Landiolol hydrochloride preparation and preparation method thereof

Abstract

The invention relates to a landiolol hydrochloride preparation and a preparation method thereof. The preparation method comprises the following steps: mixing the landiolol hydrochloride, the pH regulator and the excipient to obtain a mixed solution of the landiolol hydrochloride; the landiolol hydrochloride mixed solution is freeze-dried to prepare the landiolol hydrochloride preparation, and the excipient comprises povidone and mannitol. The povidone and the mannitol are used as excipients, the ratio of the povidone and the mannitol to the landiolol hydrochloride is adjusted, under the synergistic effect of the povidone and the mannitol, the granularity of the landiolol hydrochloride is reduced, and the aggregation phenomenon is avoided; the external structure of the freeze-dried sample is a cylindrical block, so that the contact with a rubber plug is reduced; the internal structure is loose and porous, is spongy, is quickly dissolved after being added with water, and conforms to the characteristic of convenience in administration of first-aid medicines.

Description

Technical Field

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

[0003] During surgery, catecholamines are released from the sympathetic nerves due to stimulation such as anesthesia and surgical invasion, leading to sudden tachycardia arrhythmia. Patients with high risk of myocardial ischemia such as local ischemic diseases and hypertension before surgery have increased myocardial oxygen consumption during tachycardia arrhythmia, which may cause ischemic heart disease or heart failure, and emergency treatment is required. In the past, calcium antagonists and beta blockers were used to treat tachycardia arrhythmia, but these drugs have a long duration of action and poor regulation, so they are prone to excessive reduction of cardiac function and severe heart failure when used. In addition, the injectable beta blockers used in clinical practice so far have a beta1 effect and also have an effect on beta2 receptors, which are prone to side effects such as bronchoconstriction causing deterioration of respiratory function and peripheral vasoconstriction causing circulatory disorders. For this reason, clinical expectation is to develop beta1 blockers with short duration of action and strong selectivity.

[0004] Landiolol hydrochloride is a new type of β1 blocker with good regulation, short duration of action and high selectivity. It mainly acts on receptors present in the heart and expresses its anti-arrhythmic effect by antagonizing the heart rate increase caused by norepinephrine and epinephrine released from sympathetic nerve endings and adrenal medulla. It has the following pharmacological effects: (1) β1 receptor selectivity (2) persistence of β-blocking effect (3) effect on arrhythmia (4) reduction of cardiac output during tachycardia.

[0005] Landiolol hydrochloride was developed by Ono Pharmaceutical Co., Ltd. (Ono) of Japan and approved for marketing by the Ministry of Health, Labor and Welfare of Japan on July 5, 2002. Its trade name is ONOACT, with a specification of 50 mg, and is used to treat tachycardia arrhythmias (atrial fibrillation, atrial flutter and sinus tachycardia) during surgery. In terms of both efficacy and safety, landiolol has more advantages than esmolol and can be used as a replacement product for esmolol.

[0006] Landiolol hydrochloride is often used as an emergency drug. For example, arrhythmia caused by anesthesia surgery is an emergency event that occurs suddenly and can endanger the patient's life. Therefore, a fast dissolution rate of landiolol hydrochloride is required. In existing patents, landiolol hydrochloride preparations generally use amino acids, lactose, dextran, calcium sodium edetate, etc. as excipients during the preparation process. These excipients will affect the recrystallization and dissolution rate of the drug, thereby affecting the efficiency of emergency treatment. Summary of the invention

[0007] Therefore, the technical problem to be solved by the present invention is to overcome the problem of low dissolution rate of landiolol hydrochloride preparations in the prior art.

