Compound alphasar injection and preparation method thereof

Abstract

The present application belongs to the field of veterinary chemical medicine preparation, and specifically discloses a compound alpha-fentanyl injection. The injection takes alpha-fentanyl and meloxicam as main active ingredients, and preferably adds a suspending agent and a surfactant. Specifically, the injection contains 1-10% of alpha-fentanyl, 0.03-0.3% of meloxicam, 0.5-5% of the suspending agent, 0.5-5% of the surfactant, and the rest is water for injection. The injection is a water-based nanoscale injection, has small irritancy, good stability, simple preparation process, low production cost, and is suitable for industrial mass production.

Description

Technical Field

[0001] This invention belongs to the field of veterinary chemical drug preparations, specifically relating to a compound alfasalol injection and its preparation method. Background Technology

[0002] In clinical practice, animals often need to be anesthetized for various reasons. Anesthesia is the temporary loss of consciousness, allowing the animal to undergo surgery in a quiet state, thus avoiding potential severe pain during the procedure. In actual veterinary medicine or laboratory animal research, the anesthesia procedure and monitoring are usually performed by a dedicated anesthesiologist, not the attending veterinarian. Safety is extremely important, and a zero-tolerance policy is generally adopted for anesthesia-related complications. The anesthesiologist is not only responsible for controlling the animal's circulatory, respiratory, and nervous systems, but also bears corresponding responsibility for any accidental injuries caused during the anesthesia process due to manipulation or positioning.

[0003] For older animals, or dogs and cats with complications or systemic or genetic diseases, a more comprehensive consideration is generally recommended when anesthetizing them. Responsible surgeries or diagnoses require prolonged or specialized anesthesia management. Veterinarians are also increasingly recognizing the importance of perioperative pain management, fear management, and anxiety management for sick animals.

[0004] Before surgery, we need to prepare a lot, including developing a complete anesthesia plan and conducting appropriate preoperative assessments of the sick animal, including but not limited to medical history, clinical symptoms, clinical examination, laboratory tests, and diagnosis.

[0005] From the moment a sick animal sees a veterinary hospital, it will exhibit various stress responses, such as trembling, increased breathing, temporary increase in blood pressure, mania, irritability, depression, and other symptoms. Of course, some acute conditions, such as fractures or foreign body obstruction, may also cause irritability due to pain.

[0006] These animals need to be given certain sedative and analgesic drugs before surgery. Some experienced veterinarians will give their pets pre-operative sedation at home. Some pet hospitals will perform pre-operative analgesia management to lower the pain threshold of the sick animal. This can minimize the impact on blood pressure, heart and circulation caused by pain stimulation during the operation.

[0007] Commonly used sedatives in clinical practice fall into two categories: benzodiazepines and non-benzodiazepines. Generally, non-benzodiazepine sedatives have a faster onset of action and a shorter duration of action, and they do not significantly impair the animal's memory or attention. Before clinical surgery, sedation and analgesia are often administered in combination to ensure a smooth induction of anesthesia to the appropriate depth for surgery. Commonly used sedatives include dexmedetomidine and etomidate, while commonly used analgesics include butorphanol and tramadol. However, dexmedetomidine has side effects such as decreased cardiac rhythm and output, bradycardia, and hypotension, and is not recommended for use in weak, cardiovascular, or young animals. Etomidate is associated with a high incidence of myoclonus and suppresses adrenocortical hormones for 2-6 hours. Opioids are widely recognized as the most effective analgesics, but their side effects and addictive potential are significant concerns. Therefore, we select sedatives with minimal impact on the cardiovascular and circulatory systems, and analgesics with few or no side effects or addictive properties, combining them to facilitate clinical veterinarian use and expand their application scope.

[0008] Alfasal is a novel non-benzodiazepine steroid anesthetic. When administered intravenously, it is used for induction of general anesthesia, short surgeries, and surgical procedures; when administered intramuscularly, it is used for sedation in dogs and cats. Meloxicam, a nonsteroidal anti-inflammatory drug, has antipyretic, analgesic, and anti-inflammatory effects, and is mainly used clinically for analgesia and anti-inflammatory purposes. The combination of alfasal and meloxicam provides preoperative sedation and analgesia for weak, heart, kidney, circulatory, respiratory, elderly, and young animals, facilitating rapid induction into the surgical phase.

