Carergoline long-acting injection as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and discloses a carergoline long-acting injection as well as a preparation method and application thereof. The injection comprises the following raw materials: sucrose acetate isobutyrate, absolute ethyl alcohol and medium chain triglyceride, wherein the mass ratio of the sucrose acetate isobutyrate to the absolute ethyl alcohol to the medium chain triglyceride is (68-72): (14-16): (14-16). The carergoline long-acting injection is in an in-situ gel dosage form, the optimal organic solvent and proportion are selected, the medicine directly enters blood circulation after being injected into the body, the first-pass effect is avoided, and the medicine utilization rate is increased; no stimulation is caused to gastrointestinal tracts, and adverse reactions are reduced; the long-acting release of the medicine is realized, the elimination half-life period is as long as 51.82 hours, the T max is 10 hours, the long-acting release mechanism reduces the administration frequency and the blood concentration fluctuation, and the effectiveness and the safety of the medicine can be improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations. Specifically, it relates to a long-acting cabergoline injection, a preparation method thereof, and an application thereof. Background Art

[0002] During the lactation period, ewes are usually accompanied by a relatively long anestrus period. After parturition, the nursing behavior of ewes will significantly increase the level of prolactin (PRL) in the body. Even if early weaning is implemented, PRL still remains at a relatively high level. The high level of PRL will accelerate the turnover rate of dopamine in the hypothalamus, directly inhibit the secretion of gonadotropin-releasing hormone (GnRH), and then reduce the release of pituitary gonadotropins, ultimately resulting in the inhibition of ovarian activity in ewes. This mechanism has been further confirmed in the study of cows. The lactation behavior inhibits the release of GnRH in the hypothalamus, reduces the secretion of gonadotropins in the anterior pituitary, thereby inhibiting the growth and development of ovarian follicles, and ultimately leading to estrus inhibition in female livestock. Therefore, the effect of inducing estrus in early-weaned ewes is not ideal.

[0003] Cabergoline (Cab) is a synthetic ergot derivative that has a high affinity for dopamine D2 receptors. The research by Phillipps H R et al. shows that cabergoline binds to dopamine D2 receptors, can inhibit the adenylate cyclase and cAMP-mediated PRL gene transcription and secretion mechanisms, and at the same time reduce the intracellular Ca 2+ concentration, thus exerting a strong and lasting inhibitory effect on PRL. Therefore, cabergoline is also known as a highly effective prolactin inhibitor. Cabergoline can successfully induce estrus in female dogs and sows. Based on this, it can be reasonably speculated that cabergoline can also induce estrus in early-weaned ewes. By reducing the prolactin level in early-weaned ewes, it activates the function of the ovaries, changes the ovaries from a relatively static state to a relatively active state, promotes the development and maturation of follicles, thereby inducing estrus in ewes and achieving breeding, shortening the lambing interval of ewes, and further improving the economic benefits of breeding.

[0004] Pfizer Inc. in the United States launched commercial products of cabergoline for human use in the early 1990s (specific time varies by country or region) and in 1996, namely Cabaser tablets and Dostinex tablets, for the treatment of hyperprolactinemia and Parkinson's syndrome. At the same time, cabergoline has also been widely used in the field of veterinary medicine. CEVA Santé Animale in France launched the veterinary drug product of cabergoline, Galastop oral solution (50 μg / mL), in April 1996. Subsequently, Veyx Pharma GmbH and Le Vet Beheer B.V. launched Kelactin oral solution (50 μg / mL) and Finilac oral solution (50 μg / mL) in July 2012 and February 2015 respectively. These products are used to treat pseudopregnancy in female dogs and inhibit lactation in dogs and cats. The recommended dosage is 0.1 mL / kg, once a day, for 4 - 6 days (depending on the severity of the clinical condition). T max (Peak time) is 1 h, and its elimination half-life in animals is 19 h. In addition, CEVA Santé Animale also launched the cabergoline injection Velactis (1.12 mg / mL) in December 2015 for dry cow management. The recommended dosage is 5.6 mg / head, injected after the last milking. T max is 3 h, and the average elimination half-life in animals is 20 h. Currently, most cabergoline-related products are oral preparations, and oral administration has some significant drawbacks: 1. Oral drugs will undergo the first-pass effect when passing through the liver, resulting in partial degradation or inactivation of some drugs, thus weakening the drug efficacy; 2. It stimulates the gastrointestinal mucosa, leading to adverse reactions such as nausea and vomiting; 3. The T max (Peak time) and elimination half-life time of the drug are short, and multiple repeated administrations are required, which may lead to large fluctuations in blood drug concentration and increase the risk of side effects.

