ml) of pramipexole in the first oil phase is 0.05 - 0.9, preferably 0.05 - 0.7; the mass concentration (g / ml) of PLGA in the second oil phase is 0.1 - 0.4.

[0034] In an eighth aspect, the present invention provides a method for preparing the sustained-release particles, comprising the following steps: Mixing a pharmaceutically acceptable salt of pramipexole with PLGA and adding the mixture to the feed hopper of a hot melt extruder; Extrusion: Using a hot melt extruder, extruding under a pressure of 60 bar at an extrusion rate of 100 rpm while controlling the torque to 7-8 N.cm; Pelletization: After extrusion, drawing and stretching, and pelletizing with a pelletizer; Grinding: Grinding the granulated product to 50-100 μm, preferably 60-100 μm, with a low-temperature ball mill to obtain the sustained-release particles.

[0035] In certain embodiments, in the method for preparing the sustained-release particles, during the extrusion step, both the feed temperature and the extrusion temperature are at room temperature, the mixing temperature is controlled at 70-140°C, the degassing temperature is the same as the mixing temperature, the extrusion temperature is controlled at 55-120°C, and the die orifice temperature is controlled at 50-75°C.

[0036] In certain embodiments, in the method for preparing the sustained-release particles, during the extrusion step, both the feed temperature and the extrusion temperature are at room temperature, the mixing temperature is controlled at 100-110°C, the degassing temperature is the same as the mixing temperature, the extrusion temperature is controlled at 85-110°C, and the die orifice temperature is controlled at 65-72°C.

[0037] In a ninth aspect, the present invention provides a method for preparing the subcutaneous implant, comprising the following steps: Mixing a pharmaceutically acceptable salt of pramipexole with PLGA and adding the mixture to the feed hopper of a hot melt extruder; Extrusion: Using a hot melt extruder, extruding under a pressure of 60 bar at an extrusion rate of 100 rpm while controlling the torque to 7-8 N.cm; Pelletization: After extrusion, drawing and stretching, and pelletizing with a pelletizer to obtain the subcutaneous implant.

[0038] In one embodiment, in the method for preparing a subcutaneous implant, during the extrusion step, both the supply temperature and the pressing temperature are at room temperature, the mixing temperature is controlled at 70 - 140 °C, the degassing temperature is the same as the mixing temperature, the extrusion temperature is controlled at 55 - 120 °C, and the die orifice temperature is controlled at 65 - 75 °C.

[0039] In one embodiment, in the method for preparing a subcutaneous implant, during the granulation step, the die orifice size is 3 mm and the cutting length is 35 mm. Detailed Description of the Invention

[0040] Definitions and Terms As used herein, the "microsphere" refers to a microscopic spherical preparation formed by dispersing a drug within a polymer matrix.

[0041] As used herein, the "sustained-release particle" is also known as a long-acting sustained-release particle or a long-acting sustained-release microparticle. In contrast to microspheres, it is a type of preparation obtained by dispersing a drug within a polymer matrix but by methods such as grinding into fine particles. Compared with microspheres, the sustained-release microparticles have an irregular polyhedral shape.

[0042] As used herein, the "subcutaneous implant" is also known as a subcutaneous insert and refers to a type of drug delivery preparation formed in a rod shape that is implanted subcutaneously to slowly release a drug.

[0043] Regarding the polymer materials related to the present invention, the Chinese name of PLGA is poly(lactic acid - glycolic acid) copolymer, LA represents lactic acid, and GA represents glycolic acid; the Chinese name of PLA is poly(lactic acid); the Chinese name of mPEG - PLA is methoxypolyethylene glycol - poly(lactic acid); the Chinese name of PEG - PLA - PEG is poly(ethylene glycol) - poly(lactic acid) - poly(ethylene glycol); the Chinese name of PEG is poly(ethylene glycol).

