Efficient paricalcitol injection and preparation method thereof

Abstract

The invention provides a high-efficiency paricalcitol injection and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the high-efficiency paricalcitol injection comprises an oil phase substance containing paricalcitol and a water phase substance containing chitosan; the preparation method comprises the following steps: simultaneously pouring a water-phase substance and an oil-phase substance into a container of a high-speed shearing emulsifying machine, carrying out ultrasonic emulsification, filtering, carrying out high-pressure homogenization, centrifuging, taking supernate to obtain the paricalcitol injection, enabling the paricalcitol injection to pass through a pretreated cation exchange resin column, collecting effluent, recording data, and determining the content of the paricalcitol. And enabling the effluent after cation exchange to pass through a pretreated anion exchange resin column, collecting the effluent, filtering, and sterilizing to obtain the efficient paricalcitol injection.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a highly effective paricalcitol injection and a preparation method thereof. Background Art

[0002] Paricalcitol is a synthetic active vitamin D analogue, mainly used to prevent and treat secondary hyperparathyroidism (SHPT) associated with chronic kidney disease (CKD). As a third-generation vitamin D receptor activator, paricalcitol is highly effective and low in toxicity. It can effectively inhibit the synthesis and secretion of parathyroid hormone (PTH), while regulating blood calcium and phosphorus levels and reducing complications in CKD patients. Although the existing paricalcitol injection has achieved certain success in the market, it still has some technical shortcomings and deficiencies: some injection products have low bioavailability in the body due to limitations in preparation process and formula, which affects the therapeutic effect. Some injection products are prone to degradation or deterioration during long-term storage, resulting in reduced drug activity or the production of Harmful substances increase the risk of medication for patients. Due to individual differences and the characteristics of the drug itself, some patients may experience adverse reactions such as hypercalcemia and allergic reactions when using paricalcitol injection, which affects the patient's treatment experience and safety. The preparation process of some injection products is relatively complex, requiring high-precision equipment and strict operating procedures, which increases the production cost and preparation difficulty. However, with the continuous increase in the number of chronic kidney disease patients and the improvement of medical standards, the demand for paricalcitol injection is also growing. Patients and doctors have extremely high requirements for the efficiency and safety of paricalcitol injection. They hope that the drug can play a therapeutic role quickly and accurately, while reducing adverse reactions and medication risks. Since some patients need long-term treatment, the stability of the injection has become an important consideration. Stable injection products can ensure that the drug does not change during storage and transportation, thereby ensuring the treatment effect. There are differences in the condition and physical condition of different patients. Therefore, the market needs more personalized paricalcitol injection products to meet the treatment needs of different patients. Under the premise of ensuring quality, reducing production costs and improving drug cost-effectiveness are also a major demand in the market. This helps to reduce the economic burden on patients, improve the popularity of drugs and therapeutic effects. With the advancement of medical technology and the diversification of patient needs, the market has also put forward higher requirements for the convenience and comfort of paricalcitol injection. For example, simplifying the injection process, reducing the number of injections, and improving the solubility of the drug can improve the patient's treatment experience and satisfaction. In summary, the existing paricalcitol injection still has some technical shortcomings and deficiencies in preparation process, formula optimization, and clinical application. At the same time, with the continuous development of the medical market and the diversification of patient needs, the demand for efficient, safe, stable and personalized paricalcitol injection products is also continuing to grow. Therefore, the development of a new type of efficient paricalcitol injection and its preparation method has important clinical significance and market value. Summary of the invention

[0003] The present invention provides a highly effective paricalcitol injection and a preparation method thereof, which are used to solve the problems raised in the above-mentioned background technology.

[0004] In order to solve the above technical problems, the present invention discloses a high-efficiency paricalcitol injection and a preparation method thereof. The high-efficiency paricalcitol injection comprises an oil phase substance containing paricalcitol and an aqueous phase substance containing chitosan.

[0005] Furthermore, the raw materials for preparing the oil phase substance containing paricalcitol include phospholipids, Tween 80, olive oil, medium chain triglycerides, structured triglycerides and paricalcitol.

[0006] Furthermore, the raw materials for preparing the oil phase material containing paricalcitol include, by weight, 2-4 parts of phospholipids, 2.5-6 parts of Tween 80, 3-5 parts of olive oil, 8-14 parts of medium-chain triglycerides, 3-5 parts of structural triglycerides and 0.005-0.006 parts of paricalcitol.

