Stable alprostadil injection and preparation method thereof

Abstract

The invention provides a stable alprostadil injection and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The stable alprostadil injection comprises the following components: alprostadil, oil for injection, a compound emulsifier, an osmotic pressure regulator and water for injection. According to the invention, a certain amount of soybean phosphatidylinositol is used as an auxiliary emulsifier, and the auxiliary emulsifier and high-purity egg yolk lecithin (for injection) form a composite emulsifier, so that the chemical stability of the product can be remarkably improved, the product can tolerate an over-killing method, the product has a high SAL (Sterile Assurance Language), and the product can be stored for 24 months at a conventional cold chain temperature (2-8 DEG C), and the product quality still meets the national drug standard.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a stable alprostadil injection and a preparation method thereof. BACKGROUND

[0002] Alprostadil is also known as prostaglandin E1 (Alprostadil), and its chemical name is: (1R, 2R, 3R,)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentane heptanoic acid, and its chemical structural formula is:

[0003] Alprostadil is an endogenous physiologically active substance, and has various physiological and pharmacological activities.

[0004] Specific indications are as follows: 1. Treating four-limb ulcers caused by chronic arterial occlusion (thrombotic occlusive vasculitis, occlusive arteriosclerosis, etc.) and four-limb resting pain caused by microvascular circulatory disorders. Improving cardiovascular microcirculatory disorders.

[0005] 2. Anti-thrombotic treatment after organ transplantation, to inhibit thrombus formation in the blood vessels after transplantation.

[0006] 3. Arterial duct-dependent congenital heart disease, to relieve hypoxemia and maintain duct blood flow for waiting for surgical treatment.

[0007] 4. Used for the adjuvant treatment of chronic hepatitis.

[0008] The drug was developed early, and was marketed in the United States as early as 1981 (lyophilized powder injection 100 μg / branch). The United States Pharmacopoeia began to collect it in 1985, and has been marketed in many countries. Since it degrades quickly when it enters the circulation, the dosage is large when used, and there are many side effects. In 1988, Japan marketed alprostadil injection (fatty emulsion 2ml:10 μg), which greatly reduced the original dosage, expanded the treatment indications, and improved the efficacy. In 1998, the first alprostadil injection was marketed in China, with the trade name: Kaishi.

[0009] However, due to the instability of alprostadil in water, the existing alprostadil injection products on the market at home and abroad generally use residual probability method (such as 121℃ sterilization for 8 minutes) terminal sterilization process or aseptic production process (Benxi Hengkang product, trade name: Bexiang, and Chongqing Pharmaceutical Friend's dry emulsion, trade name: Youdi'er) in the production process, the sterility assurance value (SAL) of the product is low, the fat emulsion preparation is rich in nutrients, and the safety of the terminal high-pressure sterilization will be reduced. On the other hand, due to the degradation of alprostadil during sterilization and storage, a higher excess dosage is executed in actual production, and the degraded prostaglandin A1 is also an endogenous substance, which has a synergistic effect with alprostadil due to its similar physiological effect. The excess dosage of non-terminal sterilization products is lower, so the clinical efficacy will also be correspondingly reduced.

[0010] CN101664390 discloses a preparation method of alprostadil lipid microspheres, which is prepared from alprostadil, injection oil, emulsifier, stabilizer, isotonic agent, and injection water. By dissolving the drug and phospholipid into a suitable solvent first, and then adding the oil phase after removing the solvent, the encapsulation efficiency of the prepared product is significantly improved, the drug encapsulation efficiency is more than 97%, the free alprostadil in water is less than 5%, and the generation of degradation products is reduced. However, in fact, any alprostadil injection will be degraded by more than 10% after heat-pressure sterilization (overkill). Moreover, in the presence of oleic acid and phosphatidylethanolamine, this degradation will further increase. This patent uses a solvent to dissolve the main drug, which only improves the reliability of the dissolution step operation.

[0011] CN101474150 discloses a stable alprostadil injection emulsion, which contains alprostadil as the active ingredient, and pharmaceutically acceptable injection oil, emulsifier, injection glycerol, and injection water prepared by emulsification technology. The emulsifier contains 3g~30g of poloxamer 188 and 1g~6g of injection lecithin. Compared with the existing alprostadil injection emulsion, the thermal stability of alprostadil can be significantly enhanced, the shelf life of alprostadil injection emulsion can be prolonged, and the degradation of alprostadil in the lungs can be significantly reduced. However, due to the absence of oleic acid as a co-emulsifier, the emulsion will have oil floating phenomenon, and the average particle size will become larger after heat-pressure sterilization, so the emulsification effect needs to be further improved, and the emulsification effect of poloxamer 188 is not very ideal.

