Analgesic pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention relates to an analgesic pharmaceutical composition as well as a preparation method and application thereof, and belongs to the technical field of medicines. The technical problem to be solved by the invention is to provide a pharmaceutical composition with a good analgesic effect. The analgesic pharmaceutical composition comprises the following components: dezocine, meloxicam, an organic solvent, a cosolvent and water, wherein the mass ratio of dezocine to meloxicam is 2: (1-6); the organic solvent is at least one of propylene glycol, ethanol, polyethylene glycol and glycerol; the cosolvent is arginine or tromethamine; the pH value of the pharmaceutical composition ranges from 6.0 to 9.0. The preparation method of the analgesic pharmaceutical composition is simple and stable, large-scale industrial production is easy to realize, and the analgesic pharmaceutical composition is effectively used for analgesic treatment of patients, especially postoperative analgesia or cancer pain treatment.

Description

Technical Field

[0001] The invention relates to an analgesic pharmaceutical composition and a preparation method and application thereof, belonging to the technical field of pharmaceuticals. Background Art

[0002] The global analgesic market is worth $71 billion and is expected to grow to $92 billion by 2027. In terms of indications, cancer pain is the fastest growing. In terms of drug types, opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate analgesics, with opioid analgesics dominating the European and American markets, while NSAIDs lead the market in Asia Pacific, Eastern Europe, and Latin America.

[0003] Most of the painkiller market in China is used for surgical analgesia, that is, acute pain that occurs after surgery. Postoperative pain includes somatic pain and visceral pain, which usually lasts about three to seven days, especially in the first three days, when patients feel the most pain. About 86% of patients experience pain after surgery, of which 75% experience moderate or severe pain after surgery. According to the "China Health Statistics Yearbook Report", in 2020, there were 67 million inpatient surgeries (excluding outpatient surgeries and day surgeries, etc.) in China, with a compound growth rate of 7% from 2016 to 2020. It is expected to exceed 100 million in 2026. Standardized perioperative pain management is crucial to improving patients' postoperative recovery, quality of life and avoiding the development of chronic pain.

[0004] At present, there is a widespread phenomenon of insufficient postoperative analgesia. The analgesia rate in my country's tertiary hospitals is only 30%, and moderate to severe pain is still high (40-60%). Analgesics and treatment methods with clinical advantages need to be further popularized and promoted. Modern postoperative analgesia management guidelines represented by the concept of accelerated recovery surgery advocate: preventive analgesia (such as preoperative administration of COX-2 selective inhibitors), multimodal analgesia, individualized analgesia, focus on inflammation management, and reduce the use of postoperative opioids. The American Pain Society published a postoperative analgesia management guideline, which proposed "only four" high-quality analgesia and strongly recommended analgesia plans: multimodal analgesia, nonsteroidal anti-inflammatory drugs as the cornerstone of postoperative analgesia, local anesthetic analgesia for surgical incision, and local anesthetic neuraxial analgesia for large-scale thoracic and abdominal surgery. Opioids are the most commonly used drugs for the treatment of moderate to severe acute and chronic pain. There are many types of opioids, which are clinically divided into strong opioids and weak opioids according to the intensity of analgesia. The United States also advocates reducing the use of opioids and not using opioids or using low-addictive weak opioids. my country also encourages the development of low-addictive anesthetic analgesic preparations, and multimodal analgesia has gradually become a research hotspot in the industry. Since the analgesic effects and adverse reactions of opioids are prone to dose dependence, multimodal analgesia can reduce the use of opioid doses and reduce patients' dependence on anesthetic analgesics.

[0005] Dezocine is a potent opioid analgesic drug that is a κ receptor agonist and a μ receptor antagonist. Dezocine is a poorly soluble drug with a chemical formula of C 16 H 23 NO, molecular weight is 245.36, molecular formula is shown in formula I.

