WO2022193975A1

WO2022193975A1 - Ropivacaine long-acting solution preparation for injection, and preparation method therefor

Info

Publication number: WO2022193975A1
Application number: PCT/CN2022/079539
Authority: WO
Inventors: 易木林
Original assignee: 湖南慧泽生物医药科技有限公司
Priority date: 2021-03-16
Filing date: 2022-03-07
Publication date: 2022-09-22
Also published as: CN115068414A; TW202237108A; CN115068414B

Abstract

Disclosed is a ropivacaine long-acting solution preparation for injection, comprising an active ingredient, a sustained-release carrier and an alcohol solvent, wherein the active ingredient comprises at least one of ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate, and the sustained-release carrier comprises sucrose acetate isobutyrate. Further disclosed is a method for preparing a ropivacaine long-acting solution preparation for injection, the method comprising: mixing an active ingredient, a sustained-release carrier and an alcohol solvent, encapsulating the mixture and sterilizing same. After single administration of the ropivacaine long-acting solution preparation for injection, a continuous local anesthesia or a post-operation analgesia effect can be achieved for more than 72 h.

Description

Ropivacaine long-acting solution preparation for injection and preparation method thereof

This application requires that the Chinese patent application with the application number of 202110280601.2 be filed with the China Patent Office on March 16, 2021, and the invention name is "Ropivacaine Long-acting Solution Formulation for Injection and Its Preparation Method", and May 31, 2021 The priority of the Chinese patent application with the application number of 202110603696.7 and the invention title "Ropivacaine long-acting solution preparation for injection and its preparation method" filed with the China Patent Office on 2008, the entire contents of which are incorporated in this application by reference.

technical field

The invention relates to the technical field of controlled release administration of pharmaceutical preparations, in particular to a long-acting solution preparation of ropivacaine for injection and a preparation method thereof.

Background technique

Postoperative pain is a complex response to tissue damage during surgery. It includes pain directly related to surgery and pain related to central nervous system hypersensitivity. Postoperative pain can increase the burden on the cardiovascular system, reduce lung compliance, ventilation function and blood oxygenation function, etc., thereby inducing a variety of complications. If acute postoperative pain cannot be controlled in the initial state, it may develop into chronic pain lasting six months to several years. Effective postoperative analgesia can provide more favorable conditions for the recovery of surgical patients. Generally speaking, postoperative pain can last for 48 to 72 hours, and this time period is the most difficult to control. Local application of anesthetics is the most direct method of postoperative analgesia, but conventional injections in clinical applications can only provide analgesia for less than 7 hours. The development of long-acting local anesthetics has become a research hotspot today. As a result, the US FDA approved Exparel ^™ , a long-acting sustained-release liposomal bupivacaine suspension developed by Pacira Pharmaceuticals Co., Ltd., for direct injection into the surgical site to help control postoperative pain. Exparel ^TM adopts novel DepoFoam technology. It is a kind of multilamellar liposomes containing 1.3% bupivacaine. It has been gradually applied in foreign medical market. A single administration can produce analgesic effect for up to 72h. good.

Ropivacaine is the first pure L-body long-acting amide local anesthetic, developed by Sweden AstraZeneca Pharmaceutical Co., Ltd. It was first marketed in the Netherlands in 1996, and was approved by the FDA in the United States on September 24 of the same year. Like local anesthetics, by blocking the influx of sodium ions into the nerve fiber cell membrane, it can reversibly block the impulse conduction along the nerve fibers, and has dual effects of anesthesia and analgesia. block (analgesia) with only limited non-progressive motor block. Ropivacaine has sensory and motor dissociative blocking effects at low concentrations, and is commonly used for surgical anesthesia and epidural anesthesia, including cesarean section, regional block for acute pain control, continuous epidural infusion or intermittent single-dose administration, such as Postoperative or childbirth pain, regional block.

It is worth noting that ropivacaine has less cardiovascular and central neurotoxicity than bupivacaine at the same concentration and dose. However, since ropivacaine is insoluble in pH above 6.0, the ropivacaine preparations currently marketed at home and abroad are mainly ropivacaine hydrochloride or mesylate injections, which are used for surgical anesthesia and acute pain control. Ropivacaine hydrochloride or mesylate injection usually takes effect in 10-20 minutes, but the terminal half-life of ropivacaine is only 1.8h, and the drug effect can only last for 2-6 hours. A satisfactory analgesic effect was obtained. However, repeated single injections should take into account the risk of reaching plasma toxic concentrations or inducing local nerve damage. In order to reduce the number of repeated single administrations, reduce toxicity, and improve patient compliance, the development of ropivacaine long-acting solution formulations that can provide 72-hour local anesthesia or postoperative analgesia has important clinical application value and is also an urgent medical treatment. issues that need resolving.

Patent application CN104606129A discloses an injectable ropivacaine hydrochloride thermosensitive gel, the composition includes: main drug, PLGA-PEG-PLGA copolymer and solvent, it is liquid at room temperature, and turns into solid condensation when the temperature reaches about 36 °C. Glue, the drug release in vitro is ≤35-45% in 12h, ≥65%-75% in 48h, and ≥80% in 72h. The results of the rat thermal pain threshold test showed that it could be effectively sustained release for 48 hours.

The existing liposome technology and PLGA microsphere technology have very low drug loading, complicated process, difficult sample quality control, unsuitable for terminal sterilization, unstable properties and other technical difficulties, which greatly increases the long-acting preparation of ropivacaine. development cost and difficulty.