[0044] Regarding the polymeric materials related to the present invention, 5050 PLGA 3A is abbreviated as 5050 3A, where "5050" indicates a LA:GA block ratio of 50:50, "3" indicates an intrinsic viscosity (IV) of the product of approximately 0.3 dL / g, "A" indicates carboxyl end-capping, and "E" indicates ester end-capping. PLA 2A indicates PLA having an IV of approximately 0.2 dL / g and being carboxyl end-capped. mPEG-PLA 2000-20000 represents a diblock copolymer of PLA and mPEG, where mPEG has a molecular weight of 2000 Da and PLA has a molecular weight of 20000 Da.

[0045] In the polymeric materials related to the present invention, the molecular weight of the polymer is its statistical average value. Although the molecular weights described in the present invention are specific values, in reality, they represent a range of polymeric materials. Typically, this range value is ±10% of the described molecular weight value. For example, a molecular weight of 50000 Da actually has a range from 45000 Da to 55000 Da; a molecular weight of 100000 Da actually has a range from 90000 Da to 110000 Da, and so on.

[0046] As described in the present invention, the theoretical drug loading refers to the ratio of the API in supply to the polymeric material (e.g., PLGA), and the theoretical drug loading = weight of API / (weight of API + weight of polymeric material) * 100%, where the API is calculated as the free compound of pramipexole.

[0047] When used in the present invention, the encapsulation efficiency = actual drug loading / theoretical drug loading * 100%.

[0048] In this specification, the "parts" mentioned when describing the content of formulation components mean parts by weight.

[0049] The molecular weight of the polymeric material used in this specification refers to the weight-average molecular weight.

[0050] The Chinese name of PVA used in the present invention is polyvinyl alcohol.

Brief Description of the Drawings

[0051]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Examples

[0052] To make the technical solutions and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Unless specific conditions are described in the examples, they are implemented under normal conditions or according to the conditions recommended by the manufacturer. All reagents or instruments not specified by the manufacturer are commercially available conventional products.

[0053] The Chinese names of the English chemical abbreviations related to the embodiments of the present invention are as follows:

Table 1

[0054] The molecular weight of the polymer preparation is mainly characterized by Mw and PDI. PDI indicates the molecular weight distribution, generally between 1.5 and 2.0, showing a uniform molecular weight distribution.

[0055] Example 1: Preparation of Pramipexole-containing Microsphere Preparation

Table 2

[0056] Preparation method: Preparation of the oil phase: The starting materials of the API were weighed according to the above formulation supply table, and the supply amount of the API was calculated based on the free compound of pramipexole. The molar ratio of pramipexole to various anions of the salts in Table 1 was 1:1. Solvent 1 was added and dissolved to obtain Oil Phase 1. A predetermined amount of PLGA was weighed, added to Solvent 2, and dissolved to obtain Oil Phase 2.

[0057] Preparation of the external aqueous phase: A predetermined amount of PVA was weighed and added to water. It was dissolved for later use.

[0058] Mixing of the oil phases: Oil Phase 1 and Oil Phase 2 were stirred and mixed at a temperature of 4 - 40 °C for 5 - 50 minutes to obtain a mixed oil phase.

[0059] Emulsification: The external aqueous phase was first filled into an in-line shear mixer (IKA 2000 / 03 + DR shear head). The external aqueous phase and the mixed oil phase were mixed at a speed of 8000 rpm for shear emulsification.

[0060] Solidification: Under stirring, it was heated according to the temperature rising curve, and the solvent was evaporated from the sheared solution for solidification. It was sieved and freeze-dried.

[0061] Example 2: Preparation of a sustained-release particle formulation containing pramipexole

Table 3

[0062] Weighing: The API and PLGA shown in the above table were accurately weighed, and the supply amount of the API was calculated based on the free compound of pramipexole. The molar ratio of pramipexole to pamoic acid was 2:1, and the molar ratio of pramipexole to various anions of the remaining salts in Table 2 was 1:1. After achieving their physical mixing, they were added to the feed hopper of a hot melt extruder.

[0063] Extrusion: Hot melt extrusion was initiated using a Thermo Fisher Pharma 11 equipped with a parallel opposing rotating twin screw. The supply temperature, pressing temperature, mixing, degassing, extrusion, and die orifice temperature were set according to the above table, and the pressure threshold was set at 60 bar, the extrusion speed at 100 rpm, and the torque threshold at 8 N.cm. After completing these settings, automatic feeding, mixing, and extrusion were started.

