Landiolol hydrochloride pharmaceutical composition and preparation method thereof

Abstract

The invention relates to a landiolol hydrochloride pharmaceutical composition and a preparation method thereof, and belongs to the technical field of medical chemistry, the landiolol hydrochloride pharmaceutical composition comprises raw materials of landiolol hydrochloride, a stabilizer, a PH regulator, a cross-linking agent and water for injection, and the preparation method comprises the following steps: dissolving the stabilizer in the water for injection, heating and fully stirring to obtain a mixture; uniformly mixing to obtain a solution A; dissolving landiolol hydrochloride in water for injection, regulating the pH value by using a pH regulator, and stirring at room temperature until the landiolol hydrochloride is completely dissolved to obtain a solution B; mixing the solution A and the solution B, stirring until the solution is completely dissolved, adding a cross-linking agent, heating and stirring to obtain a mixed solution C; and filtering the mixed solution C, sub-packaging, drying, filling nitrogen, and rolling to obtain the landiolol hydrochloride pharmaceutical composition. The landiolol hydrochloride powder which is stable in form, uniform in distribution and easy to redisperse is prepared, and the convenience of clinical use of the landiolol hydrochloride powder is remarkably improved.

Description

Technical Field

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

[0002] As an ultra-short-acting and highly selective β1 receptor antagonist, landiolol hydrochloride improves tachycardia by precisely antagonizing β1 receptors in the heart and inhibiting the increase in heart rate caused by catecholamines, thereby effectively regulating and improving the state of tachycardia. It plays an important and irreplaceable role in the treatment of newly-occurring rapid arrhythmias. It is mainly used for immediate intervention in emergency situations such as atrial fibrillation, atrial flutter and sinus tachycardia during surgery, as well as rapid and effective treatment of tachycardia during continuous circulation monitoring after surgery, showing its unique clinical value. However, the aqueous solution of landiol hydrochloride has poor stability and is easily degraded.

[0003] In order to achieve the desired therapeutic effect, it may be theoretically necessary to increase the concentration of the drug in the blood to ensure that a sufficient amount of active ingredients reaches and acts on the heart. However, this practice is accompanied by significant risks. Increasing blood drug concentrations may not only aggravate local reactions of the drug at the injection site, such as skin necrosis, but may also induce a series of systemic adverse reactions, including but not limited to bradycardia, central nervous system symptoms (such as confusion, hallucinations), and other systemic reactions (such as nausea, vomiting, abnormal liver and kidney function). Summary of the invention

[0004] The object of the present invention is to provide a landiolol hydrochloride pharmaceutical composition and a preparation method thereof, using pectin and ascorbic acid as stabilizers, aiming to utilize the strong cross-linking ability of pectin to construct a stable hydrogel network. By precisely regulating the ratio between pectin, ascorbic acid and the cross-linking agent, the present invention successfully encapsulates the landiolol hydrochloride drug molecule in the hydrogel skeleton, and utilizes vacuum freeze-drying technology to achieve a fine transformation of the pharmaceutical composition from liquid to solid, thereby obtaining a landiolol hydrochloride powder with stable morphology, uniform distribution and easy redispersion. This innovative design not only ensures the physical stability of the pharmaceutical preparation, but also significantly improves its convenience in clinical use.

[0005] More importantly, the unique structure of the hydrogel skeleton effectively acts as a protective barrier for drug molecules, significantly reducing the non-target binding of landiolol hydrochloride with other components in the plasma before reaching the target organs (such as the heart), thereby avoiding the risk of premature drug inactivation. This feature greatly reduces the drug concentration required for treatment, which not only improves the therapeutic effect, but also significantly reduces the occurrence of local and systemic adverse reactions, providing patients with safer and more effective treatment options.