Hanmei Li et al. developed a drug delivery system based on sucrose acetate isobutyrate and N-methylpyrrolidone, and prepared ropivacaine sustained-release tablets (Sucrose Acetate Isobutyrate as an In situ Forming Implant for Sustained Release of Local Anesthetics, 2019), although it showed a sustained release effect of more than 72 hours in the in vitro release experiment, its rat plasma concentration and rat nerve block persistence experiments showed that its drug effect could only last for 18 hours, still The efficacy of local anesthesia or postoperative analgesia for more than 72 hours cannot be satisfied.

Therefore, it is urgent to develop a long-acting preparation of ropivacaine, so that a single administration can produce long-term local anesthesia or postoperative analgesia and reduce the frequency of repeated single administration.

SUMMARY OF THE INVENTION

In order to solve the above-mentioned technical problems, the object of the present invention is to provide a ropivacaine long-acting solution preparation for injection and a preparation method thereof, by preparing ropivacaine, a sustained-release carrier and an alcohol solvent into a ropivacaine for injection. The long-acting solution preparation of pivacaine can make it work in a short time. A single administration can produce local anesthesia or postoperative analgesia for more than 72 hours. It can reduce the number of repeated single administrations, reduce toxicity, and improve patient compliance.

In order to solve the above-mentioned purpose, the present invention adopts the following technical solutions:

In one aspect, the present invention provides a long-acting solution formulation of ropivacaine for injection, comprising an active ingredient, a sustained-release carrier and an alcohol solvent.

Wherein, the active ingredient includes at least one of ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate, preferably ropivacaine. At the same concentration and dose, ropivacaine has less cardiovascular and central nervous toxicity than bupivacaine, and the duration of local infiltration anesthesia is 2 to 3 times longer than that of bupivacaine at the same concentration.

The sustained release carrier includes sucrose acetate isobutyrate; in some embodiments, the sustained release carrier includes sucrose acetate isobutyrate and glyceride; preferably, the sucrose acetate isobutyrate and the The weight ratio of glycerides is 20:1 to 5:1, and the weight ratio is preferably 13:1, 9:1, 6:1 or 5:1, or any range therebetween; further, the glycerol Esters include medium chain triglycerides, glyceryl tricaprylate, glyceryl dioleate, glyceryl triacetate, glycerol monoacetate, glycerol monooleate, glycerol monolinoleate, glyceryl monolaurate, diglyceryl At least one of palmitic acid glyceride, monodecenoic acid glyceride, etc.; more preferably, the slow-release carrier is sucrose acetate isobutyrate and medium chain triglyceride in a mass ratio of 20:1 to 5: 1 composition, the weight ratio is preferably 13:1, 9:1, 6:1 or 5:1, or any range therebetween.

The alcoholic solvents described in this application include benzyl alcohol, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol 200-600, such as PEG200, PEG400, PEG600), glycerol (glycerol), tertiary trichloroethylene At least one of butanol, 1,3-butanediol, and isopropylene glycol. The inventor found in the research that the alcoholic solvent has good solubility for ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate as active ingredients, which is beneficial to improve the effect of drug efficacy, especially in low Higher drug concentration at volume. The sustained-release carrier of the present invention has a high viscosity, and requires relatively high sterilization in the subsequent use process, and the use of an alcohol solvent is beneficial to improve the stability and efficacy of the preparation. Preferably, the alcoholic solvent includes at least one of benzyl alcohol and ethanol. The inventor found that benzyl alcohol itself has a weak anesthetic effect, which is beneficial to improve the anesthetic effect of drugs to a certain extent; in addition, benzyl alcohol has antiseptic effect , can improve the stability of the formulation.

Further, the inventor also found that the slow-release carrier adopted in the present invention has good safety, is a biodegradable in-situ gel matrix material, belongs to a small molecular substance, does not crystallize but exists in the form of a high-viscosity and hydrophobic liquid, After dissolving with a small amount of organic solvent (about 15% to 30%), especially the alcohol solvent of the present application, a solution with similar viscosity to vegetable oil will be formed, which is easy for subcutaneous and intramuscular injection. More unexpectedly, after the sustained-release carrier of the present application is dissolved by an alcohol solvent, the obtained ropivacaine long-acting solution preparation for injection of the present application can rapidly release the drug in the early stage, which is conducive to the purpose of rapid anesthesia, while alcohol The addition of the solvent can also delay the release rate of the drug in the later stage, so that the long-acting solution formulation of ropivacaine for injection of the present application can achieve the effect of taking both short-term onset and lasting analgesic effect after single administration.

Further, the inventor also found that when a combined solvent of benzyl alcohol and ethanol is used, the release rate of the drug can be further delayed, and the sustained release effect is more obvious. The preferred mass ratio between benzyl alcohol and ethanol is 0.8:1～5:1, preferably 3:1～5:1, for example, the mass ratio can be 4:5, 5:6, 3:1, 4:1 or 5:1, or any range in between. Further, the ropivacaine long-acting solution preparation for injection is calculated as ropivacaine, and the dosage range is 50-500 mg, preferably 50-200 mg.

Further, the inventor also found that when the sustained-release carrier contains glycerides, the release rate of active ingredients such as ropivacaine can be further accelerated, but it does not cause a burst release phenomenon, which is beneficial to the purpose of rapid anesthesia.