[0006]

[0007] Dezocine is an analgesic drug used for postoperative analgesia and pain caused by internal organs and cancer, and is listed as a second-category psychotropic drug. Dezocine has a strong analgesic effect and a fast onset of action, but it needs to be administered every 3-6 hours, with a maximum dose of 120 mg / day. However, it is weakly addictive, so frequent administration will lead to drug addiction and the possibility of drug resistance.

[0008] Meloxicam is an enol nonsteroidal anti-inflammatory drug, molecular formula: C14H13N3O4S2, molecular weight: 351.40, chemical name: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. The chemical structure of the compound is shown in Formula II.

[0009]

[0010] Meloxicam is almost insoluble in water, with a solubility of only 3.4ug / mL. It is slightly soluble in ethanol, chloroform, and acetone, and has a half-life of more than 20 hours in vivo. Although meloxicam has been launched in a variety of dosage forms, its solubility problem is difficult to solve, and no effective intravenous injection has been successfully launched. Although Baudax Bio has developed a meloxicam nanocrystal injection with a nanocrystal particle size of 86nm, it can meet the needs of postoperative analgesia once a day. However, the instructions for meloxicam nanocrystal injection clearly state that although the injection lasts for up to 24 hours, it has a slow onset of action and only shows analgesic effects 2-3 hours after intravenous administration. It is not suitable for postoperative analgesia that requires rapid onset, and needs to be used in combination with other analgesics. Due to the above defects, Baudax Bio announced the withdrawal of meloxicam nanocrystal injection from the market in December 2022. Summary of the invention

[0011] The technical problem to be solved by the present invention is to provide a pharmaceutical composition with better analgesic effect.

[0012] The analgesic pharmaceutical composition of the present invention comprises dezocine, meloxicam, an organic solvent, a cosolvent and water; wherein the mass ratio of dezocine to meloxicam is 2:1-6; the organic solvent is at least one of propylene glycol, ethanol, polyethylene glycol and glycerol; the cosolvent is arginine or tromethamine; and the pH value of the pharmaceutical composition is 6.0-9.0.

[0013] Among them, in a specific embodiment, the mass ratio of dezocine to meloxicam in the analgesic pharmaceutical composition of the present invention can be 2:1, 2:1.5, 2:2, 2:2.5, 2:3, 2:3.5, 2:4, 2:4.5, 2:5, 2:5.5 or 2:6.

[0014] Among them, the above-mentioned organic solvent and cosolvent can be added more if the dissolution of dezocine and meloxicam is satisfied. Taking into account the cost factor and the efficacy, as a preferred technical solution, the mass of the organic solvent is 30%-95% of the total mass of the pharmaceutical composition; the mass of the cosolvent is 0.3-15% of the total mass of the pharmaceutical composition; the sum of the mass of dezocine and meloxicam is 0.1-5% of the total mass of the pharmaceutical composition, and the balance is water. As a more preferred technical solution, the mass of the organic solvent is 30%-70% of the total mass of the pharmaceutical composition; the mass of the cosolvent is 0.3-10% of the total mass of the pharmaceutical composition; the sum of the mass of dezocine and meloxicam is 0.5-5% of the total mass of the pharmaceutical composition, and the balance is water.

[0015] In a specific embodiment, the pH of the analgesic pharmaceutical composition of the present invention may be 6.0, 6.5, 7.0, 7.5, 8.0, 8.5 or 9.0. As a preferred technical solution, the pH of the pharmaceutical composition is 7.5-9.0.

[0016] Furthermore, the analgesic pharmaceutical composition of the present invention may be added with other pharmaceutically acceptable excipients on the basis of the above components, such as pH adjusters, antioxidants or osmotic pressure regulators, etc. The amount of each excipient added may be according to the conventional pharmaceutical dosage.

