CN108379269B

CN108379269B - Sustained-release preparation for postoperative analgesia and preparation method thereof

Info

Publication number: CN108379269B
Application number: CN201810358269.5A
Authority: CN
Inventors: 罗亮; 黄丽萍; 孟凡玲
Original assignee: Wuhan Baina Likang Biopharmaceutical Co ltd
Current assignee: Wuhan Baina Likang Biopharmaceutical Co ltd
Priority date: 2018-04-20
Filing date: 2018-04-20
Publication date: 2020-08-21
Anticipated expiration: 2038-04-20
Also published as: CN108379269A

Abstract

The invention discloses a sustained-release preparation for postoperative analgesia and a preparation method thereof, wherein the sustained-release preparation is mainly prepared from the following raw materials: 10-15 parts of phospholipid, 4-7 parts of glyceride, 0.3-5 parts of poloxamer, 0.8-5 parts of cosolvent, 0.5-2 parts of cocaine, procaine and lidocaine local anesthetic mixture, wherein the mass ratio of the cocaine, procaine and lidocaine local anesthetic mixture is 1:1: 4-7.5. The phospholipid is phosphatidylcholine, preferably soybean phosphatidylcholine, the glyceride is glyceryl dioleate, and the cosolvent is ethanol, is easy to inject and can slowly release the medicine in situ; the action time of the medicine is prolonged, the medicine taking times are reduced, and the bioavailability of the medicine is improved; and simultaneously, the toxic and side effects caused by overhigh medicine concentration are avoided.

Description

Sustained-release preparation for postoperative analgesia and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release preparation for postoperative analgesia and a preparation method thereof.

Background

Pain is a protective response to the body after being subjected to noxious stimuli, often accompanied by emotional activities such as fear, nervousness, etc. Pain, in addition to being responsive to sensory pain and emotional restlessness, can also cause physiological dysfunction, cause insomnia, and even induce shock and endanger life.

Among them, the post-surgical pain (the post-surgical pain) is a clinically common symptom, and millions of post-surgical patients are afflicted with postoperative pain all over the world at present. There are various operations causing postoperative pain such as inguinal defect repair, thoracotomy, cesarean section, etc. Especially acute and chronic pain after lung cancer thoracotomy greatly hinders postoperative respiratory function and daily life recovery of patients, even causes serious complications, and has great influence on subsequent comprehensive treatment. However, the occurrence and development mechanism of the pain is not clear, and the postoperative pain is a technical problem which needs to be solved urgently from the medical and social aspects.

The primary symptoms of chronic pain are not easy to eliminate, and the pain symptoms caused by the chronic pain are treated according to symptoms. Local block therapy is generally used, particularly with local anesthetics. They can temporarily completely and reversibly block nerve conduction within a limited range of the human body, i.e., cause a part of the human body to lose sensation in a state where consciousness is not lost, thereby acting as an analgesic.

Local anesthesia is a commonly used clinical anesthesia method, which is beneficial to keeping patients awake, enables anesthesia to return smoothly and facilitates postoperative analgesia. The local anesthetic can be classified into para-aminobenzoates, amides, aminoketones, aminoethers, and carbamates according to the structural type. The common medicines include lidocaine, cocaine, procaine, etc. Generally, the activity of local anesthetic drugs is enough to relieve certain pain, but the duration is not long enough, and patients more hope to continuously input the local anesthetic drugs with lower concentration, so that the pain nerve is blocked and the motor nerve is not affected, and the aim of only exerting the analgesic effect and not affecting the movement is fulfilled. Therefore, a local anesthetic capable of sustained release and long-acting is an ideal choice.