[0006] The purpose of the present invention can be achieved through the following technical solutions:

[0007] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0008] S1. Dissolve the stabilizer in water for injection, heat to 50-60°C, and stir thoroughly to mix evenly to obtain solution A;

[0009] S2, dissolving landiolol hydrochloride in water for injection, adjusting the pH to 6.8-7.2 with a pH regulator, and stirring at room temperature until completely dissolved to obtain solution B;

[0010] S3, mixing solution A and solution B, stirring until completely dissolved, adding a cross-linking agent, heating to 40-50°C, stirring for 1-3h to obtain a mixed solution C;

[0011] S4, filtering the mixed solution C, packaging, drying, filling with nitrogen, and plugging to obtain the landiolol hydrochloride pharmaceutical composition.

[0012] Furthermore, the usage ratio of the landiolol hydrochloride, stabilizer, pH regulator, cross-linking agent and total water for injection is 1-3 mg: 15-20 mg: 1-2 mg: cross-linking agent 0.5-1 mg: 50 ml.

[0013] Furthermore, the stabilizer is pectin and ascorbic acid in a mass ratio of 1-2:0.1-0.3.

[0014] Furthermore, the cross-linking agent is one or more of glycerol, genipin, and dopamine.

[0015] Furthermore, the drying in step S3 specifically refers to: first pre-freezing at a pre-freezing temperature of -60°C to -40°C for 3 to 5 hours, then heating and sublimating at a rate of 2 to 4°C / h under vacuum conditions until the temperature rises to -10 to 0°C and remains constant, and drying to constant weight.

[0016] Furthermore, the pH regulator is one or more of hydrochloric acid, sulfuric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, boric acid, tartaric acid, malic acid, amino acid, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate or sodium hydroxide.

[0017] A landiolol hydrochloride pharmaceutical composition is prepared by the above method.

[0018] Furthermore, the landiolol hydrochloride pharmaceutical composition is a powder.

[0019] Beneficial effects of the present invention:

[0020] In the technical solution of the present invention, a gel skeleton as a stabilizer is prepared by precisely regulating the ratio between pectin, ascorbic acid and a cross-linking agent, thereby obtaining a landiolol hydrochloride powder with a stable morphology, uniform distribution and easy redispersion.

[0021] More importantly, the unique structure of the hydrogel skeleton effectively acts as a protective barrier for drug molecules, significantly reducing the non-target binding of landiolol hydrochloride with other components in the plasma before reaching the target organs (such as the heart), thereby reducing the drug concentration and toxic side effects. DETAILED DESCRIPTION

[0022] In order to make the embodiments of the present invention easier to understand, the present invention will be described in detail below with reference to specific examples. These examples are only for illustration and are not intended to limit the scope of application of the present invention.

[0023] The present invention provides a method for preparing a landiolol hydrochloride pharmaceutical composition, which adopts the following technical scheme:

[0024] Example 1

[0025] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0026] S1. Dissolve 15 mg of pectin and ascorbic acid in a mass ratio of 1:0.1 in 20 ml of water for injection, heat to 50° C., and stir thoroughly to uniformly mix to obtain solution A;

[0027] S2, dissolve 1 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 6.8 with hydrochloric acid, and stir at room temperature until completely dissolved to obtain solution B;

[0028] S3, mix solution A and solution B, stir until completely dissolved, add 1 ml of glycerol, heat to 40°C, and stir for 1 hour to obtain mixed solution C;

[0029] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -60°C for 3 hours, and then sublime it at a temperature of 2°C / h under vacuum conditions until the temperature rises to -10°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0030] Example 2

[0031] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0032] S1. Dissolve 18 mg of pectin and ascorbic acid in a mass ratio of 1.5:0.2 in 20 ml of water for injection, heat to 55° C., and stir thoroughly to uniformly mix to obtain solution A;

[0033] S2, dissolve 2 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 7.0 with sodium hydroxide, and stir at room temperature until completely dissolved to obtain solution B;

[0034] S3, solution A and solution B were mixed, stirred until completely dissolved, 1.5 mg of genipin was added, heated to 45° C., and stirred for 2 h to obtain a mixed solution C;

[0035] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -50°C for 4 hours, and then sublime it at a temperature of 3°C / h under vacuum conditions until the temperature rises to -8°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0036] Example 3

[0037] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0038] S1. Dissolve 20 mg of pectin and ascorbic acid in a mass ratio of 2:0.3 in 20 ml of water for injection, heat to 60° C., and stir thoroughly to uniformly mix to obtain solution A;

