Compound analgesic pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses a compound analgesic medicine composition and application thereof. The composition prescription comprises an active component A, an active component B and pharmaceutic adjuvants, the active component A is dexketoprofen or a pharmaceutically acceptable salt thereof, and the active component B is oxycodone or a pharmaceutically acceptable salt thereof; in the prescription of the compound analgesic medicine composition, the content of the active ingredient A is 2.5-50mg according to dexketoprofen, and the content of the active ingredient B is 5-100mg according to oxycodone. In the clinical application process, the compound analgesic composition can fully meet the analgesic requirement of a patient, meanwhile, the potential addiction possibility is avoided, the contradiction between the curative effect and addiction is effectively reconciliated, and reasonable use of opioid analgesic drugs is achieved.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and more specifically, to a compound analgesic drug composition and its application. Background Art

[0002] The use of analgesics can be traced back to the early stages of human civilization.

[0003] According to the mechanism of action and strength, analgesics can be divided into four categories: strong opioids (such as morphine and fentanyl, which have strong analgesic effects but are highly addictive), weak opioids (such as codeine and tramadol, which are less addictive but still have risks with long-term use), non-opioids (such as ibuprofen and acetaminophen, which are non-addictive but have limited analgesic strength), and local anesthetics (such as lidocaine, which is suitable for local analgesia). Among them, opioids block pain transmission by binding to opioid receptors in the central nervous system. Although they can effectively relieve moderate to severe pain, they are accompanied by side effects such as respiratory depression and constipation, and are prone to tolerance, physical dependence, and psychological addiction. Studies have shown that the risk of opioid abuse has become a global problem.

[0004] Regarding the above-mentioned related technologies, the inventor believes that although opioid analgesics can effectively control pain, long-term use of large doses will inevitably lead to addiction, while reducing the dosage will make it difficult to meet the analgesic needs, causing patients to suffer both physical and mental pain. Although attempts have been made in recent years to balance efficacy and safety through sustained-release dosage forms and compound preparations, the addiction problem has not been fundamentally solved. Summary of the invention

[0005] In the related art, the contradiction between the addictiveness and analgesic effect of opioid analgesics is difficult to reconcile, and the development of a new drug that can circumvent the opioid receptor dependence mechanism and have high analgesic ability has become a technical bottleneck that needs to be broken through. In order to improve this defect, the present application provides a compound analgesic drug composition and its application.

[0006] In the first aspect, the present application provides a compound analgesic pharmaceutical composition, which adopts the following technical solution: A compound analgesic pharmaceutical composition, wherein the components in the prescription of the composition include an active ingredient A, an active ingredient B and pharmaceutical excipients, wherein the active ingredient A is dexketoprofen or a pharmaceutically acceptable salt thereof, and the active ingredient B is oxycodone or a pharmaceutically acceptable salt thereof; in the prescription of the compound analgesic pharmaceutical composition, the content of the active ingredient A is 2.5-50 mg calculated as dexketoprofen, and the content of the active ingredient B is 5-100 mg calculated as oxycodone.

[0007] By adopting the above-mentioned technical scheme, the application selects dexketoprofen (including its pharmaceutically acceptable salt, the same below) and oxycodone (including its pharmaceutically acceptable salt, the same below) as analgesic active ingredient, and limits the prescription dosage range of dexketoprofen and oxycodone, and prepares the compound analgesic pharmaceutical composition.Oxycodone belongs to opioid analgesics, and dexketoprofen belongs to non-steroidal anti-inflammatory drugs (NSAIDs), and its mechanism of action is relevant with suppressing cyclooxygenase (COX), and plays analgesic and anti-inflammatory effects by reducing prostaglandin synthesis, and does not rely on opioid receptors.Within the scope limited by the present application, the combination of dexketoprofen and oxycodone can give play to the analgesic effect close to oxycodone, and because the adding of dexketoprofen has reduced the total amount of oxycodone, therefore the addictiveness is significantly lower than the situation when using oxycodone alone as analgesic active ingredient. In clinical applications, the compound analgesic composition of the present application can fully meet the analgesic needs of patients while avoiding potential addiction, effectively reconciling the contradiction between efficacy and addiction, and realizing the rational use of opioid analgesics.

[0008] Preferably, the pharmaceutical excipients include fillers, disintegrants, binders and lubricants.