[0009] Most of the existing patented technologies are compound preparations of meloxicam and antibiotics, which have no sedative effect. Long-acting preparations are prone to problems such as burst release. Moreover, some formulations contain water, which can cause problems such as separation after prolonged storage.

[0010] "Meloxicam-Zinc Complex Microparticle Multicapsule Liposome Formulation and Preparation Method Thereof (CN 109983013; Publication Date: July 5, 2019)" is a multicapsule liposome formulation with multiple non-concentric internal compartments, in which meloxicam is encapsulated and made into a microparticle suspension. However, this patented formulation only improves bioavailability and is used for intra-articular occlusive therapy, which differs significantly from surgical application.

[0011] "A long-acting compound injection containing ceftiofur and meloxicam and its preparation method (CN109568255; Publication date: April 5, 2019)" is a long-acting compound injection of meloxicam and ceftiofur. This injection uses a high molecular weight inhibitor to achieve a long-acting effect, but the prescription only has anti-inflammatory and analgesic effects and no sedative effect. It is not the best prescription preparation for preoperative medication.

[0012] "A compound preparation for treating rheumatoid arthritis and its preparation method (CN103908542; Publication date: July 9, 2014)" is a compound preparation of traditional Chinese medicine and meloxicam. The traditional Chinese medicine component is mainly based on drying dampness, nourishing and relieving pain. The preparation is in capsule form, which has a longer duration of action than injection and does not contain sedative components. It does not help animals enter the surgical anesthesia period faster. Summary of the Invention

[0013] For the reasons mentioned above, this invention provides a compound injection that can effectively sedate and relieve pain, solving the problems of preoperative anxiety, difficulty in entering the surgical anesthesia period, or low pain threshold and unstable anesthesia period in sick animals. The specific solution is as follows:

[0014] In a first aspect, the present invention provides a compound alfasalone injection, wherein the components and their mass percentages in the injection are as follows:

[0015] Components Dosage (W / W) Alpha Salon 1～10％ Meloxicam 0.03～0.3％ Suspending agent 0.5～5％ surfactants 0.5～5％ carrier 79.7～97.97％

[0016] Preferably, the components and their mass percentages in the compound alfasaline injection are as follows:

[0017] Components Dosage (W / W) Alpha Salon 3～7％ Meloxicam 0.1～0.25％ Suspending agent 1.5～3.5％ surfactants 0.5～3％ carrier 86.25～94.90％

[0018] More preferably, the components and their mass percentages in the compound alfasaline injection are as follows:

[0019] Components Dosage (W / W) Alpha Salon 5％ Meloxicam 0.15％ Suspending agent 2.5％ surfactants 3％ carrier 89.35％

[0020] The suspending agent is selected from one or more combinations of glycerol, propylene glycol, polyethylene glycol, hydroxyethyl starch, sodium carboxymethyl cellulose, and hydroxypropyl-β-cyclodextrin.

[0021] Preferably, the suspending agent is selected from one or more combinations of glycerol, hydroxyethyl starch, sodium carboxymethyl cellulose, and hydroxypropyl-β-cyclodextrin.

[0022] More preferably, the suspending agent is a combination of glycerol and hydroxypropyl-β-cyclodextrin, and the ratio of glycerol to hydroxypropyl-β-cyclodextrin is 1:1-3, more preferably 1:2.

[0023] The surfactant is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, Tween-80, poloxamer, lecithin, sodium deoxycholate, and sodium lauryl sulfate.

[0024] Preferably, the surfactant is selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, and lecithin.

[0025] More preferably, the surfactant is a combination of two of polyvinylpyrrolidone and lecithin, with the ratio of polyvinylpyrrolidone to lecithin being 1:1.

[0026] The carrier is water for injection.

[0027] In another aspect, the present invention provides a method for preparing compound alfasalol injection, comprising the following steps:

[0028] (1) The raw materials of Alfasalam and Meloxicam were pulverized to a particle size of less than 50 μm using a cyclone pulverizer.