[0039] S2, dissolve 3 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 7.2 with sodium carbonate, and stir at room temperature until completely dissolved to obtain solution B;

[0040] S3, solution A and solution B were mixed, stirred until completely dissolved, 1 mg of dopamine was added, heated to 50°C, and stirred for 3 h to obtain a mixed solution C;

[0041] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -40°C for 5 hours, and then sublime it at a temperature of 4°C / h under vacuum conditions until the temperature rises to 0°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0042] Comparative Example 1

[0043] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0044] S1. Dissolve 15 mg of pectin and ascorbic acid in a mass ratio of 1:0.1 in 20 ml of water for injection, heat to 50° C., and stir thoroughly to uniformly mix to obtain solution A;

[0045] S2, dissolve 1 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 6.8 with hydrochloric acid, and stir at room temperature until completely dissolved to obtain solution B;

[0046] S3, mixing solution A and solution B, and stirring until completely dissolved;

[0047] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -60°C for 3 hours, and then sublime it at a temperature of 2°C / h under vacuum conditions until the temperature rises to -10°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0048] Comparative Example 2

[0049] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0050] S1. Dissolve 15 mg of pectin in 20 ml of water for injection, heat to 50°C, and stir thoroughly to mix evenly to obtain solution A.

[0051] S2, dissolve 1 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 6.8 with hydrochloric acid, and stir at room temperature until completely dissolved to obtain solution B;

[0052] S3, mix solution A and solution B, stir until completely dissolved, add 1 ml of glycerol, heat to 40°C, and stir for 1 hour to obtain mixed solution C;

[0053] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -60°C for 3 hours, and then sublime it at a temperature of 2°C / h under vacuum conditions until the temperature rises to -10°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0054] Comparative Example 3

[0055] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0056] S1. Dissolve 15 mg of ascorbic acid in 20 ml of water for injection, heat to 50°C, and stir thoroughly to mix evenly to obtain solution A.

[0057] S2, dissolve 1 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 6.8 with hydrochloric acid, and stir at room temperature until completely dissolved to obtain solution B;

[0058] S3, mix solution A and solution B, stir until completely dissolved, add 1 ml of glycerol, heat to 40°C, and stir for 1 hour to obtain mixed solution C;

[0059] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -60°C for 3 hours, and then sublime it at a temperature of 2°C / h under vacuum conditions until the temperature rises to -10°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0060] Comparative Example 4

[0061] A method for preparing a landiolol hydrochloride pharmaceutical composition comprises the following steps:

[0062] S1. Dissolve 15 mg of pectin and ascorbic acid in a mass ratio of 1:0.1 in 20 ml of water for injection, heat to 50° C., and stir thoroughly to uniformly mix to obtain solution A;

[0063] S2, dissolve 1 mg of landiolol hydrochloride in 30 ml of water for injection, adjust the pH to 6.8 with hydrochloric acid and sodium hydroxide, and stir at room temperature until completely dissolved to obtain solution B;

[0064] S3, solution A and solution B were mixed, stirred until completely dissolved, 1 ml of glycerol was added, and stirred at room temperature for 1 h to obtain a mixed solution C;

[0065] S4. Filter the mixed solution C, divide it into packages, pre-freeze it at a pre-freezing temperature of -60°C for 3 hours, and then sublime it at a temperature of 2°C / h under vacuum conditions until the temperature rises to -10°C and remains constant, dry it to constant weight, fill it with nitrogen, and roll it to obtain the landiolol hydrochloride pharmaceutical composition.

[0066] Performance Testing

[0067] The relevant substances and content determination in the present invention are all determined by high performance liquid chromatography

[0068] 1. Chromatographic conditions

[0069] Chromatographic column: Agilent XDB C18, mobile phase: acetonitrile-water (40:60) flow rate:

[0070] 1.0ml / min, detection wavelength: 252nm, column temperature: 35℃, injection volume: 20μL 2. Sample processing

[0071] Sample preparation:

[0072] Accurately measure an appropriate amount of the landiolol hydrochloride composition, dilute it with the mobile phase to a solution containing 2 mg of landiolol hydrochloride per 1 mL, and use it as the test solution. Prepare a solution of a certain concentration.