[0009] By adopting the above technical solutions, fillers can effectively adjust the uniformity of drug content and provide necessary volume, disintegrants can promote timely disintegration of tablets by rapid water absorption and expansion, binders can improve particle compressibility and tablet mechanical strength, and lubricants can significantly reduce tableting resistance and prevent sticking. The synergistic combination of these four types of excipients can make the drug preparation have good stability, solubility and bioavailability, while effectively improving the smoothness of the production process, reducing quality problems such as flakes and sticking, and ultimately obtaining high-quality products that can give full play to the synergistic analgesic effect of dexketoprofen and oxycodone.

[0010] Preferably, the filler includes at least one of microcrystalline cellulose, lactose, mannitol, pregelatinized starch and calcium hydrogen phosphate.

[0011] By adopting the above technical solutions, microcrystalline cellulose has the functions of both filler and disintegrant. Its porous structure can increase the drug holding capacity and help achieve a good disintegration effect; lactose and pregelatinized starch can improve the fluidity and compressibility of the material, reducing the risk of sticking during tableting; the hygroscopicity of mannitol helps the rapid dissolution of active ingredients; and calcium hydrogen phosphate can enhance the mechanical strength of tablets, which is especially suitable for drugs that are sensitive to moisture absorption. The combination of these excipients can meet the needs of various processes such as direct tableting and wet granulation, while reducing strain sensitivity through the synergistic effect of different deformation mechanisms, so that the tablets have both ideal hardness and rapid disintegration characteristics.

[0012] Preferably, the disintegrant comprises at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and sodium carboxymethyl cellulose.

[0013] By adopting the above technical scheme, under the action of the above disintegrant, the compound analgesic pharmaceutical composition of the present application can achieve rapid disintegration in the gastrointestinal tract, thereby releasing the analgesic active ingredients with higher efficiency, and then can achieve a higher dissolution rate in a shorter time, which can fully meet the needs of clinical treatment.

[0014] Preferably, the binder includes at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and corn starch.

[0015] By adopting the above technical scheme, the present application optimizes the type of adhesive. By selecting the above-mentioned adhesives, the various components of the compound analgesic pharmaceutical composition can be fully combined, which not only reduces the damage caused by external forces and reduces the proportion of defective products, but also can utilize the excellent water absorption of the adhesive to promote the dissolution of the analgesic active ingredients.

[0016] Preferably, the lubricant includes at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, talc and silicon dioxide.

[0017] By adopting the above technical solution, the present application optimizes the specific type of lubricant. By selecting the above type of lubricant, an ideal tableting effect can be achieved, and adhesion between the tablet and the mold is less likely to occur, thereby reducing the breakage of the tablet during the production and processing process.

[0018] Preferably, the prescription of the compound analgesic pharmaceutical composition includes the following components: active ingredient A calculated as dexketoprofen 2.5-50 mg, active ingredient B calculated as oxycodone 5-100 mg, disintegrant 6-60 mg, binder 3-90 mg, lubricant 4.5-12.5 mg, filler 66.7-333.7 mg.

[0019] By adopting the above technical scheme, the present application optimizes the prescription dosage of the compound analgesic pharmaceutical composition. The compound analgesic pharmaceutical composition prepared according to the above formula can achieve ideal dissolution effect and analgesic effect in the form of tablets.

[0020] Preferably, the pharmaceutical excipient further comprises a cosolvent, and the cosolvent comprises modified barley starch, and the modified barley starch is prepared according to the following method: (1) soaking barley flour in a sodium hydroxide solution, then titrating with hydrochloric acid to neutrality, centrifuging and standing to separate the precipitates, collecting white precipitates, washing with anhydrous ethanol, filtering and air-drying, and grinding to obtain barley starch; (2) adding the barley starch to a ball mill, performing dry ball milling under liquid nitrogen freezing conditions, adding the ball milled product to water to obtain a starch slurry, adjusting the pH of the starch slurry to alkaline, adding an ethanol solution of octenylsuccinic acid, heating the slurry in a water bath, neutralizing the precipitates with hydrochloric acid, and then washing and drying the precipitates to obtain modified barley starch.

[0021] By adopting the above technical scheme, the present application first extracts barley starch from barley flour, then increases the specific surface area of ​​barley starch by freezing ball milling, and finally uses octenyl succinic acid and barley starch to undergo esterification reaction to obtain modified barley starch. The modified barley starch has both hydrophilic and hydrophobic groups, which can emulsify the analgesic active ingredient and promote the rapid dissolution of the analgesic active ingredient.