[0008] To solve the above technical problems, the present invention provides a landiolol hydrochloride preparation and a preparation method thereof. The present invention adopts povidone and mannitol as excipients, and regulates the ratio of povidone and mannitol and the ratio of excipients to landiolol hydrochloride, while ensuring that the freeze-dried sample stabilizes the skeleton, the internal porosity is increased, thereby reducing the re-dissolution time. The excipient forms a hydrogen bond with landiolol hydrochloride, so that landiolol hydrochloride is dispersed in the system in molecular form and prevents it from forming a lattice with adjacent drug molecules, reducing the drug particle size and improving the dissolution rate. However, if the drug particle size is too small, the surface energy will increase, and polymerization will easily occur, thereby reducing the bioavailability. The present invention adjusts the ratio of povidone and mannitol to landiolol hydrochloride, and under the loose porous and stable skeleton of povidone and mannitol, the particle size of landiolol hydrochloride is reduced, while the aggregation phenomenon is avoided. After freeze-dried re-dissolution, the landiolol hydrochloride is rapidly dissolved, and the re-dissolution time is within 25s, which meets the characteristics of convenient administration that emergency drugs should have.

[0009] The first object of the present invention is to provide a method for preparing a landiolol hydrochloride preparation, comprising the following steps:

[0010] S1. mixing landiolol hydrochloride, a pH adjuster, and an excipient to obtain a landiolol hydrochloride mixed solution;

[0011] S2, freeze-drying the landiolol hydrochloride mixed solution to obtain the landiolol hydrochloride preparation;

[0012] Wherein, the excipients include povidone and mannitol.

[0013] Furthermore, the mass ratio of the povidone to mannitol is (1-2):(1:4).

[0014] Furthermore, the pH adjuster is selected from one or more of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, sodium phosphate, sodium acetate and the like.

[0015] Furthermore, the mass ratio of the landiolol hydrochloride, the pH regulator and the excipient is (25%-75%): (0.001%-5%): (25%-75%).

[0016] Furthermore, the pH of the landiolol hydrochloride mixed solution is 5.5-6.5. Preferably, sodium hydroxide is selected as the pH regulator and the pH is adjusted to 5.7-6.3, which can minimize the generation of degradation products.

[0017] Furthermore, the freeze-drying includes pre-freezing, sublimation drying and secondary drying.

[0018] Furthermore, the pre-freezing is divided into three stages, wherein:

[0019] The first stage is cooling to -20~-50℃ and keeping warm for 0.5-2h;

[0020] The second stage is to raise the temperature to -15~-5℃ and keep it warm for 0.5-2h;

[0021] The third stage is cooling down to -20~-50℃.

[0022] Pre-freezing adopts a segmented pre-freezing method, which first lowers the temperature to near the glass transition temperature of the solution, maintains it for a period of time, and then raises the temperature to a certain temperature and then lowers the temperature again until the solution is completely frozen, which can ensure the uniformity and stability of the preparation product components to the greatest extent. At the same time, after the above segmented pre-freezing, a higher drying temperature can be selected for drying in the subsequent drying stage, which not only does not affect the product quality, but also shortens the drying time and reduces production costs.

[0023] Furthermore, the sublimation drying is divided into four stages, wherein:

[0024] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0025] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0026] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0027] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0028] The sublimation drying stage uses a gradient temperature increase combined with a full-process aeration mode to accelerate the sublimation rate of the preparation and further shorten the freeze-drying time. The resulting preparation is a block solid with a short reconstitution time, low and uniform impurity levels and moisture, and little change in moisture, pH, related substances, etc. during storage.

[0029] Furthermore, the secondary drying step is to raise the temperature to 40-50°C, keep warm for 2-8h, and increase the temperature at a rate of 1.5±0.5°C / min, while controlling the vacuum degree in the freeze drying chamber to 10-30Pa.

[0030] The second object of the present invention is to provide a landiolol hydrochloride preparation obtained by the above preparation method.

[0031] Beneficial effects of the present invention:

[0032] The present invention adjusts the ratio of povidone and mannitol to landiolol hydrochloride, and under the synergistic effect of povidone and mannitol, the external structure of the sample after freeze-drying is a cylindrical block, which reduces contact with the rubber plug, thereby preventing impurities in the rubber plug from entering the sample; the internal structure of the sample is loose and porous, and sponge-like, so it can be dissolved quickly after adding water, while reducing the particle size of landiolol hydrochloride and avoiding aggregation. After freeze-drying and re-dissolving, landiolol hydrochloride dissolves quickly, and the re-dissolution time is within 25 seconds, which meets the characteristics of convenient administration that emergency medicines should have. DETAILED DESCRIPTION

[0033] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0034] Example 1

[0035] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 10 g of povidone and 40 g of mannitol, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0036] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0037] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0038] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0039] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0040] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0041] Heating and drying is divided into four stages:

[0042] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0043] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0044] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0045] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0046] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0047] (4) Pressed plugs and rolled aluminum covers.