Further, in terms of mass percentage, the ropivacaine long-acting solution preparation for injection includes 2.5-20% of active ingredients, 40-87.5% of sustained-release carrier, and 10-40% of alcohol solvent; The composition is 4-10%, the slow-release carrier is 60-80%, and the alcohol solvent is 10-30%. Further preferably, the active ingredient content is preferably 2.63%, 4.18%, 4.65%, 4.76%, 5.13%, 6.25%, 7.45% or 18.75%; the slow release carrier content is preferably 64.1%, 65.79%, 66.67%, 68.80% or 76.74%; the alcohol solvent content is preferably 10.17%, 18.6%, 27.03%, 28.57%, 30.77%, 31.58% or 37.5%.

In some embodiments, the active ingredient is ropivacaine, the sustained-release carrier is sucrose acetate isobutyrate, and the alcoholic solvent is benzyl alcohol; further, by mass percentage, the injection The long-acting solution preparation of ropivacaine includes 2.5-20% of ropivacaine, 40-80% of sucrose acetate isobutyrate, and 10-40% of benzyl alcohol. Preferably, ropivacaine is 3-10%, sucrose acetate isobutyrate is 55-80%, and benzyl alcohol is 10-40%. More preferably, 3-10% of ropivacaine, 55-70% of sucrose acetate isobutyrate, and 20-35% of benzyl alcohol. Further preferably, the content of ropivacaine is preferably 2.63%, 4.18%, 4.65%, 4.76%, 5.13%, 6.25%, 7.45% or 18.75%; the content of sucrose acetate isobutyrate is preferably 64.1%, 65.79%, 66.67%, 68.80% or 76.74%; the benzyl alcohol content is preferably 10.17%, 18.6%, 27.03%, 28.57%, 30.77%, 31.58% or 37.5%.

Further, in terms of mass percentage, the long-acting solution preparation of ropivacaine for injection is 2.5-20% of ropivacaine, 40-87.5% of the composition of sucrose acetate isobutyrate and medium-chain triglyceride , the combined solvent of benzyl alcohol and ethanol is 10-40%; wherein, the mass ratio of sucrose acetate isobutyrate and medium-chain triglyceride is 20:1-5:1, and the mass ratio of benzyl alcohol and ethanol is 0.8:1 ~5:1. Further, in terms of mass percentage, the ropivacaine long-acting solution preparation for injection preferably has a ropivacaine content of 2.63%, 4.18%, 4.65%, 4.76%, 5.13%, 6.25%, 7.45% or 18.75%; the composition content of sucrose acetate isobutyrate and medium chain triglyceride is preferably 64.1%, 65.79%, 66.67%, 68.80% or 76.74%; the combined solvent content of benzyl alcohol and ethanol is preferably 10.17%, 18.6% %, 27.03%, 28.57%, 30.77%, 31.58% or 37.5%; wherein, the mass ratio of sucrose acetate isobutyrate and medium chain triglyceride can be 13:1, 9:1, 6:1 or 5 : 1, or any range therebetween, and the benzyl alcohol to ethanol mass ratio can be 4:5, 5:6, 3:1, 4:1, or 5:1, or any range therebetween.

"Medium-chain triglycerides" in the present application refers to a mixture of saturated triglycerides with a caprylic acid glyceride and a capric glyceride content of not less than 95%, which are commercially available.

Further, the single administration of the ropivacaine long-acting solution formulation for injection produces an analgesic effect over 72 hours. Further preferably, the single administration of the ropivacaine long-acting solution formulation for injection produces an analgesic effect exceeding or up to 96 hours.

On the other hand, the present invention provides a method for preparing a ropivacaine long-acting solution preparation for injection, which is obtained by mixing a sustained-release carrier, an alcohol solvent and an active ingredient, encapsulating and sterilizing.

Further, the preparation steps are as follows:

1) Dissolve the active ingredient in an alcohol solvent;

2) Dissolve the sustained-release carrier in the mixed solution of the active ingredient and the alcohol solvent to obtain a uniform medicinal liquid; In the mixed solution of alcoholic solvents; preheating the sustained-release carrier is conducive to its faster dissolution;

3) sterilizing the homogeneous medicinal liquid after encapsulation to obtain the long-acting solution preparation of ropivacaine for injection.

Further, the preparation steps are as follows:

1) Add the active ingredient into the alcohol solvent, seal it and perform mechanical stirring at a speed of 100-400rpm for 10-30min;

2) adding the sustained-release carrier to the solution obtained in the above step 1), and performing mechanical stirring at a speed of 100-400 rpm for 10-30 min to form a uniform medicinal liquid;

3) Pass the medicinal solution obtained in step 2) through a sterilizing filter membrane, under nitrogen protection, encapsulate it in a packaging material, and sterilize it by autoclaving at 120-130° C. for 15-30 minutes.

Further, the packaging material is selected from any one of vials, ampoules, refillable syringes, and cartridges.