[0022] Preferably, the cosolvent further comprises lauric acid-modified microcrystalline cellulose, and the lauric acid-modified microcrystalline cellulose is prepared according to the following method: (1) grinding microcrystalline cellulose, sieving it, mixing it with sodium hydroxide, and continuing to grind it, and then adding lauric acid and continuing to grind it to obtain a grinding mixture; (2) The ground mixture is placed in a hydrothermal kettle, anhydrous ethanol is added and then sealed, and after the hydrothermal treatment, the pH value of the product is adjusted to neutral using hydrochloric acid, and then the precipitate is recovered after washing and centrifugal separation, and the precipitate is dried to obtain lauric acid-modified microcrystalline cellulose.

[0023] By adopting the above technical scheme, the present application uses lauric acid to modify the microcrystalline cellulose. The hydrophobic long chain of lauric acid gives the modified microcrystalline cellulose a certain hydrophobicity, and the microcrystalline cellulose itself also has a hydrophilic group. Therefore, the lauric acid-modified microcrystalline cellulose can synergistically achieve emulsification with modified barley starch, thereby promoting the rapid dissolution of analgesic active ingredients.

[0024] In a second aspect, the present application provides an application of a compound analgesic pharmaceutical composition, using the following technical solution.

[0025] An application of a compound analgesic pharmaceutical composition, wherein any of the above compound analgesic pharmaceutical compositions is applied to clinical analgesia.

[0026] By adopting the above technical scheme, the compound analgesic composition of the present application can fully meet the analgesic needs of patients while avoiding potential addiction, effectively reconciling the contradiction between efficacy and addiction, and helping to achieve the rational use of opioid analgesics.

[0027] In summary, this application has the following beneficial effects: 1. In clinical application, the compound analgesic composition of the present application can fully meet the analgesic needs of patients while avoiding potential addiction, effectively reconciling the contradiction between efficacy and addiction, and realizing the rational use of opioid analgesics.

[0028] 2. This application has selected specific types of pharmaceutical excipients. Fillers can effectively adjust the uniformity of drug content and provide necessary volume. Disintegrants can promote timely disintegration of tablets by rapid water absorption and expansion. Binders can improve the compressibility of particles and the mechanical strength of tablets. Lubricants can significantly reduce tableting resistance and prevent sticking. The synergistic cooperation of these four types of excipients can make the drug preparation have good stability, solubility and bioavailability, while effectively improving the smoothness of the production process, reducing quality problems such as fragmentation and sticking, and finally obtaining high-quality products, which can give full play to the synergistic analgesic effect of dexketoprofen and oxycodone.

[0029] 3. The present application prepares modified barley starch and lauric acid-modified microcrystalline cellulose, and uses these two materials as cosolvents. Both lauric acid-modified microcrystalline cellulose and modified barley starch are amphiphilic and can synergistically achieve emulsification, thereby promoting the rapid dissolution of analgesic active ingredients. DETAILED DESCRIPTION

[0030] The present application is further described in detail below in conjunction with embodiments, preparation examples and comparative examples. The raw materials involved in the present application can all be obtained commercially.

[0031] Preparation example of modified barley starch The following is an explanation using Preparation Example 1.

[0032] Preparation Example 1 In this preparation example, modified barley starch was prepared according to the following method: (1) 500 g of barley flour was soaked in 2.5 L of a 0.4 wt% sodium hydroxide solution, titrated to neutrality with hydrochloric acid after 3 h, centrifuged at 4500 r / min for 15 min, and then allowed to stand for stratification, white precipitates were collected, washed with anhydrous ethanol, filtered, air-dried, ground, and sieved through a 100-mesh sieve to obtain barley starch; (2) Add barley starch into a ball mill, maintain the temperature of -15°C under liquid nitrogen freezing conditions, and perform dry ball milling at a speed of 500 r / min. After 30 minutes, add the ball milled product into water and mix to obtain a starch slurry with a starch content of 20 wt%. Adjust the pH of the starch slurry to 8.5, and add an ethanol solution of octenylsuccinic acid (the weight ratio of octenylsuccinic acid to anhydrous ethanol is 1:5, and the amount of octenylsuccinic acid is 3% of the total weight of starch). After heating in a water bath at 35°C for 2 hours, neutralize with hydrochloric acid, and then wash and dry to obtain modified barley starch.

[0033] Preparation example of lauric acid modified microcrystalline cellulose The following is an explanation using Preparation Example 2.