Several sustained release formulations of local anesthetic drugs have been developed and reported in the literature, such as polymeric microspheres of polylactic acid in combination with glycolic acid containing bupivacaine and dexamethasone to produce a prolonged local anesthetic effect. Crystals of local anesthetics have also been shown to have a longer duration of action. Lipophilic bupivacaine radicals are incorporated into multilamellar liposomal cell membranes, and large, proton-loaded unilamellar liposomes have shown efficacy, lasting 6-11 hours. Multivesicular liposomes are being developed as a lipid-based sustained release drug with local or systemic effect. In 11 months 2011, the us FDA approved bupivacaine (bupivacaine) 1.3% liposomal injection suspension Exparel developed by Pacira pharmaceuticals, inc, for direct injection to the surgical site to help control post-operative pain. Bupivacaine is a non-opioid anesthetic, and the conventional injection (0.5%) can only provide the analgesic effect for less than 7 hours, while the postoperative pain can last for 48-72 hours and is most difficult to control in the time, so that opioid is continuously administrated by using an internal catheter or an infusion pump, which causes inconvenient management and various harmful side effects.

Lidocaine is an amide intermediate-effect local anesthetic, has obvious double-phase effects of excitation and inhibition on a central nervous system after blood absorption, can not generate pioneer excitation, and has the effects of analgesia, sleepiness and pain threshold improvement when the blood concentration is lower; with the increase of dosage, the effect or toxicity is enhanced, and the sub-toxic blood concentration has the function of resisting convulsion; convulsions can occur when the blood concentration exceeds 5. mu.g/ml-1. The product can promote k + outflow in myocardial cell, reduce 4-phase slope, slow down automatic depolarization in diastole, and reduce myocardial autonomy, and has effect in resisting ventricular arrhythmia; at the treatment dose, the electrical activity of the cardiac muscle cells, the atrioventricular conduction and the contraction of the cardiac muscle are not obviously influenced; further elevation of blood levels may cause a slowing of cardiac conduction, atrioventricular block, inhibition of myocardial contractility and a reduction in cardiac output. Lidocaine can also cause hypersensitivity and anaphylactic reactions; for patients with respiratory tract hypersensitiveness, bronchospasm can be caused; excessive dosage and too rapid absorption can cause toxic reaction, manifested by central nervous excitation symptoms such as tinnitus, agitation, dysphoria, etc., and can rapidly develop convulsion, coma, blood pressure drop, etc.; excessive blood levels can cause decreased atrial conduction velocity, atrioventricular block, ventricular fibrillation and cardiac arrest.

Disclosure of Invention

The invention aims to solve the problems in the prior art and provides an injectable sustained-release preparation for postoperative analgesia with high bioavailability and long-acting sustained-release effect and a preparation method thereof.

In order to achieve the purpose, the invention adopts the technical scheme that: a sustained-release preparation for postoperative analgesia is characterized by mainly comprising the following raw materials: 10-15 parts of phospholipid, 4-7 parts of glyceride, 0.3-5 parts of poloxamer, 0.8-5 parts of cosolvent, 0.5-2 parts of cocaine, procaine and lidocaine local anesthetic mixture, wherein the mass ratio of the cocaine, the procaine and the lidocaine local anesthetic is 1:1: 4-7.5.

The three anesthetic drugs are mixed in different proportions, and are slowly released through the liquid crystal carrier, so that a strong analgesic effect can be achieved, and the toxicity of the drugs is reduced.

Further, the mass ratio of the cocaine, the procaine and the lidocaine local anesthetic is 1:1: 5.5-7.

Further, the phospholipid is at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylglycerol.

Further, the phospholipid is phosphatidylcholine, preferably soybean phosphatidylcholine.

The glyceride is one or more of glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, glyceryl stearate and glyceryl palmitate.

Further, the glyceride is glyceryl dioleate.

The cosolvent is ethanol.

In some embodiments, the sustained release preparation for postoperative analgesia is mainly prepared from the following raw materials: 12 parts of phospholipid, 5 parts of glyceride, 2 parts of poloxamer, 3 parts of cosolvent, 1.2 parts of cocaine, procaine and lidocaine.

The invention also provides a preparation method of the sustained-release preparation for postoperative analgesia.

The specific technical scheme is as follows:

a preparation method of a sustained-release preparation for postoperative analgesia comprises the following steps:

1) mixing and dissolving the cocaine, procaine and lidocaine local anesthetic in a cosolvent to obtain a medicinal solution;

2) slowly adding the melted mixed solution of the phospholipid, the glyceride and the poloxamer into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia.