Compared with the prior art, the present invention has the following beneficial effects:

The invention provides a ropivacaine long-acting solution preparation for injection with larger drug loading, less irritation and long injection sustained-release effect. Compared with the existing ropivacaine hydrochloride injection or ropivacaine mesylate Compared with pivacaine injection, the sustained-release feature is obvious, and the long-acting solution preparation of ropivacaine for injection prepared by the present invention can continue to exert the effect of local anesthesia or postoperative analgesia for more than 72 hours (detected in the embodiment of the present invention at 96h still has local anesthesia or postoperative analgesia);

Compared with the existing ropivacaine multivesicular liposomes, ropivacaine PLGA microspheres and other microspheres, and ropivacaine nanospheres, the preparation process of the present invention adopts the traditional process of mechanical stirring, and the preparation process is greatly simplified. , low cost, and can be packaged in ampoules for terminal sterilization, avoiding the use of aseptic technology, stable solution properties, long-term storage, and ensuring product effectiveness and safety.

Compared with the existing ropivacaine thermosensitive gel, the ropivacaine long-acting solution preparation for injection prepared by the present invention is not sensitive to temperature, and can avoid quality changes caused by changes in ambient temperature during storage and use; , the quality control of polyethylene glycol derivatized polylactic acid glycolic acid polymer required for the preparation of thermosensitive gel is complicated and the cost is high, and the thermosensitive gel preparation has high viscosity and needs to be produced by aseptic process.

The ropivacaine long-acting solution preparation for injection provided by the present invention is in the state of an ordinary solution before injection; after being injected into the surgical site, it contacts with local body fluids of the human body, and with the continuous diffusion of the solution preparation and the continuous infiltration of body fluids, the sustained release The viscosity of the carrier system increases sharply, forming a drug depot with controllable viscosity at the injection site, which can reduce the pain of injection, will not cause serious irritation to the administration site, and is slowly released in the local tissue, resulting in continuous local anesthesia for more than 72 hours or postoperative Analgesic effect.

The long-acting solution preparation of ropivacaine for injection provided by the present invention is colorless and clear, without sudden release phenomenon, more stable drug release effect, rapid anesthesia and slow release, longer sustained-release effect, and increased patient consumption. Compliance also reduces the side effects caused by repeated administration. In addition, the ropivacaine long-acting solution preparation for injection of the present invention is similar to the commercially available ropivacaine hydrochloride preparation under the stability test conditions.

Description of drawings

In order to illustrate the embodiments of the present invention and the technical solutions of the prior art more clearly, the following briefly introduces the drawings required in the embodiments and the prior art. Obviously, the drawings in the following description are only the For some embodiments of the invention, those of ordinary skill in the art can also obtain other drawings according to these drawings.

Fig. 1 is the release curve diagram of the ropivacaine long-acting solution formulation for injection of the present application in normal saline.

Detailed ways

In order to make the objectives, technical solutions, and advantages of the present invention more clear, the present invention will be described in further detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention fall within the protection scope of the present invention.

The reagents used in this application are all conventional reagents in the art and can be purchased from commercial sources.

Example 1

Ropivacaine long-acting solution preparation for injection, including the following components: ropivacaine 4g, sucrose acetate isobutyrate 56g, injection-grade benzyl alcohol 24g

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside;

Take 4g of ropivacaine and add it to 24g of injection-grade benzyl alcohol, seal it and stir mechanically at a speed of 100-400rpm for 10-30min until it is completely dissolved;

After preheating 56 g of sucrose acetate isobutyrate in a 50°C water bath for 30 minutes, add it to the above ropivacaine solution, and mechanically stir it at a speed of 100 to 400 rpm for 10 to 30 minutes to form a uniform liquid medicine;

The homogeneous medicinal solution was passed through a sterilizing filter membrane, and after the detected content was qualified, the obtained medicinal solution was filled in a 2 mL ampoule bottle under nitrogen protection, and autoclaved at 121° C. for 20 minutes to complete.

Example 2

Ropivacaine long-acting solution preparation for injection, including the following components:

Ropivacaine 3.4g, sucrose acetate isobutyrate 56g, injection grade benzyl alcohol 10g, injection grade ethanol 12g.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

Take 3.4g of ropivacaine and add it to 10g of injection grade benzyl alcohol and 12g of ethanol, seal it and stir mechanically at 300rpm for 20min until it is completely dissolved;

The homogeneous medicinal solution was passed through a sterilizing filter membrane, and after the detected content was qualified, the obtained medicinal solution was filled in a 2 mL ampoule bottle under nitrogen protection, and autoclaved at 121° C. for 20 minutes.

Example 3

The ropivacaine long-acting solution preparation for injection includes the following components: 4 g of ropivacaine, 52 g of sucrose acetate isobutyrate, 4 g of medium-chain triglycerides, and 24 g of injection-grade benzyl alcohol.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

52g of sucrose acetate isobutyrate was preheated in a 50°C water bath for 30min, and 4g of medium-chain triglyceride was added to the above-mentioned ropivacaine solution, and mechanically stirred at a speed of 100-400rpm for 10-30min to form a homogeneous liquid;

Example 4

The ropivacaine long-acting solution preparation for injection includes the following components: 4 g of ropivacaine, 48 g of sucrose acetate isobutyrate, 8 g of medium-chain triglycerides, and 24 g of injection-grade benzyl alcohol.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

48g of sucrose acetate isobutyrate was preheated in a 50°C water bath for 30min, and 8g of medium chain triglyceride was added to the above-mentioned ropivacaine solution, and mechanically stirred at a speed of 100～400rpm for 10～30min to form a homogeneous medicinal liquid;