[0029] (2) Heat 60% of the prescribed amount of carrier to a temperature of 65-75℃, add the prescribed amount of suspending agent under stirring, dissolve until clear and keep warm for 30 minutes, add the prescribed amount of surfactant, stir to dissolve and clarify, and then cool to room temperature.

[0030] (3) Add the above mixture to the grinding jar of a planetary ball mill, and then add the pulverized prescription amount of alfasalam and meloxicam.

[0031] (4) Put stainless steel grinding balls of different diameters into the tank, with a ball-to-material ratio of about 30 to 40:1. After sealing the tank, turn on the planetary ball mill and set the speed to 3000±50 rpm. Run for 8 to 15 hours, controlling the temperature at 35 to 45℃ during the process. When the particle size D90 of the semi-finished product is less than 500nm, it can be discharged.

[0032] (5) Discharge the ground mixture from the outlet, and rinse the grinding tank and grinding balls multiple times with a small amount of carrier. Collect the rinsing liquid and mix it with the discharged material. Finally, use the carrier to adjust the volume to the prescribed amount to obtain the product.

[0033] Preferably, the heating temperature in step (2) is 70°C.

[0034] Preferably, the ball-to-material ratio in step (4) is 35:1.

[0035] Preferably, the controlled temperature is 40°C.

[0036] Preferably, the running time is 10-13 hours.

[0037] The main drugs of this invention are alfasalam and meloxicam. Alfasalam can be used as a general anesthetic, but it can also have a sedative effect when administered intramuscularly. Meloxicam is a nonsteroidal anti-inflammatory drug with antipyretic, analgesic and anti-inflammatory effects. The combination of the two drugs is effective in the clinical application of preoperative sedation and analgesia for weak, heart disease, kidney disease, circulatory and respiratory diseases, elderly and young animals, which helps to quickly induce them into the surgical phase.

[0038] Beneficial effects:

[0039] 1. The compound alfasalol injection of this invention is an aqueous nano-scale suspension injection. Intramuscular injection is much less irritating than oil-based carrier preparations and does not produce a significant stress response in pets.

[0040] 2. The compound alfasalol injection of the present invention is relatively stable and has good uniformity. Unlike oily suspension injections, which may separate into layers after prolonged storage, oily suspension injections use soybean oil or other oils as the carrier. As the storage time increases, the unsaturated fatty acids of the oil may undergo oxidation and other changes, leading to an increased incidence of adverse reactions in the formulation. However, the present invention uses water for injection as the carrier, and the aqueous formulation does not have the above risks.

[0041] 3. In the process of this invention, a planetary ball mill is used to grind for 8 to 15 hours, and the particle size can be controlled to be below 500 micrometers. Therefore, the raw material particles in the formulation can be uniformly dispersed in the carrier with suspending agent. Moreover, the drug particle size in the formulation of this invention reaches the nanometer level. The smaller the particle size, the better the drug absorption and the faster the effect in the body.

[0042] 4. The main drugs in the formulation of this invention are alfasalam and meloxicam. By utilizing the sedative effect produced by intramuscular injection of alfasalam and the analgesic effect produced by intramuscular injection of meloxicam, the advantages of the two drugs are brought into play, which reduces the pain threshold of pets, soothes the pets' anxious and irritable emotions, and avoids the problem of excessive excitement making it difficult to enter the deep anesthesia surgical period, thus avoiding the risks of anesthesia and surgery caused by adverse factors.

[0043] 5. The formulation of this invention can solve both sedation and analgesia problems with a single injection in clinical practice, and also reduces the stress of multiple injections for pets, providing a direction for veterinary clinical practice that saves manpower and reduces stress.

[0044] 6. This invention uses ball milling to prepare nano-suspension injections. The preparation process is simple, the production cost is low, and it is suitable for large-scale industrial production. Detailed Implementation

[0045] The present invention can be illustrated by the formulation and preparation method of the following characteristic embodiments.

