Sotalol hydrochloride spray and preparation method thereof
By making sotalol hydrochloride into a spray, combined with the use of solubilizers, stabilizers and preservatives, as well as the sterile filtration process, the problems of difficulty in taking oral tablets of sotalol hydrochloride and slow onset are solved, and rapid absorption and onset are achieved, which is suitable for a variety of patient groups.
Patent Information
- Application Number
- CN202510030804.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-08
- Publication Date
- 2025-04-22
AI Technical Summary
The existing oral tablets of sotalol hydrochloride have problems such as difficulty in taking, slow absorption and slow onset of effect. Especially in case of sudden arrhythmias, they cannot be treated in time.
It is prepared by adding sotalol hydrochloride spray, by adding solubilizers such as sodium dodecyl sulfate, polyethylene glycol, etc., and using stabilizers and preservatives such as citric acid, benzoic acid, etc., combined with sterile filtration technology to ensure that the drug is uniformly dissolved, absorbed quickly and takes effect quickly.
It achieves rapid absorption and rapid onset of sotalol hydrochloride, solves the problems of difficulty in taking and slow onset of effect, and is especially suitable for children, the elderly and patients with dysphagia, and improves the efficiency and safety of clinical applications.
Smart Images
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Abstract
Description
Technical Field
[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a sotalol hydrochloride spray and a preparation method thereof. Background Art
[0002] Sotalol hydrochloride, chemical name is 4'-(1-hydroxy-2-isopropylaminoethyl) methanesulfonanilide hydrochloride, molecular formula is C 12 H 20 N 2 O 3 S·HCl has antiarrhythmic properties related to non-selective β-adrenergic receptor blocking (Vaughan Williams II class) and cardiac action potential duration prolongation (Vaughan-Williams III class). Due to its good safety in long-term use, it can be used as a first-line treatment to prevent the recurrence of atrial fibrillation (patients with normal left ventricular function and no structural heart disease, or atrial fibrillation with coronary heart disease, valvular heart disease and left ventricular hypertrophy); it also has good efficacy for ventricular arrhythmias, atrial premature beats and atrial tachycardia, and can also be used for long-term adjuvant therapy after implantable cardioverter defibrillator (ICD) surgery.
[0003] Sotalol hydrochloride tablets were first developed by Bristol-Myers Squibb and were first approved in France in August 1978 and in Germany in 1995. Currently, tablets, injections, and freeze-dried powder injections are available in China. Tablets are the most commonly used dosage form, which is convenient for patients to take and carry by themselves. The specifications of ordinary oral preparations available in China are only 80mg, and 2 to 6 tablets are taken daily, divided into two doses. The number of tablets taken is large, and it is easy to miss a dose, thus affecting the treatment effect. The specifications of ordinary oral preparations available abroad are 80mg, 120mg, and 160mg. As the drug loading increases, the number of tablets taken can be reduced, but the size of the tablets also increases, making it difficult for patients with dysphagia to take them. Clinical data show that the blood concentration of sotalol hydrochloride tablets can only reach the peak 2 to 4 hours after oral administration, and patients with sudden situations cannot be treated in time.
[0004] Patent CN115429765A discloses a sotalol hydrochloride sustained-release preparation and a preparation method thereof, which is prepared by wet granulation technology, and the prescription consists of sotalol hydrochloride, filler, disintegrant, binder, glidant, and sustained-release skeleton material. The invention prepares a skeleton-type sustained-release preparation, which is not prone to leakage, has a good sustained-release effect, and improves the problem of release decline caused by aging of the membrane control agent or the effect of dose burst release. Taking the medicine once a day can achieve the same therapeutic effect as ordinary tablets, ensuring the safety of clinical medication. However, the dosage of sotalol hydrochloride in the sustained-release preparation is 28% to 50%, and the drug loading is high, which will bring risks to production, and the stability of the sustained-release preparation has not been investigated, and the quality during use cannot be guaranteed. At the same time, the sustained-release preparation also has a slow onset of action. In the face of some emergencies, if a doctor cannot be treated in time, the patient's lesions caused by arrhythmia cannot be solved. Therefore, a preparation with a short dissolution time, fast absorption, and fast onset is urgently needed.