[0017] Furthermore, the above-mentioned pH adjuster can be a pharmaceutically acceptable conventional pH adjuster, such as at least one of citric acid, hydrochloric acid, and sodium hydroxide; the above-mentioned antioxidant can be a pharmaceutically acceptable conventional antioxidant, such as at least one of citric acid, vitamin E, and sodium metabisulfite; the above-mentioned osmotic pressure regulator can be a pharmaceutically acceptable conventional anti-osmotic pressure regulator, such as at least one of sodium chloride and glucose.

[0018] Among them, in a specific embodiment, the ingredients of the analgesic pharmaceutical composition of the present invention can be dezocine, meloxicam, water, tromethamine and propylene glycol; the ingredients of the analgesic pharmaceutical composition of the present invention can also be dezocine, meloxicam, water, tromethamine, propylene glycol and citric acid; the ingredients of the analgesic pharmaceutical composition of the present invention can also be dezocine, meloxicam, water, tromethamine, propylene glycol, citric acid and sodium hydroxide; the ingredients of the analgesic pharmaceutical composition of the present invention can also be dezocine, meloxicam, water, tromethamine, propylene glycol, citric acid, sodium hydroxide and sodium chloride.

[0019] The analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine and propylene glycol; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, propylene glycol and citric acid; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, propylene glycol and vitamin E; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, propylene glycol, vitamin E and glucose; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, propylene glycol, vitamin E, glucose and citric acid.

[0020] The analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine and ethanol; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, ethanol and citric acid; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, ethanol, citric acid and sodium chloride; the analgesic pharmaceutical composition of the present invention may also include dezocine, meloxicam, water, arginine, ethanol, citric acid and sodium chloride.

[0021] The analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, tromethamine and ethanol; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, tromethamine, ethanol and citric acid; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, tromethamine, ethanol, citric acid and sodium chloride; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, tromethamine, ethanol, citric acid and sodium chloride.

[0022] The analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, arginine, polyethylene glycol and glycerol; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, arginine, polyethylene glycol, glycerol and citric acid; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, arginine, polyethylene glycol, glycerol, citric acid and sodium chloride; the analgesic pharmaceutical composition of the present invention may also contain dezocine, meloxicam, water, arginine, polyethylene glycol, glycerol, citric acid and sodium chloride.

[0023] Among them, the analgesic pharmaceutical composition of the present invention is preferably in the form of an injection, and the specifications of the injection can be 20 mg dezocine and 10 mg meloxicam; 20 mg dezocine and 20 mg meloxicam; 20 mg dezocine and 30 mg meloxicam; 20 mg dezocine and 40 mg meloxicam; 20 mg dezocine and 50 mg meloxicam; 20 mg dezocine and 60 mg meloxicam; 10 mg dezocine and 30 mg meloxicam; 20 mg dezocine and 15 mg meloxicam; 40 mg dezocine and 30 mg meloxicam, etc.

[0024] Furthermore, the injection specification is preferably 10 mg dezocine and 30 mg meloxicam; or 20 mg dezocine and 30 mg meloxicam; or 40 mg dezocine and 30 mg meloxicam.

[0025] The present invention also provides a method for preparing the above-mentioned analgesic pharmaceutical composition, which comprises the following steps:

[0026] a. Take meloxicam and dezocine according to weight ratio, add organic solvent and cosolvent, and then heat and dissolve to a clear solution; then adjust the pH to 6.0-9.0 and fix the volume; wherein the water in the solvent is deoxygenated water for injection saturated with nitrogen;

[0027] b. After the volume is fixed, the solution is filtered and sterilized, and then packaged and capped; or sterilized and filtered, and then terminally sterilized or freeze-dried.

[0028] The present invention also provides the use of the above-mentioned pharmaceutical composition in preparing analgesic drugs.

[0029] Furthermore, the analgesic drug is preferably a postoperative analgesic drug.