[0034] Preparation Example 2 In this preparation example, lauric acid-modified microcrystalline cellulose was prepared according to the following method: (1) grinding microcrystalline cellulose for 20 minutes and then passing through a 270-mesh sieve, then mixing the microcrystalline cellulose and sodium hydroxide in a weight ratio of 30:1 and continuing to grind for 5 minutes, then adding lauric acid equivalent to 20% of the weight of the microcrystalline cellulose and continuing to grind for 5 minutes to obtain a ground mixture; (2) The ground mixture is placed in a hydrothermal autoclave, anhydrous ethanol is added to cover the ground mixture and then sealed. After hydrothermal treatment at 90° C. for 2 h, the pH of the product is adjusted to neutral (pH = 7) using hydrochloric acid. After washing and centrifugal separation (2800 r / min, 10 min), the precipitate is recovered and dried to obtain lauric acid-modified microcrystalline cellulose. Example

[0035] In the following examples, the product form of the compound analgesic pharmaceutical composition is tablets, specifically plain tablets.

[0036] Examples 1-10 The components contained in a single tablet of the compound analgesic pharmaceutical composition of Examples 1-10 are shown in Table 1, and the specific types of components of Examples 1-10 are shown in Table 2. In Table 1, the amount of active ingredient A is calculated as dexketoprofen, and the amount of active ingredient B is calculated as oxycodone.

[0037] Table 1 Ingredients contained in a single tablet of the compound analgesic drug composition (in mg) Table 2 Specific types of ingredients The production process used in Examples 1-10 is as follows: (1) According to the records in Table 1 and Table 2, weigh the active ingredient A, active ingredient B, filler, disintegrant, binder and lubricant in an amount for 1000 tablets and set aside; (2) Active ingredient A, active ingredient B, filler, binder and disintegrant are mixed at a speed of 10 rpm for 15 min, and then passed through a 30-mesh sieve to obtain a primary mixture for later use; (3) The primary mixture and the lubricant are mixed at a rotation speed of 8 rpm for 20 min, and then tableted at a hardness of 15 kg, with the weight difference controlled to ±5%, to obtain a compound analgesic pharmaceutical composition.

[0038] Embodiment 11 The difference between this embodiment and embodiment 10 is that the pharmaceutical excipients further include a solubilizing agent, the prescription dosage of the solubilizing agent is 10 mg, and the prescription dosage of the filler 2 is correspondingly reduced by 10 mg. The solubilizing agent is the modified barley starch of preparation example 1.

[0039] Example 12 The difference between this embodiment and embodiment 11 is that the co-solvent is the lauric acid-modified microcrystalline cellulose of preparation example 2.

[0040] Embodiment 13 The difference between this embodiment and embodiment 11 is that the co-solvent is prepared by mixing the modified barley starch of preparation example 1 and the lauric acid-modified microcrystalline cellulose of preparation example 2 in a weight ratio of 1:1.

[0041] The present application also provides an application of the compound analgesic pharmaceutical composition, which is used in clinical analgesia.

[0042] Comparative Examples In the following comparative examples, the product form of the analgesic pharmaceutical composition is tablets, specifically plain tablets.

[0043] The ingredients contained in the single tablets of the analgesic pharmaceutical compositions of Comparative Examples 1-4 are shown in Table 3, and the specific types of ingredients of Comparative Examples 1-4 are shown in Table 4. In Table 3, the amount of active ingredient is calculated based on oxycodone.

[0044] Table 3 Ingredients contained in a single tablet of analgesic drug composition (unit: mg) Table 4 Specific types of raw materials The production process used in Comparative Examples 1-4 is as follows: (1) According to the records in Table 3 and Table 4, weigh the active ingredient, filler, disintegrant, binder and lubricant in an amount for 1000 tablets and set aside; (2) The active ingredient, filler, binder and disintegrant are mixed at a speed of 10 rpm for 15 min, and then passed through a 30-mesh sieve to obtain a primary mixture for later use; (3) The primary mixture and the lubricant are mixed at a rotation speed of 8 rpm for 20 min, and then tableted at a hardness of 15 kg, with the weight difference controlled to ±5%, to obtain an analgesic pharmaceutical composition.

[0045] Performance testing methods 1. According to the 0921 disintegration time test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the disintegration time was tested, and the results are shown in Table 1; water was used as the dissolution medium, the dissolution volume was 900 mL, and the dissolution rate of active ingredient A and active ingredient B at 30 min was tested by the 50 rpm paddle method. The results are shown in Table 1.

[0046] 2. The percentage increase in pain threshold of mice 30 minutes after drug administration was determined by the hot plate method (55°C). The dosage conversion formula for mice was: mouse dose = 9.1X mg / kg. The results are shown in Table 1.

[0047] Table 5 Test results Combining Examples 1-10 and Comparative Examples 1-4 and Table 5, it can be seen that the pain threshold increase percentage measured in Examples 1-10 is relatively high, indicating that the analgesic drug composition of the present application has a stronger analgesic effect than pure opioid analgesics, and the actual content of opioid drug components is lower, so it can more fully meet the patient's analgesic needs while reducing opioid dependence.