[0005] In-situ gel drug delivery systems have attracted great attention from pharmaceutical scholars at home and abroad due to their excellent sustained-release characteristics, good tissue biocompatibility, and simple preparation process. Most in-situ gel long-acting injection products use poly(lactic-co-glycolic acid) (PLGA) gel technology, which has advantages such as easy minimally invasive drug delivery and reduced dosing frequency. However, there are some adverse reactions, such as inflammatory reactions and potential toxicity, which limit its practical clinical application. In contrast, long-acting injections based on sucrose acetate isobutyrate (SAIB) as a sustained-release matrix show excellent clinical potential. It has good biocompatibility, is recognized as a safe material by the Food and Drug Administration (FDA), and has inexpensive raw materials and a simple preparation process. The SAIB-based in-situ gel long-acting injection not only solves the limitations of the PLGA system but also provides a safer, more economical, and efficient drug delivery platform. After the drug is injected into the body, it directly enters the bloodstream, without a first-pass effect, improving drug utilization; it does not cause irritation to the gastrointestinal tract, reducing adverse reactions; and it also achieves long-term drug release. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a long-acting injection of cabergoline and its preparation method and application. This injection achieves long-term drug release, with an elimination half-life as long as 51.82 h and T max 10 h, and this long-acting release mechanism reduces the dosing frequency and blood drug concentration fluctuations, and can improve the effectiveness and safety of the drug.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A long-acting injection of cabergoline, the raw materials of this injection include SAIB (sucrose acetate isobutyrate), absolute ethanol, and MCT (medium-chain triglycerides), and the mass ratio of SAIB: absolute ethanol: MCT is (68 - 72):(14 - 16):(14 - 16).

[0009] Preferably, the mass ratio of SAIB: absolute ethanol: MCT is 70:15:15.

[0010] Furthermore, the present invention also provides a preparation method of the above-mentioned long-acting injection of cabergoline, including the following steps: mixing SAIB and MCT to obtain a matrix, dissolving cabergoline in absolute ethanol to obtain a cabergoline ethanol solution, then adding the cabergoline ethanol solution to the matrix to obtain a mixture, heating the mixture in a water bath and stirring until it becomes a flowing state, then stopping heating, and then continuing to stir to obtain a transparent and homogeneous solution, and filtering to obtain an in-situ gel injection.

[0011] Preferably, the mixed solution is placed in a water bath at 35-45°C, heated and stirred for 20-40 minutes, then the heating is stopped, and stirring is continued for 20-40 minutes to obtain a transparent and homogeneous solution.

[0012] Preferably, the mixed solution is placed in a water bath at 40°C, heated and stirred for 30 minutes, then the heating is stopped, and stirring is continued for 30 minutes to obtain a transparent and homogeneous solution.

[0013] Preferably, a 0.22 μm polytetrafluoroethylene filter membrane is used for filtration.

[0014] Preferably, the mass ratio of SAIB: absolute ethanol: MCT is (68-72):(14-16):(14-16).

[0015] The cabergoline long-acting injection of the present invention is an in-situ gel formulation, and the optimal organic solvent and ratio are selected. After the drug is injected into the body, it directly enters the blood circulation, without a first-pass effect, improving the drug utilization rate; it does not cause irritation to the gastrointestinal tract, reducing adverse reactions; it realizes the long-acting release of the drug, and its elimination half-life is as long as 51.82 h, and T max is 10 h. This long-acting release mechanism reduces the dosing frequency and fluctuations in blood drug concentration, and can improve the effectiveness and safety of the drug. Description of the Drawings

[0016] Figure 1 It is the solubility test result of cabergoline in different organic solvents in Example 1.

[0017] Figure 2 It is the viscosity measurement result of the blank gels prepared from different ratios of SAIB and organic solvents in Example 2.

