TW202237108A - Ropivacaine long-acting solution preparation for injection, and preparation method therefor - Google Patents

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

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

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, and induce various complications. If acute postoperative pain cannot be controlled in the initial state, it may develop into chronic pain that lasts for half a year to several years. Effective postoperative analgesia can provide more favorable conditions for the rehabilitation of surgical patients. Generally speaking, postoperative pain can last for 48 to 72 hours, and the pain during this period is the most difficult to control. Local application of anesthetics is the most direct postoperative analgesic method, but conventional clinical injections can only provide analgesic effect for less than 7 hours. The development of long-acting local anesthetics has become a research hotspot today. As a result, the U.S. FDA approved ExparelTM, a long-acting sustained-release suspension of bupivacaine liposomes developed by Pacira Pharmaceuticals Co., Ltd., for direct injection into the surgical site to help control postoperative pain. ExparelTM adopts the novel DepoFoam technology, which is a kind of 1.3% bupivacaine multilayered liposome, which has been gradually applied in the foreign medical market. A single administration can produce an analgesic effect of up to 72 hours, and the effect is good.

Ropivacaine is the first pure L-body long-acting amide local anesthetic developed by AstraZeneca Pharmaceutical Co., Ltd., Sweden. It was first launched in the Netherlands in 1996. It was approved by FDA in the United States on September 24 of the same year. Like other 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 fiber, and has dual effects of anesthesia and analgesia. Large doses can produce surgical anesthesia, and small doses can produce sensory block. Analgesia (analgesia) with limited non-progressive motor block only. At low concentrations, ropivacaine has sensory and motor separation blocking effects, and is commonly used for surgical anesthesia and epidural anesthesia, including cesarean section, regional block acute pain control continuous epidural infusion or intermittent single administration, such as After or labor pain, regional block.

It is worth noting that at the same concentration and dose, ropivacaine has less cardiovascular and central nervous system toxicity than bupivacaine. However, because ropivacaine is insoluble above pH 6.0, the currently marketed ropivacaine preparations 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 within 10 to 20 minutes, but the terminal half-life of ropivacaine is only 1.8 hours, and the drug effect can only last for 2 to 6 hours, which requires continuous injection to obtain Satisfactory analgesic effect. However, repeated single injections should consider the risk of reaching plasma toxic concentrations or inducing local neurological damage. In order to reduce the number of repeated single doses, reduce toxicity, and improve patient compliance, the development of ropivacaine long-acting solution preparations 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 thermosensitive gel of ropivacaine hydrochloride. The ingredients include: the main drug, PLGA-PEG-PLGA copolymer and solvent. It is liquid at normal temperature and turns into a solid gel when the temperature reaches about 36 °C. , the release of drug in vitro is ≤35-45% in 12 hours, ≥65%-75% in 48 hours, and ≥80% in 72 hours. The results of heat pain threshold test in rats show that it can be effectively sustained release for 48 hours.

The existing liposome technology and PLGA microsphere technology have very low drug loading and complex processes, difficult sample quality control, unsuitable for terminal sterilization, unstable properties and other technical difficulties, which greatly increase the development cost and cost of long-acting ropivacaine preparations. 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 the in vitro release test showed a sustained release effect of more than 72 hours, but its rat blood concentration and rat nerve block continued experiments showed that its drug effect can only last for 18 hours, still can not Satisfy the effect of local continuous anesthesia or postoperative analgesia for more than 72 hours.

Therefore, there is an urgent need 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.