[0073] 3. Determination steps

[0074] Instrument preparation:

[0075] Debug the HPLC instrument to the optimal working state, including the installation of the chromatographic column, the preparation and balance of the mobile phase, the setting of the detection wavelength, etc.

[0076] Injection: Inject the treated sample solution into the HPLC instrument for measurement.

[0077] Before the formal determination, the analytical method needs to be verified, including the determination of indicators such as linear range, precision, accuracy, detection limit and quantification limit.

[0078] Table 1 Experimental results of factors affecting the preparation of landiolol hydrochloride pharmaceutical composition in Example 1

[0079]

[0080] Table 2 Accelerated test results of landiolol hydrochloride pharmaceutical compositions prepared in Examples 1-3 and Comparative Examples 1-4 (40±2°C, RH 75±5%)

[0081]

[0082]

[0083] Table 3 Long-term test results of landiolol hydrochloride pharmaceutical compositions prepared in Example 1 and Comparative Examples 1-4 (25±2°C, RH 60±5%)

[0084]

[0085]

[0086] Through the above-mentioned influencing factor tests, accelerated tests, long-term test investigations and quality inspections, it is proved that the landiolol hydrochloride pharmaceutical composition prepared in the present invention has good morphological stability.

[0087] The above embodiments are only preferred embodiments of the present invention and are not any formal or substantial limitations of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as protection of the present invention.

Claims

1. A method for preparing a landiolol hydrochloride pharmaceutical composition, characterized in that: The following steps are involved: S1. Dissolve the stabilizer in water for injection, heat to 50-60°C, and stir thoroughly to mix evenly to obtain solution A; S2, dissolving landiolol hydrochloride in water for injection, adjusting the pH to 6.8-7.2 with a pH regulator, and stirring at room temperature until completely dissolved to obtain solution B; S3, mixing solution A and solution B, stirring until completely dissolved, adding a cross-linking agent, heating to 40-50°C, stirring for 1-3h to obtain a mixed solution C; S4, filtering the mixed solution C, packaging, drying, filling with nitrogen, and plugging to obtain the landiolol hydrochloride pharmaceutical composition.

2. The method for preparing a landiolol hydrochloride pharmaceutical composition according to claim 1, characterized in that: According to the dosage ratio, the dosage ratio of landiolol hydrochloride, stabilizer, pH regulator, cross-linking agent and total water for injection is 1-3 mg: 15-20 mg: 1-2 mg: 0.5-1 mg: 50 ml.

3. The method for preparing a landiolol hydrochloride pharmaceutical composition according to claim 1, characterized in that: The stabilizer is pectin and ascorbic acid in a mass ratio of 1-2:0.1-0.

3.

4. The method for preparing a landiolol hydrochloride pharmaceutical composition according to claim 1, characterized in that: The cross-linking agent is one or more of glycerol, genipin and dopamine.

5. The method for preparing a landiolol hydrochloride pharmaceutical composition according to claim 1, characterized in that: The drying in step S3 specifically refers to: first pre-freezing at a pre-freezing temperature of -60°C to -40°C for 3 to 5 hours, then heating and subliming at a rate of 2 to 4°C / h under vacuum conditions until the temperature rises to -10 to 0°C and remains constant, and drying to constant weight.

6. The method for preparing a landiolol hydrochloride pharmaceutical composition according to claim 1, characterized in that: The pH regulator is one or more of hydrochloric acid, sulfuric acid, acetic acid, lactic acid, methanesulfonic acid, phosphoric acid, citric acid, boric acid, tartaric acid, malic acid, amino acid, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium bicarbonate or sodium hydroxide.

7. A landiolol hydrochloride pharmaceutical composition, characterized in that: Prepared by the preparation method according to any one of claims 1 to 6.

8. A landiolol hydrochloride pharmaceutical composition according to claim 7, characterized in that: The landiolol hydrochloride pharmaceutical composition is a powder.

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