[0005] Patent CN1481786A discloses a freeze-dried sotalol hydrochloride for injection, which is made into a freeze-dried preparation by a low-temperature freeze-drying process, which not only overcomes the shortcomings of slow oral absorption and slow onset of action, but also overcomes the shortcomings of injection products that are unstable in the early stage of storage due to high-temperature sterilization. However, this product needs to be re-dissolved with a re-dissolving solvent when used, and the re-dissolution time is long, and there is a risk of unqualified insoluble particles, which brings safety hazards to patients and medical workers. At the same time, freeze-dried sotalol hydrochloride for injection is inconvenient to use for patients who take ordinary medications in daily life.
[0006] The invention provides a sotalol hydrochloride spray which is easy to carry and take. The sotalol hydrochloride spray has the characteristics of uniform drug distribution, low impurity level and fast absorption.
[0007] In order to avoid the precipitation of sotalol hydrochloride during use, the inventors added solubilizers, such as sodium dodecyl sulfate, polyethylene glycol, etc., during the research and development process. At the same time, in order to ensure the stability of the product during medication, the inventors added stabilizers and preservatives, such as citric acid, benzoic acid, etc., during the research and development process, and controlled the prescription dosage of solubilizers, stabilizers and preservatives at a low level, which can not only ensure the stability of the product during medication but also reduce the side effects caused by the high dosage of excipients. At the same time, this product adopts aseptic filtration technology to prepare sotalol hydrochloride spray, which not only overcomes the shortcomings of slow oral absorption and slow onset of the product, but also overcomes the shortcomings of high impurity levels and inconvenient medication caused by high-temperature sterilization of injection products.
[0008] Experimental data show that when sotalol hydrochloride is prepared into a spray, it has a fast absorption speed and a fast onset of action, thus solving the problem of slow onset of action. The spray does not need to be taken with water, can be taken anytime and anywhere, and is easy to carry. It is especially suitable for children, the elderly, and patients with dysphagia who have vomiting symptoms, thus solving the problem of difficulty in taking the drug, which has positive significance for the clinical application of sotalol hydrochloride. Summary of the invention
[0009] In order to overcome the deficiencies in the prior art, the technical problem to be solved by the present invention is to provide a sotalol hydrochloride spray and a preparation method thereof. The spray has simple ingredients, is easy to take, has a fast absorption speed, has a short blood drug peak time, and can effectively improve drug efficacy.
[0010] The technical solution of the present invention to solve the above technical problems is as follows:
[0011] A sotalol hydrochloride spray, calculated by weight, comprising:
[0012]
[0013] Preferably, calculated by weight, the spray comprises:
[0014]
[0015] Preferably, calculated by weight, the spray comprises:
[0016]
[0017] Preferably, the solubilizer is one or more of sodium lauryl sulfate, polysorbate 80, Span 85, polyethylene glycol, and poloxamer.
[0018] Preferably, the stabilizer is one or more of citric acid, ethylenediaminetetraacetic acid and their sodium salt.
[0019] Preferably, the preservative is one or more of benzoic acid and its salts, sorbic acid and its salts.
[0020] Preferably, the solvent is one of water for injection and a mixed solvent of water and ethanol. Preferably, the volume ratio of the mixed solvent of water and ethanol is water:ethanol=95:5-99.5:0.5.
[0021] Preferably, the preparation method of the sotalol hydrochloride spray comprises:
[0022] (1) preparing materials, mixing sotalol hydrochloride, a solubilizer, a stabilizer, a preservative, and a solvent according to corresponding proportions;
[0023] (2) preparing a solution by slowly adding a stabilizer and a preservative into a solvent, adding a solubilizer after they are completely dissolved, and finally adding sotalol hydrochloride, stirring until they are completely dissolved and mixed evenly;
[0024] (3) filtering, filtering the solution in (2) to obtain a sotalol hydrochloride spray solution;
[0025] (4) Finished product packaging: filling the sotalol hydrochloride spray solution to obtain a finished product sotalol hydrochloride spray.