[0007] Furthermore, the raw materials for preparing the water phase material containing chitosan include anhydrous ethanol, chitosan, a cosolvent, an auxiliary agent, an antioxidant, a stabilizer and deionized water.

[0008] Furthermore, the raw materials for preparing the aqueous phase containing chitosan include, by weight, 5-8 parts of anhydrous ethanol, 1-3 parts of chitosan, 8-13 parts of cosolvents, 10-16 parts of additives, 1-3 parts of antioxidants, 5-9 parts of stabilizers and 25-40 parts of deionized water.

[0009] Furthermore, the cosolvents are citric acid, meglumine and hydroxypropyl β-cyclodextrin; the auxiliary agents are polyethylene glycol 400, polyethylene glycol 800 and polyethylene glycol 2000; the antioxidant is vitamin E; and the stabilizer is sorbitol, mannitol and glucose.

[0010] Furthermore, the weight ratio of citric acid, meglumine and hydroxypropyl β-cyclodextrin is (1-2): (2-4): (5-7); the weight ratio of polyethylene glycol 400, polyethylene glycol 800 and polyethylene glycol 2000 is (3-5): (3-5): (4-6); and the weight ratio of sorbitol, mannitol and glucose is (2-3): (2-3): (1-3).

[0011] Furthermore, the weight ratio of the oil phase material containing paricalcitol to the water phase material containing chitosan is 1:1.

[0012] Furthermore, the preparation method of the high-efficiency paricalcitol injection comprises adding phospholipids and Tween 80 to olive oil, medium-chain triglycerides and structured triglycerides, stirring at room temperature, adding paricalcitol, stirring to obtain an oil phase substance containing paricalcitol; adding anhydrous ethanol, chitosan, cosolvent, auxiliary agent, antioxidant and stabilizer to deionized water and stirring to obtain an aqueous phase substance; pouring the oil phase substance and the aqueous phase substance into a container of a high-speed shear emulsifier at the same time, ultrasonically emulsifying, filtering, high-pressure homogenizing, centrifuging, taking the supernatant to obtain paricalcitol injection, passing the paricalcitol injection through a pretreated cation exchange resin column, collecting the effluent, passing the cation exchanged effluent through a pretreated anion exchange resin column, collecting the effluent, filtering, and sterilizing to obtain a high-efficiency paricalcitol injection.

[0013] Furthermore, the preparation method of the high-efficiency paricalcitol injection includes adding phospholipids and Tween 80 to olive oil, medium-chain triglycerides and structured triglycerides at room temperature and humidity of 40%-60%, pouring the oil phase and the water phase into the container of a high-speed shear emulsifier at the same time, setting the speed to 10,000 rpm, and the emulsification time to 30 minutes. During the emulsification process, the temperature is kept constant at 25±5°C, pouring the colostrum obtained by high-speed shear emulsification into an ultrasonic emulsifier, setting the frequency to 20 kHz, the power to 500 W, the processing time to 10 minutes, filtering with a 0.45-micron filter membrane, injecting into a high-pressure homogenizer, setting the pressure to 50 MPa, the flow rate to 5 ml / min, performing 3 cycles of homogenization, and centrifuging at a centrifugal speed of 15,000 rpm for 30-50 minutes; the flow rate of the ion exchange resin column is controlled at 1-2BV / h, and filtered using a 0.22-micron sterile filter.