Example 5

Ropivacaine long-acting solution preparation for injection, including the following components: ropivacaine 4g, sucrose acetate isobutyrate 55g, medium chain triglyceride 11g, injection grade benzyl alcohol 12g, injection grade ethanol 4g.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

Take 4g of ropivacaine and add it to 12g of injection-grade benzyl alcohol and 4g of ethanol mixed solvent, seal it and mechanically stir it at a speed of 100-400rpm for 10-30min until it is completely dissolved;

After preheating 55g of sucrose acetate isobutyrate in a 50°C water bath for 30min, add 11g of medium-chain triglyceride to the above-mentioned ropivacaine solution, and mechanically stir at a speed of 100-400rpm for 10-30min to form a homogeneous liquid;

Example 6

The ropivacaine long-acting solution preparation for injection comprises the following components: 2 g of ropivacaine, 50 g of sucrose acetate isobutyrate, and 24 g of injection-grade benzyl alcohol.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

Take 2g of ropivacaine and add it to 24g of injection-grade benzyl alcohol, seal it and mechanically stir at a speed of 100-400rpm for 10-30min until it is completely dissolved;

After preheating 50 g of sucrose acetate isobutyrate in a 50°C water bath for 30 minutes, add it to the ropivacaine solution, and mechanically stir it for 10 to 30 minutes at a speed of 100 to 400 rpm to form a uniform liquid medicine;

Example 7

The ropivacaine long-acting solution preparation for injection comprises the following components: 15 g of ropivacaine, 35 g of sucrose acetate isobutyrate, and 30 g of injection-grade benzyl alcohol.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

Take 15g of ropivacaine and add it to 30g of injection-grade benzyl alcohol, seal it and mechanically stir at a speed of 100-400rpm for 10-30min until it is completely dissolved;

After preheating 35g of sucrose acetate isobutyrate in a 50°C water bath for 30min, add it to the above-mentioned ropivacaine solution, and mechanically stir it at a speed of 100-400rpm for 10-30min to form a uniform liquid medicine;

The homogeneous medicinal liquid was passed through the sterilizing filter membrane, and after the detected content was qualified, the obtained medicinal liquid was filled and sealed in a 2mL ampoule bottle under nitrogen protection, and autoclaved at 121°C for 20 minutes.

Example 8

The ropivacaine long-acting solution preparation for injection includes the following components: 8.3 g of ropivacaine hydrochloride, 72 g of sucrose acetate isobutyrate, 8 g of monoacetin, 7.5 g of injection-grade benzyl alcohol, and 2.5 g of ethanol.

The preparation method is provided as follows:

Pass ropivacaine hydrochloride through an 80-mesh sieve and set aside.

Take 8.3g of ropivacaine hydrochloride and add it to 7.5g of injection-grade benzyl alcohol and 2.5g of ethanol mixed solvent, seal and mechanically stir at a speed of 100-400rpm for 10-30min until completely dissolved;

After preheating 72g of sucrose acetate isobutyrate in a 50°C water bath for 30min, add 8g of glycerol monoacetate to the above ropivacaine hydrochloride solution, and mechanically stir at a speed of 100-400rpm for 10-30min to form a homogeneous liquid;

The homogeneous medicinal solution was passed through a sterilizing filter membrane, and after the detected content was qualified, the obtained medicinal solution was filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121° C. for 20 minutes.

Example 9

The ropivacaine long-acting solution preparation for injection comprises the following components: 8.3 g of ropivacaine mesylate, 72 g of sucrose acetate isobutyrate, 8 g of medium-chain triglycerides, and 10 g of injection-grade ethanol.

The preparation method is provided as follows:

Pass ropivacaine mesylate through an 80-mesh sieve and set aside.

Take 8.3g of ropivacaine mesylate and add it to 10g of ethanol solvent, seal and mechanically stir at a speed of 100-400rpm for 10-30min until completely dissolved;

72g of sucrose acetate isobutyrate was preheated in a 50°C water bath for 30min, and 8g of medium chain triglyceride was added to the above solution of ropivacaine mesylate, and mechanically stirred at a speed of 100 to 400rpm for 10 to 30min to form a homogeneous drug. liquid;

Example 10

The ropivacaine long-acting solution preparation for injection comprises the following components: 8.3 g of ropivacaine mesylate, 72 g of sucrose acetate isobutyrate, 8 g of glyceryl dioleate, and 10 g of glycerin.

The preparation method is provided as follows:

Pass ropivacaine mesylate through an 80-mesh sieve and set aside.

Take 8.3g of ropivacaine mesylate and add it to 10g of glycerol solvent, seal and mechanically stir at a speed of 100～400rpm for 10～30min until completely dissolved;

After preheating 72g of sucrose acetate isobutyrate in a 50°C water bath for 30min, add 8g of glycerol dioleate to the above solution of ropivacaine mesylate, and mechanically stir at a speed of 100 to 400rpm for 10 to 30min to form a homogeneous drug. liquid;

Example 11

The long-acting solution preparation of ropivacaine for injection comprises the following components: 4 g of ropivacaine, 50 g of sucrose acetate isobutyrate, and 24 g of polyethylene glycol 600.

The preparation method is provided as follows:

Pass ropivacaine through an 80-mesh sieve and set aside.