[0012] JP5193870 discloses a prostaglandin fat emulsion and its manufacturing method, as well as its stabilization method and emulsifier, which contains prostaglandin as the active ingredient, and contains phospholipid containing phosphatidylcholine PC and phosphatidylglycerol PG, and the PC:PG ratio in the phospholipid is 85:15~99.7:0.3. Due to the excellent stability of the active ingredient and emulsion stability, no free higher fatty acid or salt thereof such as oleic acid is added as a co-emulsifier in the prescription.

[0013] In 2012, a new prescription product of egg yolk phosphatidylglycerol was added by Fuji Pharmaceutical Industry Co., Ltd. in Japan, with a validity period of 24 months. However, the price of high-purity egg yolk phosphatidylglycerol is expensive, and the imported product costs 30000 yuan / kg, and the addition amount in the prescription is 1.8%, which is a large amount, resulting in high cost of the preparation product, which limits the use of the product in the clinic.

[0014] On the other hand, the marketed injection products are all stored at an unconventional temperature (0~5℃), and the product transportation, storage and use are very inconvenient.

[0015] Therefore, how to obtain a stable alprostadil injection and a preparation method thereof is a technical problem to be solved at present. SUMMARY

[0016] The purpose of the present application is to provide a stable alprostadil injection and a preparation method thereof, to solve the above technical problems.

[0017] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions: The present application provides a stable alprostadil injection, comprising the following components with the following mass concentrations: alprostadil 5~15 μg / mL; injection oil 0.1~0.2 g / mL; compound emulsifier 10~16 mg / mL; osmotic pressure regulator 20~25 mg / mL; injection water for constant volume; The compound emulsifier is egg yolk lecithin and soybean phosphatidylinositol, and the mass ratio of the egg yolk lecithin and the soybean phosphatidylinositol is 1.0~1.5:0.02~0.08.

[0018] Further, the osmotic pressure regulator is glycerol, and the injection oil is soybean oil; the pH of the alprostadil injection is 4.5~6.0.

[0019] The present application also provides a preparation method of the above-mentioned stable alprostadil injection, comprising the following steps: 1) adding alprostadil and compound emulsifier into injection oil respectively, and dispersing by shearing emulsification to form an oil phase; 2) mixing the osmotic pressure regulator and part of the injection water, adjusting the pH of the system to 4.5~6.0 to obtain an aqueous phase; 3) adding the oil phase into the aqueous phase under shearing dispersion to form a primary emulsion; 4) Add the remaining water for injection to the colostrum until the total volume is reached. After mixing, transfer the mixture to a high-pressure microfluidic nanodispersant for homogenization several times. Fill the solution into 2ml vials with nitrogen and sterilize to obtain alprostadil injection.

[0020] Furthermore, in step 1), the rotation speed of the shear emulsification dispersion is 5000~10000 rpm, and the time is 10~30 min.

[0021] Furthermore, in step 4), the homogenization pressure is 18000~20000 Psi, and the homogenization is performed 3~5 times.

[0022] Furthermore, in step 4), the sterilization temperature is 121~126℃ and the sterilization time is 5~12min.

[0023] The beneficial effects of this invention are: 1. The amount of high-purity egg yolk lecithin used in this invention can be reduced from 1.8% in the original formulation to 1.2%, giving the product a low-cost advantage, improving product accessibility, and facilitating its widespread clinical use.

[0024] 2. This invention provides a new formulation and preparation method for alprostadil injection, which improves the safety and stability of the product, has significant inventiveness and practicality, and is sure to have good application prospects. Detailed Implementation

[0025] This invention provides a stable alprostadil injection solution comprising the following components at the following mass concentrations: Alprostadil 5~15μg / mL; Oil for injection: 0.1~0.2 g / mL; Compound emulsifier 10~16mg / mL; Osmotic pressure regulator 20~25mg / mL; Water for injection is used for volume adjustment; The composite emulsifier is egg yolk lecithin and soybean phosphatidylinositol, and the mass ratio of egg yolk lecithin to soybean phosphatidylinositol is 1.0~1.5:0.02~0.08.