[0014] Compared with the prior art, the present invention provides a highly effective paricalcitol injection and a preparation method thereof, which has the following beneficial effects: (1) Olive oil is a natural vegetable oil with good biocompatibility and stability. It is rich in unsaturated fatty acids and vitamin E that are beneficial to the human body. Medium-chain triglycerides are easily absorbed and utilized by the human body and have high stability, but have a low molecular weight. Structural triglycerides have controllable fatty acid chain length and saturation. As a lipid component, structural triglycerides help increase the solubility and stability of paricalcitol in injection, which helps to ensure the effectiveness and safety of the drug during storage and use. As a lipid carrier, it helps to improve the bioavailability of paricalcitol. By improving the absorption and distribution of the drug in the body, triglycerides can ensure that the drug reaches the target tissue more effectively, thereby exerting a therapeutic effect and reducing side effects. Triglycerides help reduce drug stimulation and side effects on the body and improve patient tolerance. When combined with olive oil in an appropriate ratio, it can make up for the low molecular weight of medium-chain triglycerides while providing more nutrition. (2) The citric acid in the cosolvent acts as a chelating agent and acidity regulator, meglumine is used to adjust the pH value of the drug and increase its solubility, and hydroxypropyl β-cyclodextrin acts as an inclusion agent and solubilizer, effectively encapsulating the drug and increasing its solubility. The combination of the three in a suitable proportion improves the solubility, stability, bioavailability and safety of paricalcitol injection. (3) Polyethylene glycol 400 (PEG400) in the excipients has a lower molecular weight and better fluidity and solubility. Polyethylene glycol 800 (PEG800) has a moderate molecular weight and certain solubility, providing better lubricity and film-forming properties. Polyethylene glycol 2000 (PEG2000) has a higher molecular weight and provides better lubricity, moisturizing and thickening effects. When the three are combined in a suitable proportion, the paricalcitol injection obtained has a higher solubility. (4) Sorbitol in the stabilizer has good water solubility and osmotic pressure regulating effect, which can protect paricalcitol from oxidation and degradation. At the same time, sorbitol can also increase the viscosity of the injection and improve stability. Mannitol has good water solubility and osmotic pressure regulating effect. Mannitol can reduce the formation of ice crystals in the injection, thereby improving the stability of the injection at low temperatures. Mannitol can also increase the viscosity of the injection to a certain extent and improve the comfort during injection. Glucose, as a simple sugar, can not only provide energy for the human body, but also be used as a stabilizer. In the injection, glucose can maintain appropriate osmotic pressure to prevent cells from being damaged by osmotic pressure imbalance. At the same time, glucose can also form hydrogen bonds and other interactions with paricalcitol to increase its solubility in water and improve the stability of the injection. (5) Ion exchange technology can effectively remove impurity ions in the injection solution and improve the purity of the drug, thereby ensuring the safety and effectiveness of the drug. The purified paricalcitol injection solution has better stability and can maintain the stability of its active ingredients during storage and use, thereby extending the shelf life of the drug. The high-efficiency paricalcitol injection solution prepared by ion exchange technology has a low impurity content and may reduce the side effects of patients during use and improve patients' tolerance. DETAILED DESCRIPTION

[0015] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0016] In addition, in the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes, and do not specifically refer to the order or sequence, nor are they used to limit the present invention. They are only used to distinguish components or operations described with the same technical terms, and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions and technical features between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0017] Unless otherwise specified, the examples and comparative examples are parallel tests with the same components, component contents, preparation steps and preparation parameters. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are analytical reagents (AR) unless otherwise specified. Parts are parts by weight unless otherwise specified, and the materials are purchased from commercial channels.

[0018] Paricalcitol was purchased from Hai Aladdin Biochemical Technology Co., Ltd., nanometer level, 50 nm, CAS No. 131918-61-1; chitosan was purchased from Shanghai Linchen Pharmaceutical Technology Co., Ltd.; structured triglycerides were purchased from Aladdin, and the rest were purchased on the market.

[0019] Example 1 Initial preparation: At room temperature and humidity of 40%-60%, add 2.0 parts of phospholipids (containing 10% phosphatidylcholine) and 2.5 parts of Tween 80 to 5 parts of olive oil, 10 parts of medium-chain triglycerides and 5 parts of structural triglycerides, stir at room temperature for 30 minutes using a magnetic stirrer, add 0.005 parts of paricalcitol, and stir for 1 hour to obtain an oil phase substance.

[0020] To 25 parts of deionized water, add 5.0 parts of co-surfactant anhydrous ethanol, 1 part of chitosan, 8 parts of co-solvents (1 part of citric acid + 2 parts of meglumine + 5 parts of hydroxypropyl β-cyclodextrin), 10 parts of auxiliary agents (3 parts of polyethylene glycol 400 + 3 parts of polyethylene glycol 800 + 4 parts of polyethylene glycol 2000) and 1 part of antioxidant (vitamin E), 5 parts of stabilizer (2 parts of sorbitol + 2 parts of mannitol + 1 part of glucose) and stir well to obtain an aqueous phase substance.

[0021] Pour the oil phase material and the water phase material into the container of the high-speed shear emulsifier at the same time, stirring while adding, use an ultrasonic emulsifier, set the power to 200 watts, and the emulsification time to 10 minutes. During the emulsification process, maintain an ice water bath to control the temperature not to exceed 25°C. Filter through a 0.45-micron filter membrane to remove large particle impurities, inject into a high-pressure homogenizer, set the pressure to 50 MPa, and the flow rate to 5 ml / min, perform 3 cycles of homogenization treatment to obtain a homogenized injection, centrifuge the homogenized injection at a centrifugal speed of 15,000 rpm for 30 minutes to remove unencapsulated drugs and impurities, take the supernatant to obtain paricalcitol injection, and record the pH value and conductivity at this time.