Take 5g of ropivacaine and add it to 24g of polyethylene glycol 600, seal it and mechanically stir at a speed of 100-400rpm for 10-30min until it is completely dissolved;

50g of sucrose acetate isobutyrate was preheated in a 50°C water bath for 30min, and 8g of medium chain triglyceride was added to the above-mentioned ropivacaine solution, and mechanically stirred at a speed of 100～400rpm for 10～30min to form a homogeneous medicinal liquid;

Comparative Example 1 Preparation of Ropivacaine Hydrochloride Thermosensitive Gel for Injection

Ropivacaine Hydrochloride 0.15g, Pluronic F127 2.3g, Pluronic F68 0.5g, Water for Injection 10mL

The above-mentioned pharmaceutical composition will be used as the content, and the content will be filled in ampoules.

The preparation method is as follows:

Pass ropivacaine hydrochloride through an 80-mesh sieve and set aside. Take 2.3g of Pluronic F127 and 0.5g of Pluronic F68 into 10ml of water for injection, stir in a water bath at 4°C for 10-30min until completely dissolved; add 0.15g of ropivacaine hydrochloride to the above Pluronic solution, stir mechanically for 10min A homogeneous medicinal solution is formed; after the detected content of the intermediate is qualified, the obtained medicinal solution is filled and sealed in a 2ml ampoule bottle under nitrogen protection.

Comparative Example 2 Preparation of ropivacaine long-acting dry suspension preparation for injection

Ropivacaine Hydrochloride 0.05g, Tween 0.25g, Mannitol 1.2g, Croscarmellose Sodium 0.25g, Water for Injection 25mL

The above pharmaceutical composition will be used as the content, the content will be freeze-dried at -40°C for 12 hours, and packaged in a vial.

The preparation method is as follows:

Pass ropivacaine through an 80-mesh sieve and set aside. Ropivacaine was micronized by a jet mill, and the D ₉₀ was less than 5 μm. Take 0.25g of Tween, 1.2g of mannitol, 0.25g of croscarmellose sodium into 25ml of water, stir in a water bath at 50°C for 10-20min until completely dissolved; add 0.05g of micronized ropivacaine to the above mannitol solution , mechanically stirred for 10 minutes to form a suspension; after the content of the intermediate was qualified, it was divided into 10ml vials, freeze-dried at -40°C for 12 hours, and then a rubber stopper was added and capped.

Test Example 1 Determination of release rate

Chromatographic conditions

Column: Agilent EC-C18 (4.6nm×150nm, 4μm)

Mobile phase: 25 mmol/L potassium dihydrogen phosphate buffer (pH 7.4): acetonitrile (30%: 70%)

Injection volume: 20μl

Column temperature: 30℃

Detection wavelength: 263nm

Example release measure:

Take the ropivacaine long-acting solution preparation (dose 50mg) for injection described in Examples 1-11, according to the US Pharmacopoeia test method, take 200mL of physiological saline as the dissolution medium, the rotating speed is 10r/min, and the temperature is (37±0.5 ) ℃, sample 2ml at 2h, 4h, 6h, 24h, 48h, 72h, 96h, immediately filter with 0.45μm microporous membrane, discard the primary filtrate, carry out HPLC analysis, and calculate the cumulative release percentage of the drug.

Table 1 Cumulative release percentage of each example drug (n=3)

It can be seen from Table 1 that the drug release rate of the ropivacaine long-acting solution for injection of the present application reaches more than 6% within 2 hours, indicating that the long-acting ropivacaine for injection solution of the present application can quickly release the drug; and 6 After hours, the drug showed a trend of smooth and stable release, and at 96 hours, the cumulative release rate was lower than 80%, indicating that it had sustained release characteristics over 96 hours.

It can be seen from the comparison between Example 1 and Example 2 that when benzyl alcohol and ethanol are used as mixed solvents, the release rate of the ropivacaine long-acting solution preparation for injection is further delayed, and the sustained-release effect is more stable; It can be seen from Example 1, Example 3 and Example 4 that the introduction of glyceride adjuvants can accelerate drug release. The inventor also found that with the increase of glyceride content, the drug release rate in the early stage is accelerated, but it does not. Caused a sudden release phenomenon; the results are shown in Figure 1.

According to the above results, it can be seen that the long-acting ropivacaine solution for injection of the present application has the effect of long-acting sustained release. At this time, the rapid release of the drug and the sustained-release characteristics of more than 96 hours can be realized; further, the addition of ethanol is conducive to further delaying the release rate of the drug, and the addition of glyceride is conducive to accelerating the drug release rate in the early stage; preferably, The long-acting ropivacaine solution for injection of the present application has 2.5-20% of active ingredients, 40-87.5% of sustained-release carrier, and 10-40% of alcoholic solvents in terms of mass percentage; for saving medication and reducing costs Considering that, more preferably, in terms of mass percentage, the ropivacaine long-acting solution preparation for injection comprises: 4-10% of active ingredient, 60-80% of sustained-release carrier, and 10-30% of alcohol solvent.