[0026] The particle size of the sotalol hydrochloride is controlled to be D90<200 μm, preferably D90<100 μm.
[0027] Preferably, the preparation method of the sotalol hydrochloride spray is as follows:
[0028] (1) Weigh sotalol hydrochloride, solubilizer, stabilizer, preservative, and solvent according to the preparation table;
[0029] (2) Add 0.01 to 0.05 parts of stabilizer and 0.01 to 0.05 parts of preservative into 10.0 to 30.0 parts of water for injection, control the temperature of the water for injection to less than 40°C, turn on the stirring paddle at 50 Hz, and stir until the stabilizer and preservative are completely dissolved;
[0030] (3) adding 0.005 to 0.03 parts of a solubilizing agent to the solution obtained in step (2), turning on a stirring paddle at 50 Hz, and stirring until the solubilizing agent is completely dissolved;
[0031] (4) adding 2.5 to 5.0 parts of sotalol hydrochloride to the solution obtained in (3) above, turning on the stirring paddle at 50 Hz, stirring until the sotalol hydrochloride is completely dissolved, and then continuing to turn on the stirring paddle at 50 Hz and stirring for 10 to 30 minutes;
[0032] (5) The clarified solution obtained in the above (4) is initially filtered through a 10 μm filter membrane, then filtered through a 0.45 μm filter membrane, and finally sterilized and filtered through a 0.22 μm filter membrane, and then packaged, filled, and packaged to obtain a sotalol hydrochloride spray.
[0033] Compared with the prior art, the present invention has the following advantages:
[0034] (1) During the preparation of the sotalol hydrochloride spray, sotalol hydrochloride is uniformly dissolved in the solvent, is quickly absorbed in the body, and can quickly exert its therapeutic effect.
[0035] (2) The present invention uses fewer types of auxiliary materials and uses less amount, has the characteristics of atomization administration, and is safe and reliable.
[0036] (3) The preparation process adopted by the present invention is easy to operate and facilitate industrial production. DETAILED DESCRIPTION
[0037] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.
[0038] Sotalol hydrochloride: Changzhou Pharmaceutical Factory Co., Ltd.;
[0039] Sodium dodecyl sulfate: Hunan Erkang Pharmaceutical Co., Ltd.
[0040] Polysorbate 80: Hunan Erkang Pharmaceutical Co., Ltd.
[0041] Polyethylene glycol 4000: Hunan Erkang Pharmaceutical Co., Ltd.;
[0042] Benzoic acid: Sichuan Jinshan Pharmaceutical Co., Ltd.;
[0043] Citric acid (citric acid): Hunan Jiudian Pharmaceutical Co., Ltd.;
[0044] Potassium sorbate: Hunan Erkang Pharmaceutical Co., Ltd.
[0045] Water for injection: Changzhou Pharmaceutical Factory Co., Ltd.;
[0046] Embodiment 1:
[0047] A preparation method of sotalol hydrochloride spray is as follows:
[0048]
[0049]
[0050] 1) Sotalol hydrochloride was crushed and passed through a 100-mesh sieve;
[0051] 2) Add 1.6 g of citric acid and 0.8 g of potassium sorbate to 1200 g of water for injection, control the temperature of the water for injection to less than 40°C, turn on the stirring paddle at 50 Hz, and stir until the citric acid and potassium sorbate are completely dissolved;
[0052] 3) Add 0.8 g of solubilizing agent to the solution obtained in 2) above, turn on the stirring paddle at 50 Hz, and stir until the solubilizing agent is completely dissolved;
[0053] 4) Add 200 g of sotalol hydrochloride to the solution obtained in 3) above, turn on the stirring paddle at 50 Hz, stir until the sotalol hydrochloride is completely dissolved, continue to turn on the stirring paddle at 50 Hz, and stir for 20 minutes;
[0054] 5) The clarified solution obtained in the above 4) is initially filtered through a 10 μm filter membrane, then filtered through a 0.45 μm filter membrane, and finally sterilized and filtered through a 0.22 μm filter membrane, packaged, and filled by a filling machine. After filling, the outer side of the can is printed and packaged to obtain a finished product of sotalol hydrochloride spray.