[0046] Examples 1-8: Compound Alfasalam Injection of the Present Invention (based on a 10kg prescription)

[0047]

[0048] Each component was taken according to the above prescription ratio and prepared using the following method:

[0049] (1) The raw materials of alfasalam and meloxicam were pulverized to a particle size of less than 50μm using a cyclone pulverizer;

[0050] (2) Heat 60% of the prescribed amount of carrier to 70°C, add the prescribed amount of suspending agent under stirring, dissolve until clear and keep warm for 30 minutes, add the prescribed amount of surfactant, stir to dissolve and clarify, and then cool to room temperature;

[0051] (3) Add the above mixture to the grinding jar of a planetary ball mill, and then add the pulverized prescription amount of alfasalamine and meloxicam;

[0052] (4) Put stainless steel grinding balls of different diameters into the tank, with a ball-to-material ratio of about 35:1. After sealing the tank, turn on the planetary ball mill and set the speed to 3000±50 rpm. Run for 10 to 13 hours, controlling the temperature at 40℃ during the process. When the particle size D90 of the semi-finished product is less than 500nm, it can be discharged.

[0053] (5) Discharge the ground mixture from the outlet, and rinse the grinding tank and grinding balls multiple times with a small amount of carrier. Collect the rinsing liquid and mix it with the discharged material. Finally, use the carrier to adjust the volume to the prescribed amount to obtain the product.

[0054] Example 9 Stability Test

[0055] 1. Materials

[0056] The formulation of the present invention was selected and prepared using conventional methods.

[0057] 2 methods

[0058] Sedimentation stratification test: Take 20 ml of each of the products in Examples 1-8, place them in a 25 ml centrifuge tube, place the tube in the empty space of the centrifuge rotor, and place the balanced blank sample in the relative position. Set the centrifuge parameters to 1500 rpm and 10 minutes.

[0059] High-temperature accelerated test: Take 10ml of the product from Examples 1-7 respectively, place it in a constant temperature chamber at 60±3℃, and take it out after 10 days. Determine the sample content according to the draft quality standard of compound alfasalol suspension.

[0060] 3 Results

[0061] The results of the settlement stratification test are as follows:

[0062] Table 1. Sedimentation stratification test of compound alfasaline injection

[0063] Sample Name Settlement Sample Name Settlement Example 1 No settlement or stratification Example 5 No settlement or stratification Example 2 No settlement or stratification Example 6 No settlement or stratification Example 3 No settlement or stratification Example 7 No settlement or stratification Example 4 No settlement or stratification Example 8 Slight stratification occurred

[0064] After centrifugation at 1500 rpm for 10 minutes, no obvious stratification was observed in the samples of Examples 1-7, and no obvious precipitate was observed at the bottom.

[0065] The sample in Example 8 showed slight, very fine turbidity at the bottom after testing, but it was not a precipitate. After shaking and standing for a long time, it did not separate into layers.

[0066] The results of the high-temperature accelerated test are as follows:

[0067] Table 2 Accelerated High-Temperature Test of Compound Alfasaline Injection

[0068]

[0069]

[0070] 4 Discussion

[0071] Based on the results of the high-temperature accelerated test, after 10 days of accelerated high-temperature testing at 60°C, the compound alfasalam injection in Examples 4-6 showed a smaller decrease in alfasalam content compared to other examples, decreasing by about 1.8%; the meloxicam content decreased by about 1.4% compared to day 0, indicating that the compound alfasalam injection in Examples 4-6 of this invention has the best accelerated stability, and it is foreseeable that it will also be stable when stored at room temperature.

[0072] Example 10 Clinical Efficacy Trial

[0073] 1. Materials and Animals

[0074] Experimental animals: 40 healthy adult beagles, divided into 5 groups of 8 each, purchased from a stray animal rescue center in Tianjin.

[0075] Blank control group: normal saline

[0076] Drug control group: Xylazine injection (Orion, Finland)

[0077] Example Sample Group: Compound Alfasalam Injection (Examples 4-6)

[0078] 2 methods

[0079] Anesthesia plan:

[0080] Propofol injection (Guangdong Jiabo) was used for induction anesthesia; endotracheal intubation was performed; isoflurane was used for respiratory anesthesia; 5 minutes after entering respiratory anesthesia, the depth of anesthesia was observed by stimulating the interdigital spaces of the dog's toes with the injection needle; the respiratory anesthesia machine was turned off and the animal was allowed to wake up.

[0081] 3 Judgment Criteria

[0082] Anesthesia induction time: measured in minutes and seconds. The shorter and smoother the induction time, the better.