[0018] Figure 3 It is the in-vitro forming result of the blank gel after screening the ratio of SAIB and organic solvents in Example 2. The organic solvents used from left to right are NMP, ethyl lactate, DMSO, and absolute ethanol.

[0019] Figure 4 It is the in-vitro release result of the drug-loaded gel in Example 3.

[0020] Figure 5 It is the in-vitro release test result of cabergoline in-situ gel in Example 6.

[0021] Figure 6 It is the forming test result of cabergoline in-situ gel under the subcutaneous tissue of the rat neck in Example 7.

[0022] Figure 7 It is the forming test result of cabergoline in-situ gel under the subcutaneous tissue of the rat abdomen in Example 7.

[0023] Figure 8For the results of the irritation test of cabergoline in-situ gel in Example 8, A is the quadriceps femoris muscle (the left side is the muscle injected with 0.9% normal saline, and the right side is the muscle injected with cabergoline in-situ gel), and B is the subcutaneous tissue of the neck (0.9% normal saline is injected subcutaneously on the left side, and cabergoline in-situ gel is injected subcutaneously on the right side).

[0024] Figure 9 For the blood concentration-time curve of cabergoline in-situ gel in rabbits in Example 9. Detailed implementation manners

[0025] The following combines the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0026] Example 1: Determination of the solubility of cabergoline in organic solvents

[0027] The method for determining the solubility of cabergoline in absolute ethanol, ethyl lactate, N-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO) is as follows: Take an appropriate amount of cabergoline in 4 centrifuge tubes, and add 3 mL of absolute ethanol, ethyl lactate, NMP, and DMSO to the centrifuge tubes respectively. Place the solution in a constant temperature oscillator at 37 °C and shake it to ensure that there is always solid drug in the solution. After equilibration for 6 h, centrifuge the centrifuge tubes at 3000 r / min for 10 min. Take the supernatant, dilute it with potassium dihydrogen phosphate acetonitrile (84:16), filter it after dilution, and inject it for detection. Determine the peak area of cabergoline according to the chromatographic method. Each solvent is measured in parallel 3 times, record the peak area, and substitute it into the standard curve for calculation. The test results show that the solubility of cabergoline in absolute ethanol is the best, and the solubility results are as Figure 1 shown.

[0028] Example 2: Determination of the rheological properties of blank gels prepared by different ratios of SAIB and organic solvents

[0029] Determination of viscosity: Measure the viscosity of the blank gel at room temperature using a rotational viscometer. Each solvent and ratio are measured in parallel three times, and record the viscosity results. The viscosity measurement results show that the effect of absolute ethanol in reducing viscosity is significantly better than the other three organic solvents, and the results are as Figure 2 shown.

[0030] Needle penetration test: Examine the needle penetration of the blank gel through a 10 mL syringe (7-gauge needle). The results are shown in Table 1.

[0031] In vitro forming test: Inject the blank gel into water and observe whether it forms. The results are shown in Table 1.

[0032] The ratio of the above SAIB to the organic solvent is (50% - 80%) : (20% - 50%) (w / w). Based on the determination results of the rheological properties of the blank gels prepared from different combinations of SAIB and organic solvents, the group with a ratio of SAIB to the organic solvent of 70% : 30% (w / w) was finally selected for the next screening. The in vitro forming results of the blank gel at this ratio are shown as Figure 3 shown. The gel formed by the blank gel with absolute ethanol as the solvent in water has a complete skeleton, a clear aqueous phase, and does not stick.

[0033] Table 1 Determination results of the rheological properties of the blank gel

[0034]

[0035] Note: "+++" indicates good needle penetration, "++" indicates general needle penetration, and "+" indicates poor needle penetration.

[0036] Example 3: In vitro release test of the drug-loaded gel

[0037] In vitro release test: The in vitro release test was carried out in a dissolution apparatus using the paddle method. The temperature was set at 37°C and the rotation speed was set at 100 r / min. The in vitro release medium was pH 6.8 phosphate buffer + 1% polysorbate 80 with a volume of 900 mL. Use a syringe to suck 2 mL of the drug-loaded gel of each formulation (SAIB: absolute ethanol / DMSO / NMP = 70% : 30%. When ethyl lactate was used as the solvent, the liquid chromatography showed an interference peak before the main drug peak, and the peak area ratio was 88.31%, so the formulation with ethyl lactate as the solvent was excluded), and slowly inject it into the release medium. Take 5 mL of samples at fixed times, and at the same time supplement fresh medium to ensure the sink conditions. Determine by HPLC method, plot the drug release amount against time to obtain the in vitro release curve, as shown in Figure 4 shown.