[0055] Embodiment 2:
[0056] A preparation method of sotalol hydrochloride spray is as follows:
[0057]
[0058] 1) Sotalol hydrochloride was crushed and passed through a 100-mesh sieve;
[0059] 2) Add 2.0 g of citric acid and 0.8 g of benzoic acid into 1500 g of water for injection, control the temperature of the water for injection to less than 40°C, turn on the stirring paddle at 50 Hz, and stir until the citric acid and benzoic acid are completely dissolved;
[0060] 3) Add 1.2 g of solubilizing agent to the solution obtained in 2) above, turn on the stirring paddle at 50 Hz, and stir until the solubilizing agent is completely dissolved;
[0061] 4) Add 200 g of sotalol hydrochloride to the solution obtained in 3) above, turn on the stirring paddle at 50 Hz, stir until the sotalol hydrochloride is completely dissolved, continue to turn on the stirring paddle at 50 Hz, and stir for 20 minutes;
[0062] 5) The clarified solution obtained in the above 4) is initially filtered through a 10 μm filter membrane, then filtered through a 0.45 μm filter membrane, and finally sterilized and filtered through a 0.22 μm filter membrane, packaged, and filled by a filling machine. After filling, the outer side of the can is printed and packaged to obtain a finished product of sotalol hydrochloride spray.
[0063] Embodiment 3:
[0064] A preparation method of sotalol hydrochloride spray is as follows:
[0065]
[0066] 1) Sotalol hydrochloride was crushed and passed through a 100-mesh sieve;
[0067] 2) Add 2.0 g of citric acid and 0.8 g of sodium benzoate to 1500 g of water for injection, control the temperature of the water for injection to less than 40°C, turn on the stirring paddle at 50 Hz, and stir until the citric acid and benzoic acid are completely dissolved;
[0068] 3) Add 1.2 g of solubilizing agent to the solution obtained in 2) above, turn on the stirring paddle at 50 Hz, and stir until the solubilizing agent is completely dissolved;
[0069] 4) Add 300 g of sotalol hydrochloride to the solution obtained in 3) above, turn on the stirring paddle at 50 Hz, stir until the sotalol hydrochloride is completely dissolved, continue to turn on the stirring paddle at 50 Hz, and stir for 20 minutes;
[0070] 5) The clarified solution obtained in the above 4) is initially filtered through a 10 μm filter membrane, then filtered through a 0.45 μm filter membrane, and finally sterilized and filtered through a 0.22 μm filter membrane, packaged, and filled by a filling machine. After filling, the outer side of the can is printed and packaged to obtain a finished product of sotalol hydrochloride spray.
[0071] Accelerated experimental investigation:
[0072] The finished preparations obtained in Examples 1 to 3 of the present invention and sotalol hydrochloride tablets (batch number: SY230408, manufacturer: Changzhou Pharmaceutical Factory Co., Ltd.) were placed in a stability assessment box at 40°C ± 2°C and 75% RH ± 5% RH, and samples were taken at 0, 3, and 6 months to examine properties, pH, related substances, content, and microbial limits. The test results are shown in Table 1.
[0073] Table 1 Results of accelerated stability tests on finished preparations of Examples 1 to 3 and sotalol hydrochloride tablets
[0074]
[0075]
[0076] Note: “ / ” means not detected.
[0077] As can be seen from Table 1, during the accelerated investigation, the properties, pH, related substances, content and microbial limits of the samples of Examples 1 to 3 did not change significantly, and their content and related substance levels were comparable to those of the sotalol hydrochloride tablets, indicating that the sotalol hydrochloride spray of the present invention has stable quality.