[0026] In this invention, the mass concentration of alprostadil is preferably 8-12 μg / mL, and more preferably 10 μg / mL, according to the mass concentration meter.

[0027] In this invention, the mass concentration of the injectable oil is preferably 0.12~0.18 g / mL, more preferably 0.15~0.17 g / mL, according to the mass concentration meter.

[0028] In this invention, the mass ratio of egg yolk lecithin to soybean phosphatidylinositol in the composite emulsifier is preferably 1.1~1.4:0.03~0.07, and more preferably 1.2~1.3:0.04~0.06, based on mass concentration.

[0029] In this invention, soybean phosphatidylinositol exhibits high emulsifying properties due to the presence of multiple hydroxyl groups at its hydrophilic end. Its structural formula is as follows: .

[0030] This invention uses a certain amount of soybean phosphatidylinositol as an auxiliary emulsifier, which, together with egg yolk lecithin (for injection), forms a composite emulsifier that significantly enhances the stability of the formulation. Based on this, the inventors investigated the stability of the sterilized formulation at conventional refrigeration temperatures (2-8°C) and compared it with commercially available formulation samples, using the content of succinate and degradation products as evaluation indicators. The results were unexpected: the product prepared using a certain amount of soybean phosphatidylinositol as an auxiliary emulsifier, combined with high-purity egg yolk lecithin (for injection) to form a composite emulsifier, and then processed through emulsification technology, can be stored at conventional refrigeration temperatures (2-8°C) for 24 months, and the product quality still meets the national drug standard WS1-(X-041)-2002Z-2008. Furthermore, the amount of high-purity egg yolk lecithin used in this invention can be reduced from 1.8% in the original formulation to 1.2%, giving the product a low-cost advantage, improving its accessibility, and facilitating its widespread clinical use.

[0031] In this invention, the mass concentration of the osmotic pressure regulator is preferably 21-24 mg / mL, and more preferably 22-23 mg / mL, according to the mass concentration meter.

[0032] In this invention, the osmotic pressure regulator is glycerin, and the oil for injection is soybean oil; the pH of the alprostadil injection solution is 4.5~6.0, preferably 5.0~6.0.

[0033] The alprostadil injection provided by this invention is prepared by emulsification technology using alprostadil as the active ingredient, along with pharmaceutically acceptable soybean oil (for injection), a compound emulsifier, glycerin (for injection), hydrochloric acid, and water for injection. The compound emulsifier contains high-purity egg yolk lecithin (model PT-98, provided by Kewpie Corporation, Japan), with a PC content of not less than 98% and a PE content of not more than 0.5%. The formulation also includes soybean phosphatidylinositol (SPI, Shanghai Taiwei Pharmaceutical Co., Ltd.) at a content of not less than 95%.

[0034] This invention also provides a method for preparing the above-mentioned stable alprostadil injection, comprising the following steps: 1) Alprostadil and the compound emulsifier are added to the injection oil separately and dispersed by shear emulsification to form an oil phase; 2) Mix the osmotic pressure regulator and part of the water for injection, and adjust the pH of the system to 4.5~6.0 to obtain the aqueous phase; 3) Under shear dispersion, the oil phase is added to the aqueous phase to form a primary emulsion; 4) Add the remaining water for injection to the colostrum until the total volume is reached. After mixing, transfer the mixture to a high-pressure microfluidic nanodispersant for homogenization several times. Fill the solution into 2ml vials with nitrogen and sterilize to obtain alprostadil injection.

[0035] In this invention, in step 1), the rotation speed of the shear emulsification dispersion is 5000~10000 rpm, preferably 5000~8000 rpm; the time is 10~30 min, preferably 15~25 min.

[0036] In this invention, in step 4), the homogenization pressure is 18000~20000 Psi, preferably 19000 Psi; the number of homogenizations is 3~5 times, preferably 4 times.

[0037] In this invention, in step 4), the sterilization temperature is 121~126℃ and the sterilization time is 5~12min, preferably 121℃ for 12min or 126℃ for 5min.

[0038] In this invention, the high-pressure microfluidizer is commercially known as Microfluidizer.

