A drotaverine freeze-dried preparation and its preparation method

Abstract

The present invention discloses a drotaverine freeze-dried preparation and a preparation method thereof. By adding excipient dextran to the prescription, adding citric acid-sodium citrate to regulate the pH, and optimizing the freeze-drying process, the obtained freeze-dried preparation is porous and has few appearance defects, and has good redissolvability. The present invention prepares a drotaverine freeze-dried preparation for the first time, which has better stability and safety compared with the existing aqueous injection.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations and relates to a rociverine freeze-dried preparation and a preparation method thereof. Background Art

[0002] Rociverine, alias: rociverine; rialatone. Pharmacological studies have shown that rociverine has a strong dual antispasmodic effect and also has a papaverine-like effect. It can selectively act on visceral smooth muscle, inhibit the influx of smooth muscle Ca²⁺, relax smooth muscle, does not affect the vascular smooth muscle tension, and has no effect on the cardiovascular system. In addition, rociverine also has an atropine-like parasympathetic blocking effect, but the adverse reactions are lower than those of atropine. Its reasonable ratio of muscle and nerve components ensures the antispasmodic effects of the two components. In the early years, rociverine was often used as a preoperative medication for gastrointestinal endoscopy. In clinical studies, rociverine has been proven to be effective in midwifery, and can shorten the uterine dilation, delivery time and recovery time during dystocia. Some studies believe that as an anticholinergic drug, the total effective rate of rociverine in the treatment of renal colic is equivalent to that of anisodamine (P>0.05). There are also studies showing that the combined maintenance use of diclofenac sodium lidocaine and rociverine is significantly more effective than pethidine hydrochloride plus anisodamine in relieving renal colic. Since the adverse reactions of rociverine are few and mild, they can all resolve on their own and the possibility of addiction is eliminated, while the incidence of adverse reactions of anisodamine is significantly higher than that of rociverine, and multiple adverse reactions occur simultaneously. Therefore, rociverine is worthy of promotion in clinical practice.

[0003] At present, the marketed dosage forms of rociverine are tablets and aqueous injections. Rociverine tablets were first marketed in Italy in 1980 and are mainly used for the antispasmodic and analgesic effects of the urogenital tract and biliary tract; it is suitable for the treatment of acute, subacute and chronic pain caused by smooth muscle spasm. Although tablets are convenient to take, after oral administration, they need to go through processes such as disintegration, dispersion, and dissolution before entering the blood circulation, and the drug takes effect relatively slowly. Although it can meet the needs of some patients, in order to quickly achieve the antispasmodic and analgesic effects, for patients who need rapid drug effects, this method may not meet their needs. Aqueous injections are used for intramuscular injection or intravenous injection and can directly enter the blood drug circulation, and the drug takes effect quickly. However, the currently marketed aqueous injections add p-hydroxybenzoate as a preservative to avoid microbial contamination during transportation, storage and use. The preservative itself has a certain toxicity and will directly produce side effects after being absorbed by the human body.

[0004] Drotaverine is an oily compound with poor solubility in water, and the resulting liquid preparation is relatively sensitive to light and has poor stability. Developing drotaverine into a freeze-dried preparation can improve the stability of the preparation, avoid the addition of preservatives in the preparation, and is safer. At present, there is no report on the freeze-dried preparation of drotaverine. In addition, due to the physical and chemical properties of drotaverine, the eutectic point is relatively low during the freeze-drying process, which easily causes problems such as floating of the freeze-dried sample, local re-dissolution and collapse, affecting the appearance and quality of the product. Therefore, how to prepare a freeze-dried preparation of drotaverine with better appearance and quality is a problem to be solved. Summary of the Invention

[0005] In view of the above problems, the present invention provides a freeze-dried preparation of drotaverine and a preparation method thereof. By adding excipient dextran to the prescription, adding citric acid-sodium citrate to regulate the pH, and optimizing the freeze-drying process at the same time, the obtained freeze-dried preparation is porous, has few appearance defects, and has good re-dissolution. The present invention prepares the freeze-dried preparation of drotaverine for the first time, which has better stability and safety compared with the existing aqueous injection.