Compared with the prior art, the invention has the beneficial effects that: the injection is easy, and the medicine can be slowly released in situ; the action time of the medicine is prolonged, the medicine taking times are reduced, and the bioavailability of the medicine is improved; and simultaneously, the toxic and side effects caused by overhigh medicine concentration are avoided.

Drawings

FIG. 1 is a graph showing the cumulative release of anesthetic from a sustained release preparation for postoperative analgesia prepared in examples 1 to 5 of the present invention.

FIG. 2 is a graph showing the cumulative release of anesthetic from a sustained release preparation for postoperative analgesia prepared in examples 6 to 9 of the present invention.

Figure 3 is a graph of the cumulative release of drug combinations in example 12.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

A sustained release preparation for postoperative analgesia is mainly prepared from the following raw materials:

120mg of soybean phosphatidylcholine, 50mg of glyceryl dioleate, 20mg of poloxamer, 30mg of absolute ethanol, 12mg of cocaine, procaine and lidocaine as local anesthetic.

The preparation method of the sustained-release preparation for postoperative analgesia is as follows:

the local anesthetics of cocaine, procaine and lidocaine are mixed according to the proportion of 1:1:4, dissolving in absolute ethyl alcohol, and uniformly mixing to obtain a medicinal solution; heating and melting soybean phosphatidylcholine, glyceryl dioleate and poloxamer at 70 ℃ to obtain a molten mixed solution; and slowly adding the molten mixed solution into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia. And (4) shading, sealing and storing in a refrigerator at 4 ℃.

Example 2

The sustained-release preparation for postoperative analgesia of the embodiment is mainly prepared from the following raw materials: 120mg of soy phosphatidylcholine, 50mg of glyceryl dioleate, 20mg of poloxamer 407, 30mg of ethanol, 12mg of cocaine, procaine and lidocaine as local anesthetic.

mixing cocaine, procaine and lidocaine in a local anesthetic mixture according to the weight ratio of 1:1:5.5, dissolving in absolute ethyl alcohol, and uniformly mixing to obtain a medicinal solution; heating and melting soybean phosphatidylcholine, glyceryl dioleate and poloxamer at 70 ℃ to obtain a molten mixed solution; and slowly adding the molten mixed solution into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia. And (4) shading, sealing and storing in a refrigerator at 4 ℃.

Example 3

The sustained-release preparation for postoperative analgesia provided by the embodiment is mainly prepared from the following raw materials: 120mg of soy phosphatidylcholine, 50mg of glyceryl dioleate, 20mg of poloxamer, 30mg of ethanol, 12mg of cocaine, procaine and lidocaine as local anesthetic.

mixing cocaine, procaine and lidocaine in a local anesthetic mixture according to the weight ratio of 1:1:6, dissolving in absolute ethyl alcohol, and uniformly mixing to obtain a medicinal solution; heating and melting soybean phosphatidylcholine, glyceryl dioleate and poloxamer at 70 ℃ to obtain a molten mixed solution; and slowly adding the molten mixed solution into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia. And (4) shading, sealing and storing in a refrigerator at 4 ℃.

Example 4

mixing cocaine, procaine and lidocaine in a local anesthetic mixture according to the weight ratio of 1:1: 7, dissolving in absolute ethyl alcohol, and uniformly mixing to obtain a medicinal solution; heating and melting soybean phosphatidylcholine, glyceryl dioleate and poloxamer at 70 ℃ to obtain a molten mixed solution; and slowly adding the molten mixed solution into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia. And (4) shading, sealing and storing in a refrigerator at 4 ℃.

Example 5

mixing cocaine, procaine and lidocaine in a local anesthetic mixture according to the weight ratio of 1:1: 7.5, dissolving in absolute ethyl alcohol, and uniformly mixing to obtain a medicinal solution; heating and melting soybean phosphatidylcholine, glyceryl dioleate and poloxamer at 70 ℃ to obtain a molten mixed solution; and slowly adding the molten mixed solution into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the liquid crystal gel sustained-release preparation precursor preparation for postoperative analgesia. And (4) shading, sealing and storing in a refrigerator at 4 ℃.