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

In order to achieve the above object, the present invention adopts the following technical solutions:

In one aspect, the present invention provides a long-acting solution preparation of ropivacaine for injection, which includes an active ingredient, a slow-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 system toxicity than bupivacaine, and the local infiltration anesthesia duration is 2-3 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 other glycerides; preferably, the sucrose acetate isobutyrate and the The weight ratio of the glycerides is 20:1 to 5:1, preferably 13:1, 6:1, 5:1 or 9:1; further, the glycerides include medium-chain triglycerides, Glyceryl Tricaprylate, Glyceryl Dioleate, Glyceryl Triacetate, Glyceryl Monoacetate, Glyceryl Monooleate, Glyceryl Monolinoleate, Glyceryl Monolaurate, Glyceryl Dipalmitate, Monodecenoic Acid At least one of glycerides, etc.; more preferably, the slow-release carrier is a composition composed of sucrose acetate isobutyrate and medium-chain triglycerides in a mass ratio of 20:1 to 5:1, preferably 13: 1, 6:1, 5:1 or 9:1.

Alcohol solvents described in this application include benzyl alcohol, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol 200~600, such as PEG200, PEG400, PEG600), glycerol (glycerin), tertiary trichloro At least one of butanol, 1,3-butanediol and mesityl glycol. The inventor found in research that alcoholic solvents have good solubility to ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate as active ingredients, which is conducive to improving the efficacy of the drug, especially in lower Higher drug concentration at lower volumes. The sustained-release carrier of the present invention has a high viscosity and requires relatively high sterilization requirements during subsequent use, and the use of alcohol solvents is beneficial to improve the stability and efficacy of the preparation. Preferably, at least one of benzyl alcohol and ethanol is included in the alcohol solvent, and the inventors have 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, The stability of the preparation can be improved.

Furthermore, the inventors also found that the slow-release carrier used in the present invention has good safety, is a biodegradable in-situ gel matrix material, and is a small molecular substance that 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 this application, it will form a solution with a viscosity similar to that of vegetable oil, which is easy for subcutaneous and intramuscular injection. It is even more surprising that after the sustained-release carrier of the present application is dissolved in an alcohol solvent, the obtained ropivacaine long-acting solution preparation for injection of the present application can quickly release the drug in the early stage, which is conducive to the purpose of rapid anesthesia. The addition of the solvent can 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 obtain both a short-term onset of action and a long-lasting analgesic effect of a single administration.

Furthermore, the inventors also found that when the 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. Wherein, it is preferred that the mass ratio between benzyl alcohol and ethanol is 0.8:1～5:1, preferably 3:1～5:1, such as 4:5, 5:6, 4:1, 5:1 or 3: 1. 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.

Furthermore, the inventors also found that when the slow-release carrier contains glyceride, 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 long-acting solution preparation of ropivacaine for injection includes 2.5-20% of the active ingredient, 40-87.5% of the slow-release carrier, and 10-40% of the alcohol solvent; preferably, the active Composition 4-10%, slow-release carrier 60-80%, alcohol solvent 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 sustained-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%.

Further, in terms of mass percentage, the long-acting solution preparation of ropivacaine for injection includes 3-20% of ropivacaine, 40-80% of sucrose acetate isobutyrate, and 10-40% of benzyl alcohol. More preferably, 3-10% of ropivacaine, 55-80% of sucrose acetate isobutyrate, and 10-40% of benzyl alcohol. Further preferably, ropivacaine is 3-10%, sucrose acetate isobutyrate is 55-70%, and benzyl alcohol is 20-35%. 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 ropivacaine long-acting solution preparation for injection includes 4-10% of ropivacaine, 60-80% of the composition of sucrose acetate isobutyrate and medium-chain triglycerides , the combined solvent of benzyl alcohol and ethanol is 10~30%; wherein, the mass ratio of sucrose acetate isobutyrate to medium chain triglyceride is 20:1~5:1, and the mass ratio of benzyl alcohol to ethanol is 0.8:1 ~5:1. Further, in terms of mass percentage, the ropivacaine content of the long-acting solution preparation of ropivacaine for injection is preferably 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 triglycerides 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 to medium chain triglycerides is 13:1, 6:1, 5:1 or 9: 1. The mass ratio of benzyl alcohol to ethanol is 5:6 or 3:1.

"Medium-chain triglycerides" in this application refers to a mixture of saturated triglycerides with a caprylic and capric glyceride content of not less than 95%, which can be obtained commercially.