[0006] The technical solution of the present invention is: a freeze-dried preparation of drotaverine, the components and parts by weight of which are: 10 parts of drotaverine, 28-32 parts of dextran (preferably 30 parts of dextran), an appropriate amount of citric acid-sodium citrate, and the acidity of the product pH is 4.5-5.5.

[0007] The preparation method of the above-mentioned freeze-dried preparation of drotaverine is characterized in that 600 parts of injection water, 28-32 parts of dextran (preferably 30 parts of dextran), an appropriate amount of citric acid-sodium citrate are added to a reaction vessel to adjust the pH, 10 parts of drotaverine are added, the stirring is controlled at pH 4.0-5.0, and the injection water is supplemented to 1000 parts. After the raw materials are dissolved and mixed evenly, they are filtered through a polyethersulfone filter element into ampoules, semi-corked, transferred to a freeze-dryer, and freeze-dried to obtain the finished product.

[0008] The freeze-drying process is as follows: the pre-cooling temperature of the shelf is 0°C; the pre-freezing temperature is -30°C, and the pre-freezing time is 4-6 hours; the primary sublimation vacuum degree is 14 Pa, the temperature is uniformly raised to -15°C, and it is maintained at this temperature for more than 10 hours; the analytical drying is uniformly heated to 35°C and dried for more than 5 hours.

[0009] Or the freeze-drying process is: the pre-cooling temperature of the shelf is 10°C; the pre-freezing temperature is -25°C, and the pre-freezing time is 3.5 hours; the primary sublimation vacuum degree is 14 Pa, the temperature is uniformly raised to -10°C, and it is maintained at this temperature for 10 hours; the analytical drying is uniformly heated to 35°C and dried for 5 hours;

[0010] Or its lyophilization process is as follows: the pre-cooling temperature of the shelf is 10°C; the pre-freezing temperature is -30°C, and the pre-freezing time is 3.5 h; the primary sublimation vacuum degree is 14 Pa, and the temperature is uniformly raised to -15°C and maintained at this temperature for 9 hours; during the analytical drying, the temperature is uniformly raised to 35°C and dried for 4.5 hours.

[0011] Further, the above pre-cooling temperature is 0°C, specifically: the semi-capped samples are placed in the lyophilizer, the freezing automatic program is started, and the temperature is reduced to 0°C in 10 min and maintained for 30 min.

[0012] The rossiveline lyophilized preparation prepared by the above method is porous, has few appearance defects, and has good redissolvability.

[0013] The technical effect of the present invention is: by adding excipient dextran to the prescription and adding citric acid-sodium citrate buffer solution to regulate the pH, and at the same time optimizing the lyophilization process, the obtained lyophilized preparation is porous, has few appearance defects, and has good redissolvability. The present invention prepares the rossiveline lyophilized preparation for the first time, which has better stability and safety compared with the existing aqueous injection. Description of the Drawings

[0014] Figure 1 It is the appearance of the rossiveline lyophilized preparation product. Detailed Embodiments

[0015] The following is combined with examples and drawings to illustrate its effects.

[0016] Example 1: Prescription Screening

[0017] Prescription: Screen the prescription as shown in Table 1, and calculate the material dosage according to a batch of 1000 vials. Among them, the pH 6.6 citric acid-sodium citrate buffer solution is prepared by mixing 7 ml of 0.1 mol / L citric acid solution and 93 ml of 0.1 mol / L sodium citrate solution.

[0018] Table 1 Raw material ratios of different prescriptions

[0019] Raw and auxiliary materials Prescription 1-1 Prescription 1-2 Prescription 1-3 Drotaverine 10g 10g 10g Dextran 30g / / Citric acid 2.94 mg 2.94 mg / Sodium citrate 54.47 mg 54.47 mg / Water 1L 1L 1L