Example 6

The sustained-release preparation for postoperative analgesia provided by the embodiment is mainly prepared from the following raw materials: a mixture of 100mg of soy phosphatidylcholine, 40mg of glyceryl dioleate, 3mg of poloxamer, 8mg of ethanol, 5mg of cocaine, procaine and lidocaine local anesthetic.

Example 7

The sustained-release preparation for postoperative analgesia provided by the embodiment is mainly prepared from the following raw materials: 150mg of soybean phosphatidylcholine, 70mg of glyceryl dioleate, 50mg of poloxamer, 50mg of ethanol, 20mg of cocaine, procaine and lidocaine as local anesthetic.

Example 8

The sustained-release preparation for postoperative analgesia provided by the embodiment is mainly prepared from the following raw materials: a mixture of 140mg of soy phosphatidylcholine, 60mg of glyceryl dioleate, 40mg of poloxamer, 40mg of ethanol, 15mg of cocaine, procaine and lidocaine local anesthetic.

Example 9

Example 10

The slow release preparation for postoperative analgesia of the invention is used for the test of the writhing response of mice

1. Purpose of the experiment: the strength of writhing reaction of the postoperative analgesic sustained-release preparation of the invention after being administrated by the abdominal cavity is observed to investigate the degree of adverse reaction of different groups of preparations.

2. The test animals were: adult healthy white mice, half male and half female, weight 20-25 g.

3. The test method comprises the following steps: mouse writhing method.

Taking 110 mice, each half of the mice, fasting (without water) for 12h, randomly dividing the mice into 4 groups, namely a solvent control group, an anesthetic control group, an example 1 group, an example 2 group, an example 3 group, an example 4 group, an example 5 group, an example 6 group, an example 7 group, an example 8 group and an example 9 group respectively, carrying out intraperitoneal injection, respectively, 0.2ml/20g of 0.8% physiological saline injection liquid is given to the solvent control group, 0.2ml/20g of anesthetic is given to the anesthetic control group, 0.65% glacial acetic acid solution is further intraperitoneally injected to the slow-release preparation injection group (each group is intraperitoneally injected to the corresponding example solution and 0.2ml/20g is injected to the corresponding example solution and 0.3h and 2h is injected to the slow-release preparation injection liquid), immediately timing, recording the times of writhing response of the mice within 15min after administration by using a counter, taking the average writhing number of each administration group and comparing the writhing number of the mice with the average writhing number of the control group, statistical tests were performed.

The specific results are as follows:

table 1: experimental result of slow-release preparation for postoperative analgesia on writhing response of mice

	Animal number (only)	Number of wriggling reactions (0.3h)	Number of wriggling reactions (2h)
				Vehicle control group	10	40±5.8	41±6.9
Anesthetic control group	10	13±4.6	14±4.8
				EXAMPLE 1 group	10	9±2.4	10±2.8
EXAMPLE 2 group	10	8±1.6	8±1.9
				EXAMPLE 3 group	10	7±1.8	6±2.0
EXAMPLE 4 group	10	8±1.3	7±1.6
				EXAMPLE 5 group	10	9±1.2	10±1.7
EXAMPLE 6 group	10	8±2.6	9±2.3
				EXAMPLE 7 group	10	9±1.8	10±1.6
EXAMPLE 8 group	10	9±1.6	10±1.1
				EXAMPLE 9 group	10	9±2.3	10±0.5

The results show that the difference between the times of writhing reaction generated by the injection of the anesthetic control group and the groups of the embodiments of the postoperative analgesic sustained-release preparation of the present invention is significant, and the results show that the degree of action intensity of the postoperative analgesic preparation of the present invention is significantly higher than that of the control group, when the components are a mixture of 120mg of soybean phosphatidylcholine, 50mg of glyceryl dioleate, 20mg of poloxamer, 30mg of ethanol, 12mg of cocaine, procaine and lidocaine local anesthetic, the ratio of the cocaine, procaine and lidocaine local anesthetic is 1:1:6, the effect is best, and the effect change caused by the change of the liquid crystal material is smaller than the effect change caused by the content of the medicine components.

Example 11

1. The sustained release preparations for postoperative analgesia prepared in examples 1 to 5 were subjected to a drug release investigation.