Further, a single administration of the ropivacaine long-acting solution preparation for injection produces an analgesic effect of more than 72 hours. Further preferably, a single administration of the long-acting solution preparation of ropivacaine for injection produces an analgesic effect of more than or as long as 96 hours.

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

Further, the preparation steps are as follows:

1) Dissolve the active ingredient in an alcoholic solvent;

2) The slow-release carrier is dissolved in the mixed solution of the active ingredient and alcohol solvent to obtain a uniform drug solution; In the mixed solution of alcohol solvent; the preheating of the slow-release carrier is conducive to its faster dissolution;

3) The homogeneous medicinal solution is packaged and then sterilized 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, and mechanically stir at a speed of 100-400 rpm for 10-30 min in a closed container;

2) Add the slow-release carrier to the solution obtained in the above step 1), and mechanically stir at a speed of 100-400 rpm for 10-30 min to form a uniform drug solution;

3) Pass the medicinal solution obtained in step 2) through a sterilizing filter membrane, under nitrogen protection, potting and sealing in packaging materials, and autoclaving at 120-130°C for 15-30 minutes to obtain the product.

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 long-acting solution preparation of ropivacaine for injection with larger drug loading, less irritation and long-lasting injection sustained-release effect, compared with the existing ropivacaine hydrochloride injection or ropivacaine mesylate Compared with the injection, the slow-release feature is obvious, and the long-acting solution preparation of ropivacaine for injection prepared by the present invention can continuously exert the effect of local anesthesia or postoperative analgesia for more than 72 h (the embodiment of the present invention detects that it is 96 h Still have local anesthesia or postoperative analgesic effect);

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, the preparation process is greatly simplified, and the cost is low , and can be terminally sterilized in ampoule packaging, avoiding the use of aseptic technology, the solution is stable, and can be stored for a long time to ensure product effectiveness and safety.

Compared with the existing ropivacaine temperature-sensitive gel, the long-acting solution preparation of ropivacaine for injection prepared by the present invention is not sensitive to temperature, and can avoid quality changes caused by environmental temperature changes during storage and use; in addition , The quality control of polyethylene glycol derivatized polylactic acid glycolic acid polymers required for the preparation of temperature-sensitive gels is complex and costly, and the temperature-sensitive gel preparations have high viscosity and need to be produced by aseptic processes.

The ropivacaine long-acting solution preparation for injection provided by the present invention is in the state of a common 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 slow-release The viscosity of the carrier system increases sharply, forming a drug reservoir with controllable viscosity at the injection site, which can reduce the pain of injection without causing severe irritation to the site of administration, and at the same time release slowly in the local tissue, resulting in local continuous anesthesia or surgery for more than 72 hours. Post-analgesic effect.

The long-acting solution preparation of ropivacaine for injection provided by the present invention is colorless and clear, does not appear sudden release phenomenon, has a more stable drug release effect, fast anesthesia and slow release at the same time, and has a longer sustained release effect, which increases the compliance of patients with medication It also reduces the side effects caused by repeated administration. In addition, the ropivacaine long-acting solution preparation for injection of the present invention has related substances similar to those of the commercially available ropivacaine hydrochloride preparation under the stability test conditions.

In order to make the object, technical solution, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and examples. Apparently, the described embodiments are only some of the embodiments of the present invention, but not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments in this application belong to the protection scope of this application.

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

Example 1

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

The preparation method is provided as follows:

Ropivacaine is crossed 80 mesh sieves, for subsequent use;

Add 4 g of ropivacaine into 24 g of injection-grade benzyl alcohol, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121 °C for 20 minutes to complete.