[0039] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0040] Example 1

[0041] Add 7 mg of alprostadil, 12 g of high-purity egg yolk lecithin (for injection), and 0.6 g of soybean phosphatidylinositol to 100 g of soybean oil. Disperse at 8000 rpm for 15 minutes under high shear for dissolution to form the oil phase. In a separate container, add 850 g of water for injection and 22 g of glycerol (for injection), then stir at low speed for 5 minutes to form the aqueous phase. Adjust the pH of the aqueous phase to 5.5 with 10 mM hydrochloric acid. Place the aqueous phase under the working head of a high-shear dispersing emulsifier. After high-speed operation, slowly add the oil phase and emulsify for 20 minutes to form the promulgated emulsion. Add water for injection to bring the volume to 1000 ml. Place the promulgated emulsion into the feed inlet of a high-pressure microfluidic nanodispersant and homogenize three times at 18000 Psi pressure. Fill, stopper, and cap. Sterilize in a rotary water bath sterilizer (provided by Zhangjiagang Shennong Pharmaceutical Machinery Co., Ltd.) at 121℃ for 8 minutes to obtain the final product.

[0042] Example 2

[0043] Add 7 mg of alprostadil, 15 g of high-purity egg yolk lecithin (for injection), and 0.6 g of soybean phosphatidylinositol to 100 g of soybean oil. Disperse at 6000 rpm under high shear for 15 minutes until dissolved to form the oil phase. In a separate container, add 850 g of water for injection and 22 g of glycerol (for injection), then stir at low speed for 5 minutes to form the aqueous phase. Adjust the pH of the aqueous phase to 5.5 with 10 mM hydrochloric acid. Place the aqueous phase under the working head of a high-shear dispersing emulsifier. After high-speed operation, slowly add the oil phase and emulsify for 20 minutes to form the promulgated emulsion. Add water for injection to bring the volume to 1000 ml. Place the promulgated emulsion into the feed inlet of a high-pressure microfluidic nanodispersant and homogenize four times at 20000 Psi pressure. Fill, stopper, and cap. Sterilize in a rotary water bath sterilizer at 126°C for 5 minutes to obtain the final product.

[0044] Example 3

[0045] Add 7 mg of alprostadil, 15 g of high-purity egg yolk lecithin (for injection), and 0.7 g of soybean phosphatidylinositol to 100 g of soybean oil. Disperse at 5000 rpm under high shear for 15 minutes until dissolved to form the oil phase. In a separate container, add 850 g of water for injection and 22 g of glycerol (for injection), then stir at low speed for 5 minutes to form the aqueous phase. Adjust the pH of the aqueous phase to 5.8 with 10 mM hydrochloric acid. Place the aqueous phase under the working head of a high-shear dispersing emulsifier. After high-speed operation, slowly add the oil phase and emulsify for 20 minutes to form the promulgated emulsion. Add water for injection to bring the volume to 1000 ml. Place the promulgated emulsion into the feed inlet of a high-pressure microfluidic nanodispersant and homogenize four times at 20000 Psi pressure. Fill, stopper, and cap. Sterilize in a rotary water bath sterilizer at 126°C for 5 minutes to obtain the final product.

[0046] Example 4

[0047] Add 7 mg of alprostadil, 14 g of high-purity egg yolk lecithin (for injection), and 0.5 g of soybean phosphatidylinositol to 100 g of soybean oil. Disperse at 7000 rpm for 15 minutes under high shear for dissolution to form the oil phase. In a separate container, add 850 g of water for injection and 22 g of glycerol (for injection), then stir at low speed for 5 minutes to form the aqueous phase. Adjust the pH of the aqueous phase to 5.6 with 10 mM hydrochloric acid. Place the aqueous phase under the working head of a high-shear dispersing emulsifier. After high-speed operation, slowly add the oil phase and emulsify for 20 minutes to form the promulgated emulsion. Add water for injection to bring the volume to 1000 ml. Place the promulgated emulsion into the feed inlet of a high-pressure microfluidic nanodispersant and homogenize it four times at 18000 Psi pressure. Fill, stopper, and cap. Sterilize in a rotary water bath sterilizer at 121°C for 12 minutes to obtain the final product.