[0020] The specific preparation method is as follows: Add 600 ml of water for injection to the reaction flask, then add the batch prescription amounts of dextran, citric acid, and sodium citrate. After stirring for 5 minutes, add the batch prescription amount of drotaverine, and stir to control the pH to 5.0 - 6.0 (if the pH is not within this range, it needs to be adjusted to this range with 0.1 mol / L citric acid - sodium citrate buffer solution with pH 6.6) until completely dissolved. Make up the volume to 1 L with water for injection, stir for 5 minutes, then filter through a 0.22 μm polyethersulfone filter element into 10 ml vials, semi - stopper, transfer to the freeze - dryer, and freeze - dry to obtain the finished product. Freeze - drying conditions: Plate pre - cooling: 10°C; Pre - freezing: Cool to - 25°C in 30 minutes and maintain for 210 minutes; Sublimation drying: Set the vacuum degree to 0.14 mbar, heat to - 10°C in 500 minutes and maintain for 600 minutes; Pressure rise test: Set the pressure rise to 0.20 mbar / min, conduct 3 times with an interval of 30 minutes; Desorption drying: Set the vacuum degree to 0.14 mbar, heat to 35°C in 60 minutes and maintain for 300 minutes.

[0021] Table 2 shows the results of the freeze - dried products

[0022] Test items Investigation conditions Appearance Prescription 1-1 With excipients, using pH buffer regulator Off-white loose mass Prescription 1-2 Without excipients, using pH buffer regulator Collapse, atrophy Prescription 1-3 Without excipients, not using pH buffer regulator Collapse, atrophy

[0023] The results of the freeze - dried products are shown in Table 2. Conclusion: The products were studied according to whether different prescriptions added excipient dextran and pH buffer regulator. Through the study of the properties, it was found that the excipient dextran is the key to obtaining qualified properties. Therefore, the excipient dextran needs to be added to the prescription, and Prescription 1 - 1 was selected to continue the investigation of different pH values of the solution.

[0024] Example 2: Investigation of different pH values of the preparation solution

[0025] The prescription was used to investigate the different pH values of the preparation solution according to Table 3, and the material usage was calculated according to a batch of 1000 vials.

[0026] Table 3 Investigation of different pH values of the preparation solution

[0027]

[0028]

[0029] Specific preparation method: Add 600 ml of water for injection to the reaction flask, then add the batch prescription amounts of dextran, citric acid, and sodium citrate. After stirring for 5 minutes, add the batch prescription amount of drotaverine, and stir to adjust the pH to 3.0, 4.0, 5.0, and 6.0 respectively (if the pH is not within this range, it needs to be adjusted with 0.1 mol / L hydrochloric acid solution or 0.1 mol / L sodium hydroxide solution). Make up the volume to 1 L with water for injection, stir for 5 minutes, then filter through a 0.22 μm polyethersulfone filter element into 10 ml vials, semi - stopper, transfer to the freeze - dryer, and freeze - dry (the freeze - drying conditions are the same as in Example 1) to obtain the finished product.

[0030] Table 4 Results of the freeze-dried products are shown as follows

[0031]

[0032] The results of the freeze-dried products are shown in Table 4. Conclusion: After investigating the different pH values of the formulated solution, it was found that the products obtained when the pH of the formulated solution was adjusted to 4.0 - 5.0 were relatively stable and their properties met the requirements. Therefore, subsequent experiments were carried out using a formulated solution with a pH of 4.0 - 5.0

[0033] Example 3: Screening of the freeze-drying process

[0034] The formulations and different freeze-drying processes are screened as shown in Table 5. The material usage of the formulation is calculated based on a batch of 1000 vials

[0035] Table 5 Different freeze-drying processes

[0036]

[0037]

[0038] Specific preparation method: Add 600 ml of water for injection to the reaction flask, then add the batch prescription amounts of dextran, citric acid, and sodium citrate. After stirring for 5 minutes, add the batch prescription amount of drotaverine, and adjust the pH to 4.0 - 5.0 by stirring (if the pH is not within this range, it needs to be adjusted to this range using a pH 6.6 citric acid - sodium citrate buffer solution). Make up the volume to 1 L with water for injection, stir for 5 minutes, filter through a 0.22 μm polyethersulfone filter into 10 ml vials, half-cork, transfer to the freeze dryer, and freeze-dry to obtain the product. The effects of different freeze-drying curves on the product were investigated

[0039] The results of different freeze-drying curves are shown in Table 6

[0040] Table 6 Results of different freeze-drying curves are shown as follows

[0041]

[0042]

[0043] Conclusion: According to the effects of the freeze-drying curve on the product, the optimal freeze-drying conditions are as follows: The results are shown in Table 6. Pre-freezing temperature: -30°C, pre-freezing time: 4 - 6 h; primary sublimation vacuum degree: 14 Pa, uniform temperature rise to -15°C, and maintain at this temperature for more than 10 hours; analytical drying, uniform temperature rise to 35°C, and dry for more than 5 hours

[0044] Example 4

[0045] Prescription (material usage calculated based on a batch of 1000 vials): Drotaverine 10 g, Dextran 30 g, Citric Acid 2.94 mg, Sodium Citrate 54.47 mg, Water 1 L.