Example 2

The long-acting solution preparation of ropivacaine for injection includes the following components:

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

The preparation method is provided as follows:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 3.4 g of ropivacaine to 10 g of injection-grade benzyl alcohol and 12 g of ethanol, and mechanically stir at a speed of 300 rpm for 20 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving 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:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 4 g of ropivacaine into 24 g of injection-grade benzyl alcohol, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

Example 4

The ropivacaine long-acting solution preparation for injection comprises 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:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 4 g of ropivacaine into 24 g of injection-grade benzyl alcohol, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

Example 5

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

The preparation method is provided as follows:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 4 g of ropivacaine into 12 g of injection-grade benzyl alcohol and 4 g of ethanol mixed solvent, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

Preheat 55 g of sucrose acetate isobutyrate in a water bath at 50 °C for 30 min, add 11 g of medium-chain triglycerides to the above ropivacaine solution, and mechanically stir at a speed of 100-400 rpm for 10-30 min Form a uniform liquid;

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

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:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 2 g of ropivacaine into 24 g of injection-grade benzyl alcohol, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

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:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 15 g of ropivacaine into 30 g of injection-grade benzyl alcohol, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

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

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

Example 8

Ropivacaine long-acting solution preparation for injection, including the following components: 8.3 g ropivacaine hydrochloride, 72 g sucrose acetate isobutyrate, 8 g glycerol monoacetate, 7.5 g benzyl alcohol for injection, 2.5 g ethanol g.

The preparation method is provided as follows:

The ropivacaine hydrochloride is passed through an 80 mesh sieve for subsequent use.

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

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

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

Example 9

The long-acting solution preparation of ropivacaine for injection includes 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:

Ropivacaine mesylate is passed through an 80 mesh sieve for subsequent use.

Add 8.3 g of ropivacaine mesylate into 10 g of ethanol solvent, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

Add 72 g of sucrose acetate isobutyrate to the above-mentioned ropivacaine mesylate solution after preheating in a 50 °C water bath for 30 min and 8 g of medium-chain triglycerides, and mechanically stir at a speed of 100-400 rpm for 10-30 min. min to form a uniform drug solution;

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

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 glycerol.

The preparation method is provided as follows:

Ropivacaine mesylate is passed through an 80 mesh sieve for subsequent use.

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

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

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

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:

The ropivacaine is passed through an 80-mesh sieve for subsequent use.

Add 5 g of ropivacaine into 24 g of polyethylene glycol 600, and mechanically stir at a speed of 100-400 rpm for 10-30 min until completely dissolved;

Preheat 50 g sucrose acetate isobutyrate in a water bath at 50 °C for 30 min, add 8 g medium-chain triglycerides to the above ropivacaine solution, and stir mechanically at a speed of 100-400 rpm for 10-30 min to form Uniform medicinal solution;

After the content of the homogeneous drug solution is qualified, the obtained drug solution is filled and sealed in a 2 mL ampoule bottle under nitrogen protection, and sterilized by autoclaving at 121°C for 20 minutes.

Comparative example 1 preparation of ropivacaine hydrochloride temperature-sensitive gel preparation for injection

Ropivacaine hydrochloride 0.15 g, Pluronic F127 2.3 g, Pluronic F68 0.5 g, water for injection 10 mL

The above pharmaceutical composition will be used as the content, and the content will be sealed in the ampoule bottle.

The preparation method is as follows:

The ropivacaine hydrochloride is passed through an 80 mesh sieve for subsequent use. Add 2.3 g of Pluronic F127 and 0.5 g of Pluronic F68 into 10 ml of water for injection, stir in a water bath at 4 °C for 10-30 min until completely dissolved; add 0.15 g of ropivacaine hydrochloride into the above Pluronic solution, and mechanically Stir for 10 min to form a uniform medicinal solution; after the content of the intermediate is qualified, the obtained medicinal solution is filled and sealed in a 2ml ampoule bottle under the protection of nitrogen.

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 was used as the content, the content was freeze-dried at -40°C for 12 h, and packaged in a vial.