[0038] The test results show that different solvents have a significant impact on the release behavior of the gel. When absolute ethanol was used as the solvent, the release amounts of the drug-loaded gel during the release time had little difference, showing good release consistency; when NMP was used as the solvent, the release amounts of the drug-loaded gel at the initial stage of release had large differences, showing release instability; when DMSO was used as the solvent, the release amounts of the drug-loaded gel at 24 h had large differences, and there was also a situation of unstable release. Therefore, based on the above results, absolute ethanol was finally selected as the organic solvent because it can provide more stable and consistent release performance.

[0039] Example 4: Determination of the rheological properties of the blank gel (added with MCT) after prescription optimization

[0040] Since cabergoline shows instability in the prescription of SAIB and absolute ethanol, MCT was added to the original prescription to stabilize the drug activity of cabergoline, and now the addition ratio of MCT is screened.

[0041] The proportion of SAIB was fixed at 70%, the addition ratios of MCT were 5%, 15%, and 25% respectively, and the proportions of absolute ethanol were 25%, 15%, and 5% correspondingly. The optimized blank gels were prepared respectively and their rheological properties were measured.

[0042] Viscosity measurement: The viscosity of the blank gel was measured at room temperature using a rotational viscometer. Each ratio was measured in parallel three times and the viscosity results were recorded.

[0043] Needle penetration test: The blank gel was passed through a 10 mL syringe (No. 7 needle) to examine its needle penetration.

[0044] In vitro forming test: The blank gel was injected into water to observe its forming situation.

[0045] The test results are shown in Table 2. When the ratio of MCT was 25%, the gel viscosity was too high and the needle penetration was poor, so this ratio was excluded.

[0046] Table 2 Results of rheological property determination of blank gel

[0047]

[0048] Note: "+++" indicates good needle penetration, "++" indicates general needle penetration, and "+" indicates poor needle penetration.

[0049] Example 5: Stability test

[0050] The proportion of SAIB was fixed at 70%, the addition ratios of MCT were 5% and 15%, and the proportions of absolute ethanol were 25% and 15%. The drug-loaded gels with two ratios were placed at 60 °C for 5 days, and the drug content was detected to determine the ratio of MCT.

[0051] The stability test results are shown in Table 3. When the ratio of MCT to absolute ethanol was 5%:25%, the stability was relatively poor, so this ratio was excluded.

[0052] Table 3 Stability test results

[0053]

[0054] Example 6: In vitro release test of cabergoline in-situ gel

[0055] Take 1 mL of cabergoline in-situ gel and place it in a centrifuge tube. Add 5 mL of release medium (pH = 4.5 citrate-disodium hydrogen phosphate buffer + 0.1% Tween 80). Place the centrifuge tube in a 37 °C constant temperature water bath oscillator and shake it horizontally (100 times / min). Take out all the release medium at the predetermined time, and replace it with fresh release medium simultaneously to ensure sink conditions. Determine it by HPLC method, plot the cumulative drug release amount against time to obtain the release curve.

[0056] The test results are as Figure 5 shown. The in-vitro release of cabergoline in-situ gel can reach 30 days, and the average cumulative release amount is 75.07%.

[0057] Example 7: Forming test of cabergoline in-situ gel at different parts in rats

[0058] Select 20 healthy SD rats, female, divided into 4 groups, 5 rats in each group. During the test, they were allowed to eat and drink freely. Slowly inject cabergoline in-situ gel subcutaneously in the abdomen, subcutaneously in the neck and intramuscularly in the quadriceps femoris of each rat, and sacrifice and dissect the rats at the 12th hour, 24th hour, 48th hour and 96th hour after injection to observe the forming situation of the gel at different parts in the body.