[0064] Pelletization: The die orifice specification was set to 3 mm and the pre-ring length for extrusion was set to 35 mm. After extrusion (the first drop of the extrudate), a glass rod was manually used to draw the strand towards the roller of the pelletizer and pelletization cutting was initiated.

[0065] Grinding: The granulated particles were transferred to a ball mill and grinding was initiated. Samples were taken every 5 minutes and the particle size was monitored. Grinding was stopped when the target particle size (D 50 = 50 - 100 μm) was reached to obtain sustained-release particles.

[0066] Example 3: Preparation of a Pramipexole-Containing Subcutaneous Implant

Table 4

[0067] Preparation method: Weighing: The API and PLGA shown in the above table were accurately weighed, and the supply amount of the API was based on the free compound of pramipexole. The molar ratio of pramipexole to pamoic acid was 2:1, and the molar ratio of pramipexole to each of the various anions of the remaining salts in Table 3 was 1:1. After their physical mixing, the combined materials were added to the feed hopper of a hot melt extruder.

[0068] Extrusion: Hot melt extrusion was initiated using a Thermo Fisher Pharma 11 equipped with a parallel opposing rotating twin screw. The feed temperature, pressing temperature, mixing, degassing, extrusion, and die orifice temperature were set according to the table above, with a pressure threshold of 60 bar, an extrusion speed of 100 rpm, and a torque threshold of 8 N.cm. With these parameters set, automatic feeding, mixing, and extrusion were started.

[0069] Granulation: The die orifice specifications in the table above were adopted, and the prilling length was set according to the table above. After extrusion (the first droplets of the extrudate), a glass rod was manually used to draw the strands towards the rollers of the pelletizer. The cutting and granulation processes were started to form subcutaneous implants.

[0070] Comparative Example 1: Preparation of Pramipexole-containing Microsphere Formulations

Table 5

[0071] Comparative Examples 1 to 5 in the table above were prepared according to the method of Example 1, with a molar ratio of pramipexole to pamoic acid of 2:1 and a molar ratio of pramipexole to hydrochloric acid or behenic acid of 1:1. In the preparation of Comparative Example 3, various solvents such as dichloromethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, tert-butanol, DMSO, DMF, acetone, and tetrahydrofuran were used as Solvent 1 for dissolving the behenate of pramipexole, but none of them could effectively dissolve it, and microsphere formulations could not be prepared.

[0072] Experimental Example 1: Quality Test of Microsphere Formulations Test Method: The actual drug loading, encapsulation efficiency, particle size, residual solvent amount, and in vitro release profile of the microspheres in the above Examples and Comparative Examples were tested.

[0073] Method for in vitro release assay: Microspheres were placed in vials, PBS buffer at pH 7.4 ± 0.1 was added, and they were placed in a water bath shaker at 37 ± 0.5 °C. Samples were taken at various time points, and the content of the drug released into the buffer was measured using HPLC.

[0074] In this test, "in vitro burst release" refers to the cumulative release on the first day of in vitro release. The test results are as follows:

Table 6

[0075]

Table 7

[0076] Test results: The microspheres prepared in Examples 1, 2, 19, 21, 22 and 45 showed high encapsulation efficiency and substantially no burst release. In contrast, Comparative Examples 1 and 2 (hydrochloride, free compound) during preparation showed significant migration of the API, resulting in serious low encapsulation efficiency, substantial burst release and poor appearance. The microspheres of Comparative Example 5 had low sphericity, were porous, had a loose structure, and the in vitro release curve was unstable; Comparative Example 4 showed a large burst release, which posed a clinical risk.

[0077] Experimental Example 2: Quality test of sustained-release particle preparation Test method: The actual drug loading capacity, encapsulation efficiency, particle size, and in vitro release of the above sustained-release particle example samples were tested. The test results are as follows:

Table 8

[0078] According to the data in the above table, it is recognized that the sustained-release particle samples prepared in each example meet the required pharmaceutical specifications and the burst release amount is at a low level.