The preparation method is as follows:

The ropivacaine is passed through an 80-mesh sieve for subsequent use. The ropivacaine was micronized with a jet mill, and the D90 was less than 5 μm. Take 0.25 g of Tween, 1.2 g of mannitol, and 0.25 g of croscarmellose sodium into 25 ml of water, and stir in a water bath at 50 °C for 10-20 min until completely dissolved; add 0.05 g of micronized ropivacaine into the above mannose In the alcohol solution, stir mechanically for 10 min to form a suspension; after the content of the intermediate is qualified, it is divided into 10 ml vials, freeze-dried at -40 ℃ for 12 hours, and then capped with a rubber stopper.

Test Example 1 Release Determination

Chromatographic conditions

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

Mobile phase: 25mmol/L potassium dihydrogen phosphate buffer (pH7.4): acetonitrile (30%: 70%)

Injection volume: 20 μl

Column temperature: 30°C

Detection wavelength: 263 nm

Embodiment Release measures:

Take the ropivacaine long-acting solution preparation for injection described in Examples 1-11 (dose 50 mg), according to the US Pharmacopoeia test method, use 200 mL of normal saline as the dissolution medium, the rotation speed is 10 r/min, and the temperature is ( 37±0.5) ℃, sample 2 ml at 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, and 96 h, filter it with a 0.45 μm microporous membrane immediately, discard the initial filtrate, and perform HPLC analysis. Calculate the cumulative release percentage of the drug. [Table 1] Cumulative release percentage of each embodiment drug ( n =3) Cumulative release percentage (%) 2 hours 4h 6 hours 24h 48h 72h 96h Example 1 6.43±0.49 10.30±0.36 13.17±0.47 23.53±0.57 33.10±0.10 40.10±0.80 45.47±0.83 Example 2 6.13±0.67 8.07±0.38 9.50±0.3 15.67±0.75 21.9±1.22 27.93±0.51 34.07±0.15 Example 3 6.20±0.66 10.93±0.81 14.83±0.99 30.63±2.42 42.43±2.84 53.53±1.16 60.37±2.49 Example 4 7.53±0.12 13.73±0.06 18.83±0.25 39.80±0.20 57.40±1.15 70.17±0.64 78.57±1.37 Example 5 7.42±0.17 11.26±0.69 16.31±0.77 32.19±0.75 46.99±1.10 61.71±0.89 70.74±0.37 Example 7 6.81±0.85 10.58±0.54 15.54±0.44 25.24±0.26 36.58±0.99 45.58±0.73 51.57±0.39 Example 8 6.28±0.63 9.61±0.86 14.35±0.42 28.28±0.78 39.30±2.01 50.33±0.48 58.49±0.57 Example 11 6.76±0.04 11.05±0.24 14.12±0.73 22.19±0.90 32.78±0.57 41.24±0.53 47.31±0.86

As can be seen from Table 1, the application embodiment 1-embodiment 11 within 2 hours, the drug release rate reaches more than 6%, illustrating that the ropivacaine long-acting solution for injection of the application can release the drug quickly; and after 6 hours, The drug showed a gentle and stable release trend, and the cumulative release rate was lower than 80% at 96 hours, indicating that it had sustained release characteristics over 96 hours.

From the comparison of Example 1 and Example 2, it can be seen that when benzyl alcohol and ethanol were used as mixed solvent, the release rate of the ropivacaine long-acting solution preparation for injection was further delayed, and the sustained-release effect was more stable; from As can be seen from Example 1, Example 3 and Example 4, the introduction of glyceride adjuvant can accelerate drug release, and the inventors also found that with the increase of glyceride content, the drug release rate in the early stage is accelerated, but not Cause burst release phenomenon; the result is shown in Figure 1.