[0048] Combining Example 10 with Examples 11-13 and Table 5, it can be seen that the dissolution measured in Examples 11-13 is higher, because both lauric acid-modified microcrystalline cellulose and modified barley starch are amphiphilic and can synergistically achieve emulsification, thereby promoting the rapid dissolution of the analgesic active ingredient. The dissolution measured in Example 12 is lower than that in Example 13, indicating that lauric acid-modified microcrystalline cellulose and modified barley starch have a synergistic effect in promoting dissolution.

[0049] The above embodiments are merely explanations of the present application and are not limitations of the present application. After reading this specification, those skilled in the art may make modifications to the embodiments of the present application without any creative contribution as needed. However, as long as they are within the scope of the claims of the present application, they are protected by the patent law.

Claims

1. A compound analgesic pharmaceutical composition, characterized in that: The components in the composition prescription include active ingredient A, active ingredient B and pharmaceutical excipients, wherein the active ingredient A is dexketoprofen or a pharmaceutically acceptable salt thereof, and the active ingredient B is oxycodone or a pharmaceutically acceptable salt thereof; in the prescription of the compound analgesic pharmaceutical composition, the content of active ingredient A is 2.5-50 mg calculated as dexketoprofen, and the content of active ingredient B is 5-100 mg calculated as oxycodone.

2. The analgesic compound pharmaceutical composition according to claim 1, characterized in that: The pharmaceutical excipients include fillers, disintegrants, binders and lubricants.

3. The analgesic compound pharmaceutical composition according to claim 2, characterized in that: The filler comprises at least one of microcrystalline cellulose, lactose, mannitol, pregelatinized starch and calcium hydrogen phosphate.

4. The compound analgesic pharmaceutical composition according to claim 2, characterized in that: The disintegrant comprises at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and sodium carboxymethyl cellulose.

5. The compound analgesic pharmaceutical composition according to claim 2, characterized in that: The binder includes at least one of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose and corn starch.

6. The compound analgesic pharmaceutical composition according to claim 2, characterized in that: The lubricant includes at least one of magnesium stearate, sodium stearyl fumarate, stearic acid, talc, and silicon dioxide.

7. The analgesic compound pharmaceutical composition according to claim 2, characterized in that: The prescription of the compound analgesic pharmaceutical composition includes the following components: active ingredient A calculated as dexketoprofen 2.5-50 mg, active ingredient B calculated as oxycodone 5-100 mg, disintegrant 6-60 mg, binder 3-90 mg, lubricant 4.5-12.5 mg, and filler 66.7-333.7 mg.

8. The compound analgesic pharmaceutical composition according to claim 2, characterized in that: The pharmaceutical excipient further comprises a cosolvent, and the cosolvent comprises modified barley starch, and the modified barley starch is prepared according to the following method: (1) Soak barley flour in a sodium hydroxide solution, then titrate it with hydrochloric acid until it is neutral, centrifuge it and let it stand to separate into layers, collect the white precipitate, wash it with anhydrous ethanol, filter it and air-dry it, and then grind it to obtain barley starch; (2) Add barley starch into a ball mill and perform dry ball milling under liquid nitrogen freezing conditions, add the ball milled product into water and mix to obtain starch slurry, adjust the pH of the starch slurry to alkaline and add an ethanol solution of octenylsuccinic acid, heat it in a water bath, neutralize it with hydrochloric acid, and then wash and dry it to obtain modified barley starch.

9. The analgesic compound pharmaceutical composition according to claim 8, characterized in that: The cosolvent further comprises lauric acid-modified microcrystalline cellulose, and the lauric acid-modified microcrystalline cellulose is prepared according to the following method: (1) grinding microcrystalline cellulose, sieving it, mixing it with sodium hydroxide, and continuing to grind it, and then adding lauric acid and continuing to grind it to obtain a grinding mixture; (2) The ground mixture is placed in a hydrothermal autoclave, anhydrous ethanol is added and the autoclave is sealed. After the hydrothermal treatment, the pH value of the product is adjusted to neutral using hydrochloric acid. The precipitate is recovered after washing and centrifugal separation, and the precipitate is dried to obtain lauric acid-modified microcrystalline cellulose.

10. An application of a compound analgesic pharmaceutical composition, characterized in that: The compound analgesic pharmaceutical composition according to any one of claims 1 to 9 is used for clinical analgesia.

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