[0079] Experimental Example 3: Quality Test of Subcutaneous Implants Test method: The actual drug loading, encapsulation efficiency and in vitro release of the above subcutaneous implant example samples were tested. The test results are as follows:

Table 9

[0080] According to the data in the above table, it is recognized that the subcutaneous implants prepared in each example have a low level of burst release and meet the required pharmaceutical specifications.

[0081] Experimental Example 4: In Vivo Pharmacokinetics Test Male rats weighing about 250 g were selected and randomly divided into 5 rats per group. The drug was administered once by intramuscular injection. Blood was collected from the vein before and after drug administration, the plasma pramipexole concentration after administration was measured, and a drug-time curve for calculating pharmacokinetic parameters was plotted.

[0082] Protocol 1: The test samples were the example samples of formulation numbers 1, 2, and 11, the dosage was 4 mg / kg, and the test results are shown in Figures 1 and 2.

[0083] Protocol 2: The test samples were the example samples of formulation numbers 27 and 38, the dosage was 8 mg / kg, and the test results are shown in Figures 3 and 4.

[0084] Protocol 3: The test samples were the example samples of formulation numbers 53 and 61, the dosage was 16 mg / kg, and the test results are shown in Figures 5 and 6.

[0085]

Table 10

[0086] According to the above test results, it is recognized that the long-acting sustained-release preparation of pramipexole prepared according to the present invention can achieve stable release over a long period of one week, two weeks, or even one month without causing significant burst release. The plasma drug concentration remains stable, meeting the conditions of clinical efficacy and dosing safety, and can significantly improve patient compliance.

[0087] The present invention provides a long-acting sustained-release preparation containing a pharmaceutically acceptable salt of pramipexole and a method for preparing the same. Those skilled in the art can implement these by referring to the content of this specification and appropriately changing starting materials, process parameters, and other elements. Although the methods and substances of the present invention have been described through preferred embodiments, it is obvious to those skilled in the relevant technical fields that improvements, appropriate changes, and combinations of the methods and substances described in this specification can be made to realize the technology of the present invention without departing from the content, spirit, and scope of the present invention. It should be particularly noted that all such similar substitutions and improvements are obvious to those skilled in the art and are considered to be within the spirit, scope, and content of the present invention.

Claims

1. A sustained-release formulation containing pramipexole with a long-acting effect, which contains a pharmaceutically acceptable salt of pramipexole and a pharmaceutical polymer material; The formulation is selected from microspheres, sustained-release particles, and subcutaneous implants; The pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, α-linolenate, heptadecanoate, pamoate, and palmitate; preferably, the pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, α-linolenate, heptadecanoate, and palmitate; more preferably, the pharmaceutically acceptable salt of pramipexole is selected from erucate, stearate, oleate, heptadecanoate, and palmitate; The polymer material is selected from PLGA, PLA, mPEG-PLA, and PEG-PLA-PEG, and is characterized by a long-acting sustained-release formulation.

2. The polymer material is PLGA with a molecular weight of 10,000 to 100,000 Da, and the LA:GA block ratio of PLGA is 5:95 to 95:5; preferably, the polymer material is PLGA with a molecular weight of 25,000 to 100,000 Da, and the LA:GA block ratio of PLGA is 50:50 to 85:15; Or, the polymer material is PLA with a molecular weight of 10,000 to 100,000 Da; Or, the polymer material is mPEG-PLA, the molecular weight of mPEG in mPEG-PLA is 1,000 to 4,000 Da, and the molecular weight of PLA is 10,000 to 100,000 Da; Or, the polymer material is PEG-PLA-PEG, the molecular weight of PEG is 1,000 to 4,000 Da, and the molecular weight of PLA is 10,000 to 100,000 Da, and is characterized by the long-acting sustained-release formulation according to Claim 1.