According to the above results, it can be seen that the ropivacaine long-acting solution for injection of the present application has the effect of long-acting sustained release. When, can realize the rapid release of medicine and have the sustained release characteristic of exceeding 96 h; Further, the addition of ethanol is conducive to further delaying the release rate of medicine, and the addition of glyceride is conducive to accelerating the early drug release rate; preferably, The ropivacaine long-acting solution for injection of the present application is calculated by mass percentage, and the active ingredient accounts for 2.5-20%, the slow-release carrier accounts for 40-87.5%, and the alcohol solvent accounts for 10-40%; for the purpose of saving medicine and reducing costs More preferably, the ropivacaine long-acting solution preparation for injection comprises: 4-10% active ingredient, 60-80% sustained-release carrier, and 10-30% alcohol solvent in terms of mass percentage.

Comparative ratio release determination:

Add 2 ml of the ropivacaine hydrochloride thermosensitive gel preparation for injection described in Comparative Example 1 into a 10 ml EP tube, and place the EP tube in a constant temperature water bath (37±0.5°C) for 5 min to allow the solution to gel change. Add 5 ml of 37 ℃ normal saline as the release medium, shake in a constant temperature vibration box at 50 r/min, and take out 4 mL of the release medium at 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, and 96 h, respectively. Rehydrate again. Immediately filter the sample with a 0.45 μm microporous membrane, discard the primary filtrate, perform HPLC analysis, and calculate the cumulative release percentage of the drug. Calculate the cumulative release. Take the ropivacaine long-acting dry suspension preparation described in Comparative Example 2, reconstitute it with 3 mL of normal saline, and add it to the dialysis bag. With 200 mL of normal saline as the dissolution medium, the rotation speed was 10 r/min, and the temperature was (37±0.5) °C, and 2 mL of samples were taken at 2 h, 4 h, 6 h, 24 h, 48 h, 72 h, and 96 h. Immediately filter with a 0.45 μm microporous membrane, discard the primary filtrate, perform HPLC analysis, and calculate the cumulative release percentage of the drug. [Table 2] Cumulative release percentage of each comparative drug ( n =3) Sampling time (h) 2 4 6 twenty four 48 72 96 Comparative example 1 10.77±0.38 16.7±1.12 26.37±1.02 66.57±1.06 88.43±0.96 93±2.43 94.33±1.46 Comparative example 2 13.77±1.35 24.83±3.29 32.67±4.66 61.53±5.37 86.57±11.31 99.9±6.7 102.1±2.45

It can be seen from Table 2 that although the temperature-sensitive gel preparation of ropivacaine hydrochloride for injection in Comparative Example 1 has temperature-sensitive sustained-release characteristics, it released more than 85% within 48 hours. Although the long-acting dry suspension preparation of ropivacaine for injection in Comparative Example 2 has sustained-release characteristics, the release rate exceeds 85% within 48 hours. Neither of them has long-term release characteristics of more than 72 h.

Test Example 2 Drug efficacy test in rats

1. Determination of Mechanical Paw Withdrawal Reflex Threshold

Preparation of the incision pain model: select 6 SD rats, weighing 200-250 g, fast for 6 hours and drink for 1 hour before the operation, put the rats into a cotton ball soaked with about 0.3 mL of isoflurane liquid, Put a cover in a transparent glass cup with a volume of 1 L, observe the disappearance of consciousness, and disinfect the sole of the left rear foot of the rat with povidone iodine, and make an incision about 1 cm long from the proximal 0.5 cm of the sole to the toe according to the Brennan method , cut the skin, use ophthalmic tweezers to pick up the plantar muscles and cut them longitudinally, but keep the start and end of the muscles and their attachments intact. After pressing to stop the bleeding, the skin was sutured with a fine needle for 2 stitches, and groups A and B were injected with corresponding drugs in the incision at the sutured area, among which,

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 (based on ropivacaine);

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

The whole operation took about 5 minutes and was completed by the same person. The postoperative wound was disinfected with povidone iodine and a small amount of erythromycin ointment was applied. The rats were fed in a quiet, warm environment avoiding strong light.