2. The experimental method comprises the following steps: weighing a proper amount of postoperative analgesic sustained-release preparation in a dry EP tube, then adding a certain volume of pH7.4 phosphate buffer solution, sealing, putting into a constant-temperature shaking table for oscillation release, and setting parameters of the constant-temperature shaking table: the temperature was 37 ℃ and the rotation speed was 100 rpm. Samples were taken at different time points, respectively, and the same volume of release medium was then added to the release system. The released medium was kept at-20 ℃ for future use and the content of anesthetic in the released medium was determined by HPLC.

3. The experimental results are shown in fig. 1: under the condition of simulating in-vivo environment, the liquid crystal gel of the postoperative analgesic sustained-release preparation with different anesthetic component contents releases in vitro an accumulated release rate of one week not more than 20%, the accumulated release rates of the anesthetics in various embodiments are respectively 18.27 +/-1.25%, 9.15 +/-1.55, 3.12 +/-0.62, 8.34 +/-1.32% and 10.15 +/-1.14%, and the slow release effect on the anesthetics is related to the anesthetic component contents.

4. The sustained-release preparations prepared in examples 6 to 9 were examined for the release of the anesthetic by the experimental method described in step 2, and the results are shown in FIG. 2.

Example 12

1. The preparation of the combined medicine carrying of the invention, anti-inflammatory drugs and analgesics comprises the following steps:

respectively preparing the preparation molecular solution, the anti-inflammatory drug molecular solution and the analgesic drug molecular solution, uniformly mixing the preparation molecular solution and the anti-inflammatory drug molecular solution, incubating and standing to obtain a nano micelle solution, and marking as A solution; the preparation molecular solution is uniformly mixed with the analgesic molecular solution, incubated and stood to obtain a nano-micelle solution, which is marked as solution B, and the preparation molecular solution is uniformly mixed with the anti-inflammatory drug molecular solution and the analgesic molecular solution, incubated and stood to obtain a nano-micelle solution, which is marked as solution C.

Further, the solvent for preparing the solution is phosphate buffer solution, the incubation temperature is 30-50 ℃, and the incubation time is 10-30 min.

Further, the freeze-dried powder combined with drug loading can be prepared, and the specific steps are that the solution is filtered by a 0.22 mu m filter membrane, and a certain amount of freeze-drying protective agent is added, wherein the freeze-drying protective agent can be mannitol. The release of the three solutions was examined and the results are shown in figure 3.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A sustained-release preparation for postoperative analgesia, which is characterized by comprising the following raw materials: 10-15 parts of phospholipid, 4-7 parts of glyceride, 0.3-5 parts of poloxamer, 0.8-5 parts of cosolvent, 0.5-2 parts of cocaine, procaine and lidocaine local anesthetic mixture, wherein the mass ratio of the cocaine, the procaine and the lidocaine local anesthetic is 1:1: 6.

2. The sustained-release preparation for postoperative analgesia according to claim 1, wherein the phospholipid is at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylglycerol.

3. The sustained-release preparation for postoperative analgesia according to claim 2, wherein the phospholipid is phosphatidylcholine.

4. The sustained-release preparation for postoperative analgesia according to claim 1, wherein the glyceride is one or more of glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol stearate and glycerol palmitate.

5. The sustained-release preparation for postoperative analgesia according to claim 4, wherein the glyceride is glycerol dioleate.

6. The sustained-release preparation for postoperative analgesia according to claim 1, wherein the cosolvent is ethanol.

7. The sustained-release preparation for postoperative analgesia according to claim 1, which is prepared from the following raw materials: 12 parts of phospholipid, 5 parts of glyceride, 2 parts of poloxamer, 3 parts of cosolvent, 1.2 parts of cocaine, procaine and lidocaine local anesthetic.

8. A method of preparing a sustained release formulation for post-operative analgesia as claimed in any one of claims 1 to 7 which comprises the steps of:

2) slowly adding the mixed solution of the melted phospholipid, the glyceride and the poloxamer into the medicinal solution, uniformly mixing by vortex, and standing at room temperature to obtain the sustained-release preparation for postoperative analgesia.