[0030] The present invention uses a specific organic solvent and a cosolvent to prepare the insoluble dezocine and meloxicam into an injection, thereby solving the technical problem that meloxicam is difficult to be used as an injection in the prior art. The analgesic pharmaceutical composition of the present invention can utilize the rapid onset of dezocine and the continuous analgesic effect of meloxicam to achieve analgesic administration once a day. In addition, once a day injection effectively solves the problem of slow onset of meloxicam, and also greatly reduces the dosage of dezocine, solving the addiction and drug resistance problems caused by excessive daily dosage due to frequent injection of dezocine alone. The dezocine injection is acidic and can be used for intramuscular or intravenous injection, while the meloxicam injection is alkaline and can only be injected intramuscularly. The mixture of the two has drug precipitation due to changes in pH value, so the direct combination of the two injections has certain insecurity and cannot be used clinically. The preparation method of the analgesic pharmaceutical composition of the present invention is simple and stable, easy to realize large-scale industrial production, and effectively used for analgesic treatment of patients, especially postoperative analgesia or cancer pain treatment. DETAILED DESCRIPTION

[0031] The specific implementation modes of the present invention are further described below in conjunction with embodiments, but the present invention is not limited to the scope of the embodiments.

[0032] Example 1 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine 10 mg + Meloxicam 30 mg / 2 ml compound injection

[0033] Weigh 100 mg of dezocine and 300 mg of meloxicam, add 10 g of propylene glycol and 300 mg of tromethamine; then add 5 ml of nitrogen-saturated deoxygenated water for injection, stir and dissolve in a 60°C water bath until clear, then adjust the pH to 8.0 with citric acid, finally make up to 20 ml with nitrogen-saturated deoxygenated water for injection, then sterilize and filter with a 0.2 um sterilizing filter, and package in 2 ml bottles.

[0034] The 30-day stability test showed that the changes in the content of dezocine and meloxicam were less than 0.10 mg / ml. After preparation and 30 days later, the color of the solution was light yellow without precipitation.

[0035] Example 2-8 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine 10 mg + Meloxicam 30 mg / 4 ml compound injection

[0036] Different pH values ​​were screened, and the preparation method was the same as in Example 1. The example table is as follows:

[0037]

[0038] The products were screened by examples, and it was found that the suitable pH range of Dezocine Meloxetine Rehabilitation Formula Injection was 6.0-9.0.

[0039] The 30-day stability test of Examples 3-8 showed that the changes in the contents of dezocine and meloxicam were less than 0.10 mg / ml, and the solution color was light yellow immediately after preparation and 30 days later without precipitation.

[0040] Example 9-12 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine 10 mg + Meloxicam 30 mg / 4 ml compound injection

[0041] The preparation method is the same as in Example 1, and the example table is as follows:

[0042]

[0043] Dezocine Meloxetine Convalescent Formula Injection requires that the propylene glycol co-solvent content is greater than or equal to 30%.

[0044] The 30-day stability test of Examples 10-13 showed that the changes in the contents of dezocine and meloxicam were less than 0.10 mg / ml, and the solution color was light yellow immediately after preparation and 30 days later without precipitation.

[0045] Example 13-17 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine Meloxic Acid Reinjection

[0046] The preparation method is the same as in Example 1, and the example table is as follows:

[0047]

[0048] The 30-day stability test of Examples 13-17 showed that the changes in the contents of dezocine and meloxicam were less than 0.10 mg / ml after preparation and 30 days, and the color of the solution was light yellow without precipitation.

[0049] Example 18-19 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine Meloxic Acid Reinjection

[0050] The preparation method is the same as in Example 1, and the example table is as follows:

[0051]

[0052] The 30-day stability test of Examples 18-19 showed that the content changes of dezocine and meloxicam were less than 0.10 mg / ml, and the solution color was light yellow after preparation and 30 days later without precipitation.