[0022] Cation exchange treatment: Pass the paricalcitol injection through a pretreated cation exchange resin column to remove cationic impurities. The flow rate of the resin column is controlled at 1-2BV / h (BV is the resin bed volume), and the resin particle size is 20-40 mesh to ensure sufficient exchange. Collect the effluent, measure its pH value, conductivity and osmotic pressure, and record the data.

[0023] Anion exchange treatment: The effluent after cation exchange is passed through a pre-treated anion exchange resin column to remove anionic impurities. The flow rate is also controlled at 1-2BV / h to ensure sufficient exchange. The effluent is collected, and its pH value, conductivity and osmotic pressure are measured again, and the data is recorded. During the adjustment process, the pH value, conductivity and osmotic pressure need to be continuously measured and monitored until they meet the specified standards.

[0024] Filtration and sterilization: Filter the adjusted injection solution with a 0.22 micron sterile filter to remove possible microorganisms and particles. Fill the filtered injection solution into a sterile container and sterilize it in an autoclave to obtain a highly effective paricalcitol injection solution.

[0025] Example 2 The difference from Example 1 is that during the initial preparation, 4 parts of phospholipids and 6 parts of Tween 80 are added to 5 parts of olive oil, 14 parts of medium-chain triglycerides and 5 parts of structural triglycerides at room temperature and humidity of 40%-60%, and stirred at room temperature for 30 minutes using a magnetic stirrer, 0.006 parts of paricalcitol are added, and stirred for 1 hour to obtain an oil phase substance containing paricalcitol, and the rest is the same.

[0026] Example 3 The difference from Example 1 is that when preparing the aqueous phase material, 8 parts of co-surfactant anhydrous ethanol, 3 parts of chitosan, 13 parts of co-solvents (2 parts of citric acid, 4 parts of meglumine, 7 parts of hydroxypropyl β-cyclodextrin), 16 parts of additives (5 parts of polyethylene glycol 400, 5 parts of polyethylene glycol 800 and 6 parts of polyethylene glycol 2000) and 3 parts of antioxidants (vitamin E), 9 parts of stabilizers (3 parts of sorbitol, 3 parts of mannitol, 3 parts of glucose) are added to 40 parts of deionized water and stirred evenly to obtain an aqueous phase material. The rest is the same.

[0027] Example 4 The difference from Example 1 is that during the initial preparation, 3 parts of phospholipids and 4 parts of Tween 80 are added to 4 parts of olive oil, 12 parts of medium-chain triglycerides and 4 parts of structural triglycerides at room temperature and humidity of 40%-60%, stirred at room temperature for 30 minutes using a magnetic stirrer, 0.005 parts of paricalcitol are added, and stirred for 1 hour to obtain an oil phase substance containing paricalcitol, and the rest are the same.

[0028] Example 5 The difference from Example 1 is that when preparing the aqueous phase material, 7 parts of co-surfactant anhydrous ethanol, 2 parts of chitosan, 10 parts of co-solvents (1 part of citric acid, 3 parts of meglumine, 6 parts of hydroxypropyl β-cyclodextrin), 16 parts of additives (5 parts of polyethylene glycol 400, 5 parts of polyethylene glycol 800 and 6 parts of polyethylene glycol 2000) and 3 parts of antioxidants (vitamin E), 9 parts of stabilizers (3 parts of sorbitol, 3 parts of mannitol, 3 parts of glucose) are added to 30 parts of deionized water and stirred evenly to obtain an aqueous phase material. The rest is the same.

[0029] Comparative Example 1 The difference from Example 1 is the lack of ion exchange technology, and the others are the same.

[0030] Comparative Example 2 The difference from Example 1 is that an equal weight portion of Tween 80 is missing, and the other contents are the same.

[0031] Comparative Example 3 The difference from Example 1 is that an equal weight portion of chitosan is missing, and the other parts are the same.

[0032] Comparative Example 4 The difference from Example 1 is that 2.0 parts of phospholipids (containing 10% phosphatidylcholine) and 2.5 parts of Tween 80 are added to 15 parts of medium-chain triglycerides and 5 parts of structural triglycerides, and the rest are the same.