[0048] Example 2

[0049] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 20 g of povidone and 30 g of mannitol, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0050] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0051] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0052] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0053] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0054] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0055] Heating and drying is divided into four stages:

[0056] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0057] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0058] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0059] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0060] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0061] (4) Pressed plugs and rolled aluminum covers.

[0062] Example 3

[0063] (1) Preparation: Measure about 800 ml of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.2, add 25 g of povidone and 25 g of mannitol, stir until dissolved; dilute to 1000 ml with water for injection cooled to room temperature, and stir evenly;

[0064] (2) Sterilization filtration and canning: The solution prepared in step 1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 ml / bottle;

[0065] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0066] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0067] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0068] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0069] Heating and drying is divided into four stages:

[0070] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0071] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0072] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0073] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0074] (4) Pressed plugs and rolled aluminum covers.

[0075] Comparative Example 1

[0076] The preparation method of this comparative example is the same as that of Example 1, except that mannitol is not added in this comparative example. The specific steps are as follows:

[0077] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 50 g of povidone, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0078] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0079] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0080] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0081] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0082] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0083] Heating and drying is divided into four stages:

[0084] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0085] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0086] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0087] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0088] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0089] (4) Pressed plugs and rolled aluminum covers.

[0090] Comparative Example 2

[0091] The preparation method of this comparative example is the same as that of Example 1, except that povidone is not added in this comparative example. The specific steps are as follows:

[0092] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 50 g of mannitol, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0093] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0094] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0095] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0096] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0097] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0098] Heating and drying is divided into four stages:

[0099] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0100] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0101] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0102] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0103] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0104] (4) Pressed plugs and rolled aluminum covers.

[0105] Comparative Example 3

[0106] The preparation method of this comparative example is the same as that of Example 1, except that the mass ratio of povidone to mannitol in this comparative example is 3:1. The specific steps are as follows:

[0107] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 30 g of povidone and 10 g of mannitol, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0108] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0109] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0110] The first stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 1 hour;

[0111] The second stage of pre-freezing: the temperature of the plate layer is raised to -5℃, and the insulation time is 0.5h;

[0112] The third stage of pre-freezing: lower the plate temperature to -45°C and keep warm for 2 hours;

[0113] Heating and drying is divided into four stages:

[0114] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0115] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0116] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0117] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0118] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0119] (4) Pressed plugs and rolled aluminum covers.

[0120] Comparative Example 4

[0121] The preparation method of this comparative example is the same as that of Example 1, except that the freeze-drying conditions are changed in this comparative example, and the temperature of the plate layer in the second stage of pre-freezing is raised to 0° C. The specific steps are as follows:

[0122] (1) Preparation: Measure about 800 mL of water for injection and cool it to room temperature, add 50 g of landiolol hydrochloride, stir until dissolved, then add an appropriate amount of sodium hydroxide to adjust the pH to 6.0, add 10 g of povidone and 40 g of mannitol, stir until dissolved; dilute to 1000 mL with water for injection cooled to room temperature, and stir evenly;

[0123] (2) Sterilization filtration and canning: The solution prepared in step (1) is filtered through a 0.45 μm filter membrane, and then filtered through a 0.22 μm filter membrane, and canned into 1 mL / bottle;

[0124] (3) Freeze drying: Place the filled product into the freeze drying box, start the freeze dryer, and perform freeze drying according to the following steps:

[0125] The first stage of pre-freezing: lower the plate temperature to -20℃ and keep warm for 1h;

[0126] The second stage of pre-freezing: raise the plate temperature to 0℃ and keep warm for 0.5h;

[0127] The third stage of pre-freezing: the temperature of the plate layer is reduced to -20℃, and the insulation time is 2h;

[0128] Heating and drying is divided into four stages:

[0129] The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa;

[0130] The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa;

[0131] The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa;

[0132] The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

[0133] Secondary drying: After the temperature-raising drying is completed, the temperature is maintained at 45° C. to dry to the end point to obtain a freeze-dried pharmaceutical composition.