Threshold measurement: 8 von Frey fiber rods with different scales (2, 4, 6, 8, 10, 15, 26 g, 64 g) were used to measure mechanical allodynia in rats. On a grid frame made of metal wires 30 cm high from the test bench, several transparent plexiglass boxes of 20 cm × 20 cm × 25 cm were placed on it, and the rats to be tested were put inside to make them adapt to the environment. A period of time, generally controlled at more than 30 minutes. After the rats were quiet, the von-Frey fiber was used to directly stimulate the soles of the rats' feet through the wire grid, so that the filaments were bent 90 degrees, and the stimulation time was 5 s. If the rats lifted their feet or licked their feet, it was considered positive. The initial stimulation intensity was 2 g, and the stimulation intensity was gradually increased, and each intensity was repeated 5 times with an interval of 5 minutes. If the positive reaction is ≥ 3 times, then the strength is the upper limit strength, and the positive reaction rate of this strength (positive reaction times/5) is calculated as the upper limit strength positive rate. The upper intensity is the lower limit intensity, and the positive reaction rate of this intensity is calculated as 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 is the mechanical paw withdrawal threshold of rats. For each rat, the mechanical paw withdrawal reflex threshold was measured 2 hours before operation (before the establishment of the incision pain model) as the basic mechanical pain threshold, and 2 hours, 4 hours, 10 hours, and 24 hours after the operation (after the establishment of the incision pain model). , 48 h, 72 h, 96 h to measure the change of mechanical paw withdrawal reflex threshold. [Table 3] Comparison of average value of mechanical paw withdrawal reflex threshold in rat drug efficacy test Preoperative postoperative Sampling time (h) 2 2 4 10 twenty four 48 72 96 Ropivacaine hydrochloride solution group 34.9 16.7 14.7 11.3 9.4 8.2 7.9 7.4 Example 1 30.4 24.4 23.7 19.3 18.9 17.6 15.8 13.2 Example 2 32.6 25.6 24.9 20.4 20.3 19.6 19.4 18.9 Example 3 33.1 24.3 20.6 20.1 19.3 18.7 18.3 18.2 Example 5 31.6 22.6 22.4 22.1 21.3 20.6 20.3 20.1 Example 6 34.5 21.1 20.7 19.2 18.5 17.8 17.4 16.7 Example 7 30.9 24.9 24.1 23.9 22.8 20.5 20.6 19.9

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

2 Pharmacodynamic experiment of regional blockade in rats

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

Six rats (half male and half male) were subcutaneously injected into one thigh respectively, and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h after injection h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h, 108 h, 120 h, 132 h, 144 h, 156 h, 168 h to stimulate the injection site with silver needles (about 1 cm away from the injection point) place), observe and record whether the rats have a sting reaction. At the same time, silver needles were used to stimulate the non-administered side of the thigh, and it was observed whether the rats had a tingling reaction as a control. If all rats had sting reactions at three consecutive time points, the experiment was over, and the sting reactions were no longer observed at subsequent time points. See Table 4 for the experimental results of the analgesic effect at the injection site in rats. [Table 4] time ( h ) Rat ID 1 2 3 4 5 6 0.5 √ √ √ √ √ √ 1 √ √ √ √ √ √ 1.5 √ √ √ √ √ √ 2 √ √ √ √ √ √ 3 √ √ √ √ √ √ 4 √ √ √ √ √ √ 6 √ √ √ √ √ √ 8 √ √ √ √ √ √ 12 √ √ √ √ √ √ twenty four √ √ √ √ √ √ 36 √ √ √ √ √ √ 48 √ √ √ √ √ √ 60 √ √ √ √ √ √ 72 √ √ √ √ √ √ 84 x √ √ √ √ √ 96 x √ √ √ √ √ 108 x √ x √ √ x 120 x √ x √ √ x 132 x √ x √ x x 144 x √ x √ x x 156 x √ x x x x 168 x x x x x x 180 x x x x x x 192 x x x x x x

Note: "√" means analgesic effect; "×" means 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 in this application can reach 96 hours, even longer, indicating that the ropivacaine long-acting solution preparation for injection of the present application The anesthesia effect can be achieved for more than 96 h.