[0033] Comparative Example 5 The difference from Example 1 is that 2.0 parts of phospholipids (containing 10% phosphatidylcholine) and 2.5 parts of Tween 80 are added to 5 parts of olive oil and 15 parts of medium-chain triglycerides, and the other parts are the same.

[0034] Comparative Example 6 The difference from Example 1 is that 2.0 parts of phospholipids (containing 10% phosphatidylcholine) and 2.5 parts of Tween 80 are added to 20 parts of medium chain triglycerides, and the other parts are the same.

[0035] Comparative Example 7 The difference from Example 1 is that the co-solvent of equal weight parts lacks meglumine and is 8 parts of co-solvent (1 part of citric acid + 7 parts of hydroxypropyl β-cyclodextrin), and the rest is the same.

[0036] Comparative Example 8 The difference from Example 1 is that the stabilizer of equal weight parts lacks sorbitol, and is 5 parts of stabilizer (4 parts of mannitol + 1 part of glucose), and the rest is the same.

[0037] Comparative Example 9 The difference from Example 1 is that the stabilizer of equal weight parts lacks mannitol, and is 5 parts of stabilizer (4 parts of sorbitol + 1 part of glucose), and the rest is the same.

[0038] Performance Testing 1. Impurity test Impurity content: The injections prepared in the examples and comparative examples were accelerated for 12 months at 40°C and RH75%, and the contents (%) of degradation impurities (impurity A, impurity B, PCL-9 and PY5) were detected. / means the detected amount is less than 0.01%. The measured values ​​were averaged over 10 groups and recorded in Table 1.

[0039] Table 1

[0040] 2. Effect of light exposure test on the stability of highly effective and stable paricalcitol injection The highly efficient and stable paricalcitol injection prepared in the example and the injection prepared in the comparative example were used as test samples, and the opening was placed in a light box equipped with a fluorescent lamp, and placed under an illumination of 4500lx±500lx for 30 days. Samples were taken on the 0th day, the 10th day, and the 30th day, respectively, to detect the calcitriol content.

[0041] Table 2

[0042] Table 2 shows the effect of light exposure test on the paricalcitol content in paricalcitol injection. The results show that the high-efficiency paricalcitol injection prepared by the present invention has high tolerance to light exposure.

[0043] 3. Accelerated Test The high-efficiency paricalcitol injection prepared in the example, the injection prepared in the comparative example, and the reference preparation (National Medicine Standard No. H20143141) were respectively used as test samples for accelerated testing, packaged as the reference preparation, and placed at a temperature of 40±2°C and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first month, the second month, and the sixth month during the test to detect the paricalcitol content.

[0044] Table 3

[0045] Table 3 shows that in the accelerated test, the change of paricalcitol content in the high-efficiency paricalcitol injection prepared by the present invention is relatively small, indicating that the high-efficiency paricalcitol injection prepared by the present invention has high stability under high temperature and high humidity conditions.

[0046] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A highly effective paricalcitol injection, the preparation raw materials comprising an oil phase substance containing paricalcitol and an aqueous phase substance containing chitosan.

2. The high-efficiency paricalcitol injection according to claim 1, characterized in that: The raw materials for preparing the oil phase material containing paricalcitol include phospholipids, Tween 80, olive oil, medium chain triglycerides, structured triglycerides and paricalcitol.

3. The high-efficiency paricalcitol injection according to claim 2, characterized in that: The raw materials for preparing the oil phase material containing paricalcitol include, by weight, 2-4 parts of phospholipids, 2.5-6 parts of Tween 80, 3-5 parts of olive oil, 8-14 parts of medium chain triglycerides, 3-5 parts of structural triglycerides and 0.005-0.006 parts of paricalcitol.

4. The high-efficiency paricalcitol injection according to claim 1, characterized in that: The raw materials for preparing the water phase material containing chitosan include anhydrous ethanol, chitosan, a cosolvent, an auxiliary agent, an antioxidant, a stabilizer and deionized water.

5. The high-efficiency paricalcitol injection according to claim 1, characterized in that: The raw materials for preparing the water phase containing chitosan include, by weight, 5-8 parts of anhydrous ethanol, 1-3 parts of chitosan, 8-13 parts of cosolvent, 10-16 parts of auxiliary agent, 1-3 parts of antioxidant, 5-9 parts of stabilizer and 25-40 parts of deionized water.

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