[0134] (4) Pressed plugs and rolled aluminum covers.

[0135] Table 1 Freeze-dried sample states of Examples 1-3 and Comparative Examples 1-4

[0136]

[0137] Table 2 Total impurity results of Examples 1-3 and Comparative Examples 1-4

[0138]

[0139] According to Table 1 and Table 2, it can be seen that by adjusting the ratio of povidone and mannitol, in Example 1-3, under the synergistic effect of povidone and mannitol, the lyophilized landiolol hydrochloride presents a loose and porous round cake-like object, and the whole is a block structure, which reduces the contact with the rubber plug and avoids the introduction of impurities; and the interior presents a loose and porous sponge-like structure, which can reduce the re-dissolution time, and then quickly dissolve to meet the characteristics of rapid administration that emergency medicines should have. And by changing the composition of the excipients and the mass ratio of povidone and mannitol, it is found that the obtained lyophilized product presents a loose block and powder as a whole, and the block structure is also easy to break into powder after shaking, and then easily contact with the rubber plug, so that impurities are easily introduced. In addition. The internal structure of the lyophilized product of Comparative Examples 1-3 is relatively dense, which increases the re-dissolution time and affects the use of the drug. According to Comparative Example 4, it can be seen that the freeze-drying process is also very important for the quality of the lyophilized product. Since the freeze-drying temperature was changed in Comparative Example 4, the excipient concentration increased, the ionic strength increased, the viscosity increased, and the excipient crystallized, which in turn affected the state of the freeze-dried product and resulted in an increase in impurities in the final landiolol hydrochloride preparation and an increase in the reconstitution time.

[0140] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing a landiolol hydrochloride preparation, characterized in that: The following steps are involved: S1. mixing landiolol hydrochloride, a pH adjuster, and an excipient to obtain a landiolol hydrochloride mixed solution; S2, freeze-drying the landiolol hydrochloride mixed solution to obtain the landiolol hydrochloride preparation; Wherein, the excipients include povidone and mannitol.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the polyvidone to mannitol is (1-2):(1:4).

3. The preparation method according to claim 1, characterized in that: The pH adjuster in step S1 is selected from one or more of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium citrate, sodium phosphate, and sodium acetate.

4. The preparation method according to claim 1, characterized in that: The mass ratio of the landiolol hydrochloride, the pH regulator and the excipient in step S1 is (25%-75%): (0.001%-5%): (25%-75%).

5. The preparation method according to claim 1, characterized in that: The pH of the landiolol hydrochloride mixed solution is 5.5-6.

5.

6. The preparation method according to claim 1, characterized in that: The freeze-drying in step S2 includes pre-freezing, sublimation drying and secondary drying.

7. The preparation method according to claim 6, characterized in that: The pre-freezing is divided into three stages, wherein: The first stage is cooling to -20~-50℃ and keeping warm for 0.5-2h; The second stage is to raise the temperature to -15~-5℃ and keep it warm for 0.5-2h; The third stage is cooling down to -20~-50℃.

8. The preparation method according to claim 6, characterized in that: The sublimation drying is divided into four stages, wherein: The first stage is to heat up to -25~-15℃, keep warm for 0.5-2h, heating rate is 1.5±0.5℃ / min, vacuum degree is 10-30Pa; The second stage is heating to -10~0℃, keeping warm for 0.5-2h, heating rate 1.5±0.5℃ / min, vacuum degree 10-30Pa; The third stage is heating to 0-15℃, keeping warm for 0.5-2h, heating rate of 1.5±0.5℃ / min, vacuum degree of 10-30Pa; The fourth stage is to heat up to 15-30°C, keep warm for 0.5-1h, the heating rate is 1.5±0.5°C / min, and the vacuum degree is 10-30Pa.

9. The preparation method according to claim 6, characterized in that: The secondary drying step is to heat the temperature to 40-50°C, keep the temperature for 2-8h, increase the temperature at a rate of 1.5±0.5°C / min, and keep the vacuum degree at 10-30Pa.

10. A landiolol hydrochloride preparation prepared according to the preparation method according to any one of claims 1 to 9.

Images