Test example 3 Influencing factor test

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

Conclusion: The example product and the reference product prepared by the present invention were respectively placed under 60°C high temperature, 90%RH high humidity, and light; placed in a constant temperature and humidity chamber with a temperature of 40°C±2°C and a relative humidity of 75%±5%. Preservation; related substance determination results are basically consistent with the analysis results before the experiment, product impurities have no obvious change, and the product quality is stable, which shows that the preparation of the present invention can maintain good stability.

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

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only the present invention. It is an implementation manner of the invention, and those skilled in the art can also obtain other implementation manners according to these drawings. Fig. 1 The release curve of the ropivacaine long-acting solution preparation for injection in physiological saline of the present application.

Claims (10)

A long-acting solution preparation of ropivacaine for injection, which includes an active ingredient, a slow-release carrier and an alcoholic solvent; Wherein, the active ingredient includes at least one of ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate; The slow-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 mesityl glycol. The long-acting solution preparation of ropivacaine for injection according to claim 1, wherein the alcoholic solvent includes at least one of benzyl alcohol and ethanol. The long-acting solution preparation of ropivacaine for injection according to claim 2, wherein the alcoholic solvent comprises benzyl alcohol and ethanol, and the mass ratio of benzyl alcohol to ethanol is 0.8:1-5:1. Ropivacaine long-acting solution preparation for injection as described in Claim 1, wherein the slow-release carrier also includes glycerides, wherein the glycerides include medium-chain triglycerides, tricaprylycerin, At least one of glyceryl dioleate, glyceryl triacetate, glyceryl monoacetate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl dipalmitate, glyceryl monodecenoate A sort of. The long-acting solution preparation of ropivacaine for injection as described in Claim 4, wherein the weight ratio of the sucrose acetate isobutyrate to the glyceride is 20:1-5:1. The ropivacaine long-acting solution preparation for injection according to any one of claims 1 to 5, wherein, in terms of mass percentage, the ropivacaine long-acting solution preparation for injection comprises: active ingredients 2.5- 20%, slow release carrier 40~87.5%, alcohol solvent 10~40%. The long-acting solution preparation of ropivacaine for injection as described in Claim 6, wherein, in terms of mass percentage, the long-acting solution preparation of ropivacaine for injection comprises: active ingredient 4-10%, slow-release carrier 60~80%, alcohol solvent 10~30%. Ropivacaine long-acting solution preparation for injection as described in claim item 6, wherein, when the active ingredient is ropivacaine, the slow-release carrier includes sucrose acetate isobutyrate and medium-chain triglycerides, alcohols When the solvent includes benzyl alcohol and ethanol, the mass ratio of the sucrose acetate isobutyrate to medium-chain triglycerides is 20:1 to 5:1, and the mass ratio of benzyl alcohol to ethanol is 0.8:1 to 5:1; or The active ingredient is ropivacaine, the slow-release carrier is sucrose acetate isobutyrate, and the alcohol solvent is benzyl alcohol. The long-acting solution preparation of ropivacaine for injection according to Claim 1, wherein a single administration of the long-acting solution preparation of ropivacaine for injection produces an analgesic effect of more than 72 hours. A method for preparing a long-acting solution preparation of ropivacaine for injection as described in any one of claims 1 to 9, wherein, after mixing the slow-release carrier, alcohol solvent and active ingredient, potting and sterilizing to obtain ; Preferably, the specific steps of the preparation method are as follows: 1) Add the active ingredient into the alcohol solvent, and mechanically stir at a speed of 100-400 rpm for 10-30 min in a closed container; 2) Add the slow-release carrier to the solution obtained in the above step 1), and mechanically stir at a speed of 100-400 rpm for 10-30 min to form a uniform drug solution; 3) Pass the medicinal solution obtained in step 2) through a sterilizing filter membrane, under nitrogen protection, potting and sealing in packaging materials, and autoclaving at 120-130°C for 15-30 minutes to obtain the product.

Images