[0048] Comparative Example 1 (Publicly Disclosed Formula for Original Product)

[0049] Add 7 mg of alprostadil, 18 g of high-purity egg yolk lecithin (for injection), 2.4 g of oleic acid, and 100 g of soybean oil to a container and disperse at 8000 rpm for 15 minutes until dissolved to form the oil phase. In a separate container, add 850 g of water for injection and 22 g of glycerol (for injection), then stir at low speed for 5 minutes to form the aqueous phase. Place the aqueous phase under the working head of a high-shear dispersing emulsifier and, after high-speed operation, slowly add the oil phase, emulsifying for 20 minutes to form the promulgated emulsion. Adjust the pH of the aqueous phase to 5.5 with 10 mM sodium hydroxide, and add water for injection to bring the volume to 1000 ml. Place the promulgated emulsion into the inlet of a high-pressure microfluidic nanodispersant and homogenize four times at 20000 Psi pressure. Fill, cap, and seal. Sterilize in a rotary water bath sterilizer at 126°C for 5 minutes to obtain the final product.

[0050] Test Example 1: Sterilization Stability Test

[0051] The sterilized alprostadil injection samples prepared in Examples 1, 2, and Comparative Example 1 were evaluated, and their post-sterilization properties, pH value, and alprostadil degradation rate (1 - alprostadil content / alprostadil dosage) were investigated. The results are shown in Table 1.

[0052] Table 1. Sterilization stability of different formulations of alprostadil injection

[0053] As shown in Table 1, the alprostadil injection prepared by this invention can withstand the excessive sterilization process compared with samples prepared by commercially available prescriptions, which can significantly enhance its safety and stability.

[0054] Example 2 Storage Stability Test

[0055] The alprostadil injections prepared in Examples 1, 2, and Comparative Example 1 were sterilized and stored at conventional refrigeration temperatures (2-8°C) for 24 months. Long-term stability was assessed using the degradation rate of the active pharmaceutical ingredient as the evaluation index. The results are shown in Table 2.

[0056] Degradation rate calculation method: (Feed amount - Formulation content) / Feed amount 100%.

[0057] Table 2. Degradation rate of different formulations of alprostadil injection under storage conditions of 2–8℃.

[0058] As shown in Table 2, the alprostadil injection prepared by this invention can be stored for 24 months at a conventional refrigeration temperature of 2~8℃ compared with samples prepared by commercial prescriptions, and the product quality still meets the national drug standard WS1-(X-041)-2002Z-2008.

[0059] As can be seen from the above embodiments, the present invention provides a stable alprostadil injection and its preparation method. The amount of high-purity egg yolk lecithin used in this invention can be reduced from 1.8% in the original formulation to 1.2%, resulting in a low-cost advantage, improved product accessibility, and facilitating its widespread clinical use. The method of this invention improves the safety and stability of the product, demonstrating significant inventiveness and practicality, and is poised for promising applications.

[0060] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A stable alprostadil injection, characterized in that, Components containing the following mass concentrations: Alprostadil 5~15μg / mL; Oil for injection: 0.1~0.2 g / mL; Compound emulsifier 10~16mg / mL; Osmotic pressure regulator 20~25mg / mL; Water for injection is used for volume adjustment; The composite emulsifier is egg yolk lecithin and soybean phosphatidylinositol, and the mass ratio of egg yolk lecithin to soybean phosphatidylinositol is 1.0~1.5:0.02~0.

08.

2. The stable alprostadil injection according to claim 1, characterized in that, The osmotic pressure regulator is glycerol, and the oil for injection is soybean oil; the pH of the alprostadil injection solution is 4.5~6.

0.

3. The method for preparing the stable alprostadil injection according to claim 1 or 2, characterized in that, Includes the following steps: 1) Alprostadil and the compound emulsifier are added to the injection oil separately and dispersed by shear emulsification to form an oil phase; 2) Mix the osmotic pressure regulator and part of the water for injection, and adjust the pH of the system to 4.5~6.0 to obtain the aqueous phase; 3) Under shear dispersion, the oil phase is added to the aqueous phase to form a primary emulsion; 4) Add the remaining water for injection to the colostrum until the total volume is reached. After mixing, transfer the mixture to a high-pressure microfluidic nanodispersant for homogenization several times. Fill the solution into 2ml vials with nitrogen and sterilize to obtain alprostadil injection.

4. The preparation method according to claim 3, characterized in that, In step 1), the rotation speed of the shear emulsification dispersion is 5000~10000 rpm, and the time is 10~30 min.

5. The preparation method according to claim 3 or 4, characterized in that, In step 4), the homogenization pressure is 18000~20000 Psi, and the homogenization is performed 3~5 times.

6. The preparation method according to claim 5, characterized in that, In step 4), the sterilization temperature is 121~126℃ and the sterilization time is 5~12min.

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