[0046] Specific preparation method: Add 600 ml of injection water to the reaction flask, then add the batch prescription amount of Dextran, Citric Acid, and Sodium Citrate. After stirring for 5 minutes, add the batch prescription amount of Drotaverine. Stir to control the pH to 4.0 - 5.0 (if the pH is not within this range, adjust it to this range with pH 6.6 Citric Acid - Sodium Citrate buffer solution). Make up the injection water to 1 L. After stirring for 5 minutes, filter through a 0.22 μm polyethersulfone filter into 10 ml vials, semi-plug the vials, and transfer to a freeze dryer (the freeze-drying curve is pre-freezing temperature -30 °C, pre-freezing time 4 - 6 h; the primary sublimation vacuum degree is 14 Pa, uniformly heat up to -15 °C, and maintain at this temperature for more than 10 hours; the analytical drying uniformly heats up to 35 °C and dries for more than 5 hours), and freeze-dry to obtain the product.

[0047] Detect the appearance and re-dissolution of the product. The appearance of the product is as Figure 1 shown, and the re-dissolution results are shown in Table 7. Conclusion: According to the detection results, the Drotaverine freeze-dried preparation is porous, has few appearance defects, good re-dissolution, and good stability.

[0048] Table 7 Re-dissolution Results

[0049]

[0050]

Claims

1. A preparation method of drotaverine freeze-dried preparation, characterized in that the components and parts by weight of the drotaverine freeze-dried preparation are: 10 parts of drotaverine, 28 - 32 parts of dextran, appropriate amount of citric acid - sodium citrate, and the product acidity is pH 4.5 - 5.5; The preparation method is as follows: Add water for injection, 28 - 32 parts of dextran, and an appropriate amount of citric acid - sodium citrate to adjust the pH into a reaction vessel, add 10 parts of drotaverine, stir to control the pH at 4.0 - 5.0, make up water for injection to 1000 parts, filter through a polyethersulfone filter element into a vial after the raw materials are dissolved and mixed evenly, semi-plug the vial, transfer it to a freeze-dryer, and freeze-dry to obtain the finished product; The freeze-drying process adopted for the freeze-drying is any one of the following three freeze-drying processes: 1) The pre-cooling temperature of the shelf is 0°C; the pre-freezing temperature is -30°C, and the pre-freezing time is 4 - 6 h; the primary sublimation vacuum degree is 14 Pa, and it is heated uniformly to -15°C at a constant speed and maintained at this temperature for more than 10 hours; the analytical drying is heated uniformly to 35°C and dried for more than 5 hours; 2) The pre-cooling temperature of the shelf is 10°C; the pre-freezing temperature is -25°C, and the pre-freezing time is 3.5 h; the primary sublimation vacuum degree is 14 Pa, and it is heated uniformly to -10°C at a constant speed and maintained at this temperature for 10 hours; the analytical drying is heated uniformly to 35°C and dried for 5 hours; 3) The pre-cooling temperature of the shelf is 10°C; the pre-freezing temperature is -30°C, and the pre-freezing time is 3.5 h; the primary sublimation vacuum degree is 14 Pa, and it is heated uniformly to -15°C at a constant speed and maintained at this temperature for 9 hours; the analytical drying is heated uniformly to 35°C and dried for 4.5 hours.

2. The preparation method according to claim 1, characterized in that, The components and parts by weight of the drotaverine freeze-dried preparation are: 10 parts of drotaverine, 30 parts of dextran, appropriate amount of citric acid - sodium citrate, and the product acidity is pH 4.5 - 5.

5.

3. The preparation method according to claim 1, characterized in that the pre-cooling temperature is 0°C, specifically: put the semi-plugged sample into the freeze-drying chamber, start the automatic freezing program, cool to 0°C in 10 min and maintain for 30 min.

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