[0083] Depth of anesthesia:

[0084] Stage I: Consciousness and eyelash reflex are lost, but pain sensation remains.

[0085] Stage II: Irregular breathing, unstable circulation, hyperalgesia, and strong stimulation can cause tearing and increased secretions.

[0086] Stage III: Surgical period, eyeball fixed, pupil constricted, respiratory and circulatory stable, reflexes inhibited, pain sensation insensitive.

[0087] Stage IV: Bulbar paralysis or overdose danger stage, characterized by respiratory and circulatory depression, leading to decreased blood pressure, irregular breathing, and dilated pupils.

[0088] 4. Experimental Results

[0089] The results of anesthesia induction time and depth for the blank control group, drug control group, and sample group of the example are shown in the table below.

[0090] Table 3. Clinical anesthesia trial of compound alfasaline injection

[0091] Experimental Groups Time taken for anesthesia induction (in seconds) Depth of anesthesia Blank control group 6’27” Endotracheal intubation is not possible, Stage II Drug control group 2’47” Intubation was successful, Stage III Example 4 Sample Group 2’53” Intubation was successful, Stage III Example 5 Sample Group 2’09” Intubation was successful, Stage III Example 6 Sample Group 2’16” Intubation was successful, Stage III

[0092] 5 Discussions

[0093] The experimental results clearly show that preoperative management with sedation and analgesia before anesthesia induction allows animals to undergo stable and smooth anesthesia induction, entering a stage III anesthesia state suitable for surgery, with virtually no noticeable pain from needle pricks. The clinical assisted anesthesia induction of samples in Examples 4-6 showed no significant difference compared to the drug control group. However, the main active ingredient in Example 4 may not have been fully bound to the solubilizer, resulting in slightly poorer clinical efficacy. The effect of Example 6 was not significantly better than that of Example 5; therefore, Example 5 showed the best effect.

[0094] Although the present invention has been described with reference to specific embodiments, this description is not intended to limit the invention. Other variations of the disclosed embodiments, based on the description of the invention, will be foreseeable to those skilled in the art. Therefore, such variations do not depart from the scope and spirit defined by the appended claims.

Claims

1. A compound alfasalone injection, characterized in that, The components and their mass percentages in the injection solution are as follows: ； The suspending agent is a combination of glycerol and hydroxypropyl-β-cyclodextrin; the surfactant is a combination of polyvinylpyrrolidone and lecithin; the ratio of glycerol to hydroxypropyl-β-cyclodextrin in the suspending agent is 1:1-3; and the carrier is water for injection.

2. The compound alfasalone injection according to claim 1, characterized in that, The components and their mass percentages in the injection solution are as follows: 。 3. A method for preparing compound alfasaline injection according to any one of claims 1-2, comprising the following steps: (1) The raw materials of alfasalam and meloxicam were pulverized to a particle size of less than 50 μm using a cyclone pulverizer; (2) Heat 60% of the prescribed amount of carrier, add the prescribed amount of suspending agent under stirring, dissolve until clear and keep warm for 30 minutes, add the prescribed amount of surfactant, stir to dissolve and clarify, and then cool to room temperature; (3) Add the mixture prepared in step (2) into the grinding jar of a planetary ball mill, and then add the pulverized prescription amount of alfasalamine and meloxicam; (4) Place stainless steel grinding balls of different diameters into the tank, seal the tank and turn on the planetary ball mill. Set the speed to 3000±50 rpm and run it. Control the temperature during operation. When the particle size D90 of the semi-finished product is less than 500nm, it can be discharged. (5) Discharge the ground mixture from the outlet, and rinse the grinding tank and grinding balls multiple times with a small amount of carrier. Collect the rinsing liquid and mix it with the discharged material. Finally, use the carrier to adjust the volume to the prescribed amount to obtain the product.

4. The preparation method according to claim 3, characterized in that, The heating temperature in step (2) is 65-75℃; the ball-to-material ratio in step (4) is 30-40:1, the controlled temperature is 35-45℃, and the running time is 8-15 hours.

5. The preparation method according to claim 4, characterized in that, The heating temperature in step (2) is 70°C; the ball-to-material ratio in step (4) is 35:1, the controlled temperature is 40°C, and the running time is 10-13 hours.

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