[0078] Animal in vivo test investigation:
[0079] The finished preparation obtained in Example 1 of the present invention, sotalol hydrochloride tablets (batch number: SY230408, manufacturer: Changzhou Pharmaceutical Factory Co., Ltd.) was subjected to in vivo pharmacokinetic study in Beagle dogs. This experiment adopted a two-cycle crossover test design with a wash-out period of 7 days. The subjects fasted for 12 hours before taking the medicine (water was not prohibited). They had a unified meal 4 hours after taking the medicine. A catheter was placed in the small saphenous vein of the forelimb for blood sampling. The blood sampling times were 0.25h, 0.50h, 1.00h, 1.33h (1h20 min), 1.67h (1h40 min), 2.00h, 2.33h (2h20min), 2.67h (2h40 min), 3.00h, 3.33h (3h20 min), 3.67h (3h40 min), 4.00h, 4.50h, 5.00h, 6.00h, 8.00h, 10.00h, 12.00h, 24.00h, 36.00h, 48.00h, and 72.00h. The experimental results are shown in Table 2.
[0080] Table 2 Results of in vivo animal testing of finished preparations and sotalol hydrochloride tablets in Example 1
[0081]
[0082] Note: * In Example 1, the drug was sprayed twice, which is equivalent to administering 80 mg. One tablet of sotalol hydrochloride tablet (specification: 80 mg) was administered.
[0083] **Tmax is expressed as Mean±SD (%CV) (minimum, median, maximum).
[0084] As can be seen from Table 2, the time when the blood drug concentration of the sample in Example 1 reaches the peak in the animal body is significantly faster than that of the sotalol hydrochloride tablets, indicating that compared with the sotalol hydrochloride tablets, the sotalol hydrochloride spray of the present invention has faster mass absorption and faster onset of effect.
[0085] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.
Claims
1. A sotalol hydrochloride spray, characterized in that: Calculated by weight, the spray comprises:
2. The sotalol hydrochloride spray according to claim 1, characterized in that Calculated by weight, the spray comprises:
3. The sotalol hydrochloride spray according to claim 2, characterized in that Calculated by weight, the spray comprises:
4. The sotalol hydrochloride spray according to any one of claims 1 to 3, characterized in that The solubilizing agent is one or more of sodium lauryl sulfate, polysorbate 80, Span 85, polyethylene glycol, and poloxamer.
5. The sotalol hydrochloride spray according to any one of claims 1 to 3, characterized in that: The stabilizer is one or more of citric acid, ethylenediaminetetraacetic acid and sodium salt thereof.
6. The sotalol hydrochloride spray according to any one of claims 1 to 3, characterized in that: The preservative is one or more of benzoic acid and its salts, sorbic acid and its salts.
7. The sotalol hydrochloride spray according to any one of claims 1 to 3, characterized in that The solvent is one of water for injection and a mixed solvent of water and ethanol.
8. The sotalol hydrochloride spray according to claim 7, characterized in that The volume ratio of the water and ethanol mixed solvent is water:ethanol=95:5-99.5:0.
5.
9. The method for preparing the sotalol hydrochloride spray according to any one of claims 1 to 3, characterized in that: include: (1) preparing materials, mixing sotalol hydrochloride, a solubilizer, a stabilizer, a preservative, and a solvent according to corresponding proportions; (2) preparing a solution by slowly adding a stabilizer and a preservative into a solvent, adding a solubilizer after they are completely dissolved, and finally adding sotalol hydrochloride, stirring until they are completely dissolved and mixed evenly; (3) filtering, filtering the solution in (2) to obtain a sotalol hydrochloride spray solution; (4) Finished product packaging: filling the sotalol hydrochloride spray solution to obtain a finished product sotalol hydrochloride spray.
10. The method for preparing the sotalol hydrochloride spray according to claim 9, characterized in that: In the step (1), the particle size of sotalol hydrochloride is controlled to be D90<200 μm.