[0053] Example 20-23 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine + Meloxic acid Kangkang prescription injection

[0054] The arginine is replaced by tromethamine, and the other organic solvents are replaced by propylene glycol. The preparation method is the same as that of Example 1. The example table is as follows:

[0055] Embodiment 20 Embodiment 21 Embodiment 22 Embodiment 23 Dezocine 100mg 100mg 400mg 100mg Meloxicam 300mg 300mg 300mg 300mg Ethanol 20g / / 20g Propylene glycol / / 32g / Polyethylene glycol / 10g / / glycerin / 20g / / Tromethamine 300mg / / 300mg Arginine / 300mg 600mg 300mg Citric Acid Adjust pH to 8.0 Adjust pH to 8.0 Adjust pH to 8.0 Adjust pH to 8.0 Sodium chloride / / / 30mg Water for injection 40ml 50ml 40ml 40ml Phenomenon clarify clarify clarify clarify

[0056] The 30-day stability test of Examples 20-23 showed that the changes in the content of dezocine and meloxicam were less than 0.10 mg / ml, and the color of the solution was light yellow immediately after preparation and 30 days later without precipitation.

[0057] Example 24 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine 10 mg + Meloxicam 30 mg / 4 ml compound injection

[0058] Weigh 100 mg of dezocine and 300 mg of meloxicam, add 20 g of propylene glycol and 450 mg of arginine; then add 300 mg of sodium chloride and 10 ml of nitrogen-saturated deoxygenated water for injection, stir and dissolve in a 60°C water bath until clear, then adjust the pH to 8.0 with citric acid, finally make up to 40 ml with nitrogen-saturated deoxygenated water for injection, then sterilize and filter with a 0.2 um sterilizing filter, package in 4 ml bottles, and sterilize at 121°C for 15 min.

[0059] Example 25 Preparation of the analgesic pharmaceutical composition of the present invention Dezocine 20 mg + Meloxicam 30 mg / 5 ml compound injection

[0060] Weigh 200 mg of dezocine and 300 mg of meloxicam, add 30 g of propylene glycol and 300 mg of tromethamine; then add 30 mg of sodium chloride and 10 ml of nitrogen-saturated deoxygenated water for injection, stir and dissolve in a 60°C water bath until clear, then adjust the pH to 8.0 with citric acid, finally make up to 50 ml with nitrogen-saturated deoxygenated water for injection, then sterilize and filter with a 0.2 um sterilizing filter, and package in 5 ml bottles.

[0061] Comparative Example 1: Dezocine 10mg + Meloxicam 30mg / 4ml compound injection

[0062] Weigh 100 mg of dezocine and 300 mg of meloxicam, add 20 g of propylene glycol and 450 mg of arginine; then add 300 mg of sodium chloride and 10 ml of nitrogen-saturated deoxygenated water for injection, stir and dissolve in a 60°C water bath until clear, then adjust the pH to 8.0 with phosphoric acid, finally make up to 40 ml with nitrogen-saturated deoxygenated water for injection, then sterilize and filter with a 0.2 um sterilizing filter, package in 4 ml bottles, and sterilize at 121°C for 15 min.

[0063] Comparative Example 2: Dezocine 20mg + Meloxicam 30mg / 5ml compound injection

[0064] Weigh 200 mg of dezocine and 300 mg of meloxicam, add 30 g of propylene glycol and 300 mg of tromethamine; then add 30 mg of sodium chloride and 10 ml of nitrogen-saturated deoxygenated water for injection, stir and dissolve in a 60°C water bath until clear, then adjust the pH to 8.0 with sulfuric acid, finally make up to 50 ml with nitrogen-saturated deoxygenated water for injection, then sterilize and filter with a 0.2 um sterilizing filter, and package in 5 ml bottles.

[0065] The product quality of Example 24 and Example 25 and Comparative Examples 1 and 2 was evaluated. The evaluation results are shown in the following table

[0066]

[0067] Through the study of Example 1 and Comparative Example 1, it was found that citric acid can effectively inhibit the growth of impurities of dezocine and meloxicam, while using other acids as a buffer system or adjusting the pH cannot control impurities well. Therefore, citric acid can effectively stabilize the dezocine and meloxicam rehabilitation formula injection, making the product more stable, with fewer impurities and safer.