[0059] As Figure 6 shown, obvious formed gel can be observed at the 12th hour, 24th hour, 48th hour and 96th hour after subcutaneous injection of cabergoline in-situ gel in the neck of rats. As Figure 7 shown, at the 12th hour, 24th hour, 48th hour and 96th hour after subcutaneous injection in the abdomen of rats, obvious formed gel can be observed in 85% of them, and the gel forms in 15% of them, but not obviously (as Figure 7 A). There is no formed gel after intramuscular injection of cabergoline in-situ gel in the quadriceps femoris of rats at the 12th hour, and it is in a liquid state. 40% of the gel forms at the 24th hour after injection, and the gel forming ratio is the highest at the 48th hour after injection, reaching 80%. The gel forming ratio decreases at the 96th hour after injection, which may be due to the degradation and gradual absorption of SAIB in the body. Therefore, based on the comprehensive test results, the forming situation of subcutaneous injection of cabergoline in-situ gel is better than intramuscular injection.

[0060] Example 8: Safety evaluation of cabergoline in-situ gel

[0061] Hemolytic test: Take 7 clean test tubes. Tubes 1 - 5 are test drug tubes, and add 0.1 - 0.5 mL of cabergoline in-situ gel respectively. Tube 6 is the negative control tube without adding gel, and tube 7 is the positive control tube. After adding the samples, gently mix them, place them in a constant temperature water bath at 37°C for 30 minutes, then put them in a constant temperature water bath oscillator (100 r / min, 37°C) and shake for 1 hour, 2 hours, 3 hours, and 12 hours, and then record and observe the results. If the red blood cell suspension turns into a red clear liquid, it indicates a hemolytic reaction; if all the red blood cells sink and the supernatant is colorless and clear, it can be judged as no hemolysis. Table 4 is the sample addition table for the hemolytic test.

[0062] Table 4 Sample Addition Table for Hemolytic Test

[0063]

[0064]

[0065] The test results showed that the red blood cells in tubes 1 - 5 with cabergoline in-situ gel added sank, and the supernatant was colored and clear, but there was no significant difference from tube 6 (negative control tube), and no hemolysis occurred; tube 7 (positive control tube) was a red clear solution, showing hemolysis. Therefore, cabergoline in-situ gel does not cause hemolysis.

[0066] Irritation test: Select 3 healthy female SD rats. During the test, they were allowed to eat and drink freely. According to the method of comparing the two sides of the same body, inject cabergoline in-situ gel into the quadriceps femoris of the left hind limb of the rats, and inject 0.9% normal saline into the quadriceps femoris of the right hind limb as a control; select 3 healthy female SD rats. During the test, they were allowed to eat and drink freely. According to the method of comparing the two sides of the same body, place the rats in the prone position, inject cabergoline in-situ gel subcutaneously on the left side of the neck, and inject 0.9% normal saline subcutaneously on the right side of the neck as a control. 48 hours after administration, sacrifice and dissect the rats, and observe whether there are any abnormalities at the injection sites.

[0067] The autopsy results are shown in Figure 8。Figure A shows the dissection diagram of the quadriceps femoris muscle. 48 hours after administration, both the quadriceps femoris muscle injected with 0.9% normal saline (left) and the quadriceps femoris muscle injected with cabergoline in-situ gel (right) were rosy in color, elastic to the touch, and showed no obvious abnormalities. According to the "Average Score and Grade of Muscle Stimulation" and the "Judgment Standard of Muscle Stimulation Response Grade", the average scores of both the cabergoline in-situ gel injection group and the 0.9% normal saline injection group were 0, indicating that cabergoline in-situ gel has no irritation to the muscle. Figure B shows the dissection diagram of the subcutaneous tissue of the neck. 48 hours after administration, there were no obvious abnormalities in the subcutaneous tissue injected with 0.9% normal saline (left) and the subcutaneous tissue injected with cabergoline in-situ gel (right). Referring to the "Evaluation Standard of Skin Stimulation Response" and the "Skin Stimulation Intensity Standard", the average scores of both the cabergoline in-situ gel injection group and the 0.9% normal saline injection group were 0, indicating that cabergoline in-situ gel has no irritation to the subcutaneous tissue.