Comparative Release Determination:

Take 2ml of the ropivacaine hydrochloride thermosensitive gel preparation for injection described in Comparative Example 1 and add it to a 10ml EP tube, and place the EP tube in a (37±0.5°C) constant temperature water bath to balance for 5min to gel the solution. Add 5ml of normal saline at 37°C as the release medium, shake it in a constant temperature vibration box at 50r/min, take out 4mL of the release medium at 2h, 4h, 6h, 24h, 48h, 72h, and 96h, and then refill. The samples were immediately filtered through a 0.45 μm microporous membrane, the initial filtrate was discarded, and the HPLC analysis was performed to calculate the cumulative release percentage of the drug. Calculate the cumulative release. The ropivacaine long-acting dry suspension preparation described in Comparative Example 2 was taken, reconstituted with 3 mL of normal saline, and added to the dialysis bag. Take 200 mL of normal saline as the dissolution medium, the rotation speed is 10 r/min, the temperature is (37 ± 0.5) °C, and 2 mL is sampled at 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, and 96 h, and immediately filtered with a 0.45 μm microporous membrane. , discard the primary filtrate, carry out HPLC analysis, and calculate the cumulative release percentage of the drug.

Table 2 The cumulative release percentage of each comparative drug (n=3)

It can be seen from Table 2 that although the ropivacaine hydrochloride thermosensitive gel preparation for injection in Comparative Example 1 has thermosensitive sustained-release characteristics, the release exceeds 85% in 48 hours. Comparative Example 2 Although the long-acting dry suspension preparation of ropivacaine for injection has the characteristics of sustained release, the 48h release also exceeds 85%. Both of them do not have the long-term release characteristics of more than 72h.

Test Example 2 Drug Efficacy Test in Rats

1. Determination of mechanical withdrawal reflex threshold

Preparation of the incision pain model: 6 SD rats, 200-250 g, were selected. The rats were fasted for 6 h and drinking for 1 h before the operation. The rats were placed in a cotton ball soaked in about 0.3 mL of isoflurane with a volume of 1 L. Put a lid on the transparent glass of the rat, and after observing the disappearance of consciousness, the left hind sole of the rat was disinfected with iodophor, and an incision of about 1 cm in length was made from the proximal 0.5 cm of the sole of the foot to the toe according to the Brennan method, and the skin was incised. Lift the plantar muscle with ophthalmic forceps and cut longitudinally, leaving the origin, stop and attachment of the muscle intact. After pressing for hemostasis, the skin was sutured with fine needles for 2 stitches, and the corresponding drugs were injected into the incision in groups A and B at the sutured skin.

A. Ropivacaine hydrochloride solution group: the injection concentration near the incision is 17 mg/ml ropivacaine hydrochloride injection, and the dose is 17 mg/kg (calculated by ropivacaine);

B. Each example group: 50 mg/kg of ropivacaine long-acting solution formulations (calculated by ropivacaine) of each example in Table 3 were injected near the incision.

The entire surgical operation was performed by the same person for about 5 minutes. After the operation, the wounds were disinfected with iodophor and a small amount of erythromycin ointment was applied. The rats were fed in a quiet, warm, and protected environment.

Threshold Determination: Mechanical allodynia was measured in rats using 8 different scale von Frey fiber rods (2, 4, 6, 8, 10, 15, 26g, 64g). In a grid frame made of wire 30cm high from the test bench at the bottom, several transparent plexiglass boxes of 20cm×20cm×25cm are placed on it, and the rats to be tested are put inside to make them adapt for a period of time. Control over 30min. After the rat was quiet, the soles of the rats were directly stimulated with von-Frey fibers through the wire mesh, the filaments were bent 90 degrees, and the stimulation time was 5 s. The initial stimulation intensity was 2g, and the stimulation intensity gradually increased. Each intensity was repeated 5 times with an interval of 5 minutes. If the positive reaction is more than 3 times, the intensity is the upper limit intensity, and the positive reaction rate of this intensity (number of positive reactions/5) is calculated as the upper limit intensity positive rate. The upper intensity is the lower limit intensity, and the positive reaction rate of this intensity is calculated, that is, the lower limit intensity positive rate.

According to the 50% positive reaction value PMWT formula: upper limit intensity - [(upper limit intensity - lower limit intensity) ÷ (upper limit intensity positive rate - lower limit intensity positive rate)] × (upper limit intensity positive rate - 50%)

The PMWT value was the mechanical withdrawal reflex threshold of rats. The mechanical paw withdrawal reflex threshold of each rat was measured 2 hours before operation (before the establishment of the incision pain model) as the basic mechanical pain threshold. The change of mechanical withdrawal reflex threshold was measured at 96h.

Table 3 Comparison of the mean values of mechanical withdrawal reflex thresholds in the drug efficacy test in rats

It can be seen from Table 3 that there is no incision before operation, so the effect of pain perception in rats is not obvious, which is reflected in a higher threshold; the single injection of ropivacaine hydrochloride solution group can only maintain the efficacy of 4-10h. Compared with the injection group of ropivacaine hydrochloride solution, the long-acting ropivacaine solution for injection of the present application can maintain the anesthetic effect for more than 96 hours.

2 Pharmacodynamic experiment of regional blockade in rats

The recommended dose of ropivacaine for regional block (such as peripheral nerve block and infiltration anesthesia) is 7.5-225mg/person. Assuming that the reference human clinical dose is 225mg/person, the dose converted into rats based on the body surface area method is about 4mg/rat. According to the concentration of ropivacaine long-acting solution for injection adopted in Example 1 in this experiment, the concentration of ropivacaine for injection was 48 mg/mL, and the dosage of the rat was determined to be 4.8 mg/rat (that is, the dosage was 0.1 mL/rat).