3. The formulation is in the form of microspheres, and the active ingredient is heptadecanoate or palmitate of pramipexole; each unit formulation contains 1 to 3 parts of pramipexole and 9 to 7 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50, and the theoretical drug loading is 10% to 30%, preferably, the theoretical drug loading is 15% to 25%, and is characterized by the long-acting sustained-release formulation according to Claim 1 or 2.

4. The preparation is in the form of microspheres, and the active ingredient is the eluate, stearate or oleate of pramipexole; each unit preparation contains 2 to 4 parts of pramipexole and 8 to 6 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 75:25 to 85:15, and the theoretical drug loading is 20% to 40%, preferably, the theoretical drug loading is 25% to 35%. The long-acting sustained-release preparation according to claim 1 or 2, characterized in that.

5. The preparation is in the form of microspheres, and the active ingredient is the eluate, palmitate or oleate of pramipexole; each unit preparation contains 3 to 5.5 parts of pramipexole and 7 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 75:25 to 85:15, and the theoretical drug loading is 30% to 55%, preferably, the theoretical drug loading is 35% to 50%, more preferably, the theoretical drug loading is 35% to 45%. The long-acting sustained-release preparation according to claim 1 or 2, characterized in that.

6. The preparation is in the form of sustained-release particles, and the active ingredient is the eluate, pamoate, stearate, oleate, palmitate or heptadecanoate of pramipexole; each unit preparation contains 1 to 5.5 parts of pramipexole and 9 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50 to 85:15, and the theoretical drug loading is 20% to 55%. The long-acting sustained-release preparation according to claim 1 or 2, characterized in that.

7. The preparation is in the form of a subcutaneous implant, and the active ingredient is the eluate, pamoate, stearate, oleate or palmitate of pramipexole; each unit preparation contains 2 to 5.5 parts of pramipexole and 8 to 4.5 parts of PLGA calculated as the free compound, the LA:GA block ratio of PLGA is 50:50 to 85:15, and the theoretical drug loading is 20% to 55%. The long-acting sustained-release preparation according to claim 1 or 2, characterized in that.

8. A method for preparing the microspheres according to any one of claims 3 to 5, comprising the following steps: Oil phase preparation: Dissolving a pharmaceutically acceptable salt of pramipexole in a first solvent to obtain a first oil phase; Dissolving PLGA in a second solvent to obtain a second oil phase; External aqueous phase preparation: Dissolving PVA in water for later use; Oil phase mixing: Stirring and mixing the first oil phase and the second oil phase to obtain a mixed oil phase; Emulsification: Filling the external aqueous phase into an in-line shear mixer and mixing it with the mixed oil phase at a speed of 5000 - 13000 rpm for shear emulsification; Solidification: Evaporating the solvent from the sheared solution under stirring, heating according to a temperature rising curve for solidification, and then freeze-drying to form microspheres; Preferably, during the solidification step, evaporating the solvent from the sheared solution under stirring, heating according to a temperature rising curve for solidification, sieving, and then freeze-drying to form microspheres. [

9. ] A method for preparing the sustained-release particles according to claim 6, comprising the following steps: Mixing a pharmaceutically acceptable salt of pramipexole with PLGA and adding the mixture to the feed hopper of a hot melt extruder; Extrusion: Using a hot melt extruder to extrude under a pressure of 60 bar at an extrusion speed of 100 rpm while controlling the torque to 7 - 8 N.cm; Pelletization: Drawing and stretching after extrusion and pelletizing with a pelletizer; Grinding: Grinding the pelletized product to 50 - 100 μm, preferably 60 - 100 μm, with a cryogenic ball mill to obtain the sustained-release particles. [

10. ] A method for preparing the subcutaneous implant according to claim 7, comprising the following steps: Mixing a pharmaceutically acceptable salt of pramipexole with PLGA and adding the mixture to the feed hopper of a hot melt extruder; Extrusion: Using a hot melt extruder to extrude under a pressure of 60 bar at an extrusion speed of 100 rpm while controlling the torque to 7 - 8 N.cm; Pelletization: Drawing and stretching after extrusion, pelletizing with a pelletizer to obtain the subcutaneous implant.

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