[0068] Test Example 1 Simulated plasma protein test

[0069] According to the human plasma volume of about 4-5L, 10ul of the meloxicam-dezocine compound injection (abbreviated as: meloxicam) of Examples 1, 24, and 25 were added to 10mL of 5% HSA simulated plasma incubated at 37°C, and the particle size was quickly measured after 1 minute, as well as the blank simulated plasma particle size, and the precipitation of the drug of the meloxicam injection in the simulated plasma was observed.

[0070] Test results:

[0071]

[0072] Through experiments, it was found that when the meloxicam-dezocine compound injection of Examples 1, 24 and 25 of the present invention was injected into 5% HSA simulated plasma, a clear solution was quickly formed, and the measured particle size was consistent with the blank 5% HSA simulated plasma particle size. There was no drug precipitation and no safety risk. The meloxicam-dezocine injection can be injected intravenously to quickly exert an analgesic effect.

[0073] The present invention is not limited to the above-mentioned embodiments. Those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and purpose of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. An analgesic pharmaceutical composition, characterized in that: Its components include dezocine, meloxicam, an organic solvent, a solubilizing agent and water; wherein the mass ratio of dezocine to meloxicam is 2:1-6; the organic solvent is at least one of propylene glycol, ethanol, polyethylene glycol and glycerol; the solubilizing agent is arginine or tromethamine; and the pH value of the pharmaceutical composition is 6.0-9.

0.

2. The analgesic pharmaceutical composition according to claim 1, characterized in that: The mass of the organic solvent is 30%-95% of the total mass of the pharmaceutical composition; the mass of the cosolvent is 0.3-15% of the total mass of the pharmaceutical composition; the sum of the masses of dezocine and meloxicam is 0.1-5% of the total mass of the pharmaceutical composition, and the remainder is water.

3. The analgesic pharmaceutical composition according to claim 2, characterized in that: The mass of the organic solvent is 30%-70% of the total mass of the pharmaceutical composition; the mass of the cosolvent is 0.3-10% of the total mass of the pharmaceutical composition; the sum of the masses of dezocine and meloxicam is 0.5-5% of the total mass of the pharmaceutical composition, and the remainder is water.

4. The analgesic pharmaceutical composition according to claim 1, characterized in that: The pH of the pharmaceutical composition is 7.5-9.

0.

5. The analgesic pharmaceutical composition according to any one of claims 1 to 4, characterized in that: The ingredients may also include a pH adjuster, an antioxidant or an osmotic pressure adjuster.

6. The analgesic pharmaceutical composition according to claim 5, characterized in that: The pH adjuster is at least one of citric acid, hydrochloric acid and sodium hydroxide; The antioxidant is at least one of citric acid, vitamin E, and sodium metabisulfite; The osmotic pressure regulator is at least one of sodium chloride and glucose.

7. The analgesic pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The dosage form of the pharmaceutical composition is an injection, and the specifications of the injection are 10 mg dezocine and 30 mg meloxicam; or 20 mg dezocine and 30 mg meloxicam; or 40 mg dezocine and 30 mg meloxicam.

8. A method for preparing the analgesic pharmaceutical composition according to any one of claims 1 to 7, characterized in that The steps include: a. Take meloxicam and dezocine according to weight ratio, add organic solvent and cosolvent, and then heat and dissolve to a clear solution; then adjust the pH to 6.0-9.0 and fix the volume; wherein the water in the solvent is deoxygenated water for injection saturated with nitrogen; b. After the volume is fixed, the solution is filtered and sterilized, and then packaged and capped; or sterilized and filtered, and then terminally sterilized or freeze-dried.

9. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of analgesic drugs.

10. The use according to claim 9, characterized in that: The analgesic drug is a postoperative analgesic drug.

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