6 rats (half male and half female) were injected subcutaneously on one thigh respectively, and the ropivacaine long-acting solution preparation of Example 1 was administered; 0.5h, 1h, 1.5h, 2h, 3h, 4h after injection , 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 132h, 144h, 156h, 168h, use the silver needle to stimulate the injection site (about 1cm away from the injection point), and the observation record is large. Whether the mouse has a stinging response. At the same time, use a silver needle to stimulate the untreated thigh to observe whether the rat has a tingling reaction as a control. If all rats showed stinging response at three consecutive time points, the experiment was over, and the stinging response was no longer observed at subsequent time points. The experimental results of the analgesic efficacy at the injection site in rats are shown in Table 4.

Table 4

Note: "√" indicates analgesic effect; "×" indicates no analgesic effect.

As can be seen from the results in Table 4, the regional blocking effect of the ropivacaine long-acting solution preparation for injection of the present application can reach 72 hours, or even longer, indicating that the long-acting ropivacaine solution preparation for injection of the present application Anesthesia effect can be achieved for more than 72h.

Test Example 3 Influencing factor test

The ropivacaine long-acting solution preparations for injection prepared in Examples 1-11 were packaged in carton boxes, placed in a constant temperature box with a temperature of 60°C, placed in a 90% RH high-humidity environment, and placed under light conditions for 10 days; Example 1 The long-acting solution preparation of ropivacaine for injection prepared by -11 is packaged in a carton and stored in a constant temperature and humidity box with a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 3 months.

Conclusion: The example products prepared by the present invention are respectively placed in a high temperature of 60 degrees, high humidity of 90% RH, and light; placed in a constant temperature and humidity box with a temperature of 40 ° C ± 2 ° C and a relative humidity of 75% ± 5%; related The substance determination results are basically consistent with the pre-experiment analysis results, the product impurities have no obvious change, and the product quality is stable, indicating that the preparations of the present invention can maintain good stability.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection of the present invention. within the range.

Claims

A ropivacaine long-acting solution preparation for injection, characterized in that it comprises an active ingredient, a sustained-release carrier and an alcohol solvent;

Wherein, the active ingredient includes at least one of ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate;

The sustained-release carrier includes sucrose acetate isobutyrate;

The alcohol solvent includes at least one of benzyl alcohol, ethanol, propylene glycol, polyethylene glycol, glycerol, chlorobutanol, 1,3-butanediol and isopropylene glycol.
The long-acting solution formulation of ropivacaine for injection according to claim 1, wherein the alcoholic solvent comprises at least one of benzyl alcohol and ethanol.
The long-acting solution formulation of ropivacaine for injection according to claim 2, wherein the alcoholic solvent comprises benzyl alcohol and ethanol, and the mass ratio of the benzyl alcohol to ethanol is 0.8:1 to 5:1 .
The long-acting solution formulation of ropivacaine for injection according to claim 1, wherein the sustained-release carrier further comprises glycerides, wherein the glycerides comprise medium-chain triglycerides, glycerol tricaprylate glycerol dioleate, glyceryl triacetate, glycerol monoacetate, glycerol monooleate, glycerol monolinoleate, glyceryl monolaurate, glyceryl dipalmitate, glyceryl monodecenoate at least one of.
The long-acting solution formulation of ropivacaine for injection according to claim 4, wherein the weight ratio of the sucrose acetate isobutyrate to the glyceride is 20:1 to 5:1.
The ropivacaine long-acting solution preparation for injection according to any one of claims 1-5, characterized in that, by mass percentage, the ropivacaine long-acting solution preparation for injection comprises: an active ingredient 2.5-20%, slow-release carrier 40-87.5%, alcoholic solvent 10-40%.
The long-acting solution preparation of ropivacaine for injection according to claim 6, characterized in that, by mass percentage, the long-acting solution preparation of ropivacaine for injection comprises: The release carrier is 60-80%, and the alcohol solvent is 10-30%.
The long-acting solution formulation of ropivacaine for injection according to claim 6, wherein when the active ingredient is ropivacaine, the sustained-release carrier comprises sucrose acetate isobutyrate and medium chain triglyceride When the ester and the alcoholic solvent include benzyl alcohol and ethanol, the mass ratio of the sucrose acetate isobutyrate to the medium-chain triglyceride is 20:1 to 5:1, and the mass ratio of the benzyl alcohol to the ethanol is 0.8: 1 to 5:1; or

The active ingredient is ropivacaine, the sustained-release carrier is sucrose acetate isobutyrate, and the alcohol solvent is benzyl alcohol.
The ropivacaine long-acting solution preparation for injection according to claim 1, wherein the single administration of the ropivacaine long-acting solution preparation for injection produces an analgesic effect exceeding 72 hours.
A method for preparing the ropivacaine long-acting solution preparation for injection according to any one of claims 1 to 9, characterized in that, after mixing a sustained-release carrier, an alcoholic solvent and an active ingredient, potting, sterilizing bacteria can be obtained;

Preferably, the specific steps of the preparation method are as follows:

1) Add the active ingredient into the alcohol solvent, seal it and perform mechanical stirring at a speed of 100-400rpm for 10-30min;

2) adding the sustained-release carrier to the solution obtained in the above step 1), and performing mechanical stirring at a speed of 100-400 rpm for 10-30 min to form a uniform medicinal liquid;

3) Pass the medicinal solution obtained in step 2) through a sterilizing filter membrane, under nitrogen protection, encapsulate it in a packaging material, and sterilize it by autoclaving at 120-130° C. for 15-30 minutes.