[0068] Example 9: Pharmacokinetic Study of Cabergoline In-situ Gel in Rabbits

[0069] Six healthy, sexually mature female New Zealand white rabbits, weighing 4 - 4.5 kg, were used for the pharmacokinetic study of cabergoline in-situ gel. During the experiment, they had free access to food and water. The six female white rabbits were randomly divided into two groups, A and B, with 3 rabbits in each group. Group A was injected subcutaneously in the neck with cabergoline in-situ gel, and Group B was injected subcutaneously in the neck with cabergoline aqueous solution. Blank blood samples were collected before administration, and blood samples were collected from the ear artery of the rabbits after administration at the time points of 1 h, 2 h, 4 h, 8 h, 10 h, 1 d, 2 d, 3 d, 4 d, 5 d, 6 d, 7 d, 8 d, 9 d, and 10 d. The blood samples were centrifuged at 3000 r / min for 15 min, and the supernatants were aliquoted. The plasma concentration of cabergoline was detected using an ultra-high performance liquid chromatography - triple quadrupole mass spectrometry. The pharmacokinetic parameters of cabergoline in-situ gel and cabergoline aqueous solution are shown in Table 5.

[0070] Table 5 Pharmacokinetic Parameters of Cabergoline In-situ Gel and Aqueous Solution

[0071]

[0072]

[0073] Note: HL_Lambda_z represents the elimination half-life; AUC last represents the area under the curve from the administration time to the last sampling point; AUCINF_obs represents the area under the curve from the start of administration to the time of theoretical extrapolation to infinity; Vz_F_obs represents the apparent volume of distribution; Cl_F_obs represents the clearance rate; MRT last represents the mean residence time of the drug.

[0074] The experimental results showed that the pharmacokinetic parameters of cabergoline in situ gel group in rabbits were significantly better than those of cabergoline aqueous solution group. Specifically, the elimination half-life, mean residence time and Tmax of the in situ gel injection group were significantly prolonged, indicating that this preparation had more persistent drug release characteristics. This sustained-release property could not only improve the bioavailability of the drug, but also reduce the fluctuation of blood drug concentration, thereby reducing the risk of adverse reactions, which was safer for the animal body.

[0075] The above is the description of the embodiments of the present invention. Through the above description of the disclosed embodiments, those skilled in the art can implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but will conform to the widest scope consistent with the principles and novel points disclosed herein.

Claims

1. A long-acting cabergoline injection, characterized in that The raw materials of the injection include sucrose acetate isobutyrate, anhydrous ethanol and medium-chain triglycerides, and the mass ratio of sucrose acetate isobutyrate: anhydrous ethanol: medium-chain triglycerides is (68-72): (14-16): (14-16).

2. A cabergoline long-acting injection according to claim 1, characterized in that, The mass ratio of sucrose acetate isobutyrate: anhydrous ethanol: medium chain triglyceride is 70:15:

15.

3. A method for preparing a long-acting cabergoline injection according to claim 1 or 2, characterized in that: The method comprises the following steps: mixing sucrose acetate isobutyrate and medium-chain triglyceride to obtain a matrix, dissolving cabergoline in anhydrous ethanol to obtain a cabergoline ethanol solution, adding the cabergoline ethanol solution to the matrix to obtain a mixed solution, heating the mixed solution in a water bath while stirring until the mixed solution reaches a fluid state, stopping the heating, continuing to stir to obtain a transparent uniform solution, and filtering to obtain a cabergoline long-acting injection.

4. A method for preparing a long-acting cabergoline injection according to claim 3, characterized in that, The mixed solution was heated and stirred in a water bath at 35-45°C for 20-40 minutes, then heating was stopped and stirring was continued for 20-40 minutes to obtain a transparent uniform solution.

5. A method for preparing a long-acting cabergoline injection according to claim 3, characterized in that, The mixed solution was heated and stirred in a water bath at 40° C. for 30 minutes, then heating was stopped and stirring was continued for 30 minutes to obtain a transparent uniform solution.

6. A method for preparing a long-acting cabergoline injection according to claim 3, characterized in that, Filter using a 0.22 μm polytetrafluoroethylene filter.

7. A method for preparing a long-acting cabergoline injection according to claim 3, characterized in that, The mass ratio of sucrose acetate isobutyrate: anhydrous ethanol: medium chain triglycerides is (68-72): (14-16): (14-16).

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