CN115068414B

CN115068414B - Ropivacaine long-acting solution preparation for injection and preparation method thereof

Info

Publication number: CN115068414B
Application number: CN202110603696.7A
Authority: CN
Inventors: 易木林
Original assignee: Hunan Huize Bio Pharmaceutical Co ltd
Current assignee: Hunan Huize Bio Pharmaceutical Co ltd
Priority date: 2021-03-16
Filing date: 2021-05-31
Publication date: 2023-07-21
Anticipated expiration: 2041-05-31
Also published as: TW202237108A; WO2022193975A1; CN115068414A

Abstract

The invention belongs to the technical field of controlled release administration, and discloses a ropivacaine long-acting solution preparation for injection and a preparation method thereof. The ropivacaine long-acting solution preparation for injection provided by the invention is easy to prepare, store and use for injection. Compared with ropivacaine hydrochloride or ropivacaine mesylate injection, the active ingredient is released slowly and has no burst release phenomenon, can take effect in a short time, can generate local continuous anesthesia or postoperative analgesic effect for more than 72 hours after single administration, can reduce the repeated single administration times, reduce toxicity and improve the compliance of patients. In addition, the preparation process of the long-acting solution preparation is simple, ampoule bottle packaging terminal sterilization can be adopted, a sterile process is avoided, the solution property is stable, and the long-acting solution preparation can be stored for a long time.

Description

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

The present application claims priority from the chinese patent office, application number 202110280601.2, entitled "ropivacaine long-acting solution formulation for injection and method of preparing same" filed on day 3 and 16 of 2021, the entire contents of which are incorporated herein by reference.

Technical Field

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

Background

Postoperative pain is a complex response to tissue damage during surgery. It includes pain directly associated with surgery and pain associated with central nervous system allergies. Postoperative pain can lead to increased burden on the cardiovascular system, reduced lung compliance, ventilation and blood oxygenation, etc., thereby inducing a variety of complications. If the postoperative acute pain cannot be controlled in the initial state, the postoperative acute pain can also develop into chronic pain lasting from half a year to years, and effective postoperative pain relief can provide more favorable conditions for rehabilitation of a patient in operation. Generally, postoperative pain can last for 48-72 hours, and pain during this period is the most difficult to control. Local application of narcotics is one of the most direct postoperative analgesic methods, but conventional injections used clinically only provide less than 7 hours of analgesic effect. The development of long-acting local anesthetics is a current research hotspot. Thus, the U.S. FDA approved bupivacaine liposomes extended release suspensions Exparel (TM) developed by Pacira pharmaceutical Co., ltd, for direct injection to the surgical site to help control post-operative pain. Exparel (TM) adopts a novel DepoFoam technology, is a type of bupivacaine multi-layer liposome which encapsulates 1.3%, is gradually applied to the overseas medical market, and can produce an analgesic effect for 72 hours after single administration, and has good effect.

Ropivacaine is the first pure levorotatory long-acting amide local anesthetic developed by the company of aslican pharmaceutical, sweden, and was first marketed in the netherlands in 1996, and was approved by the FDA in the united states for 24 days as other local anesthetics, which has the dual effects of anesthesia and analgesia by blocking sodium ion from flowing into nerve fiber cell membranes to reversibly block impulse conduction along nerve fibers, and can produce surgical anesthesia at large doses, and sensory block (analgesia) with only limited non-progressive motor nerve block at small doses. Ropivacaine has sensory and motor separation blocking effects at low concentrations, and is commonly used in surgical anesthesia for epidural anesthesia, including caesarean section, regional blocking acute pain control with continuous epidural infusion or intermittent single use, such as postoperative or childbirth pain, regional blocking.

Notably, ropivacaine has less cardiovascular and central neurotoxicity than bupivacaine at the same concentration and dose. However, as ropivacaine is indissoluble at pH above 6.0, the ropivacaine preparations currently marketed at home and abroad are mainly ropivacaine hydrochloride or mesylate injections 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 1.8 hours, the drug effect can last for 2-6 hours, and satisfactory analgesic effect can be obtained by continuous injection administration. However, repeated single injections should be considered to reach plasma toxic concentrations or to induce the risk of local nerve damage. In order to reduce the repeated single administration frequency, reduce toxicity and improve patient compliance, the research and development of the ropivacaine long-acting solution preparation capable of providing 72-hour local continuous anesthesia or postoperative analgesic efficacy has important clinical application value and is also a medical urgent problem to be solved.

An injectable ropivacaine hydrochloride temperature-sensitive gel is disclosed in patent application CN104606129A, and comprises the following components: the main medicine, PLGA-PEG-PLGA copolymer and solvent are liquid at normal temperature, and when the temperature reaches 36 ℃, the main medicine is converted into solid gel, the medicine is released in vitro for 12 hours to be less than or equal to 35-45%, the release for 48 hours to be more than or equal to 65-75%, and the release for 72 hours to be more than or equal to 80%. The test result of the rat thermal pain threshold shows that the sustained release can be effectively carried out for 48 hours.

The existing liposome technology and PLGA microsphere technology have very low drug loading, complex technology, difficult control of sample quality, and are not suitable for terminal sterilization, unstable properties and other technical difficulties, so that the development cost and difficulty of the ropivacaine long-acting preparation are greatly increased.

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), which showed sustained release effects for more than 72 hours in an in vitro release experiment, but their rat plasma concentrations and rat nerve block sustained experiments showed that their efficacy was only 18 hours in duration and still failed to meet the efficacy of local sustained anesthesia or postoperative analgesia for more than 72 hours.

Therefore, there is an urgent need to develop a long-acting formulation of ropivacaine to achieve long-term local continuous anesthesia or postoperative analgesia efficacy with a single administration, and to reduce the frequency of repeated single administrations.

Disclosure of Invention

In order to solve the technical problems, the invention aims to provide a ropivacaine long-acting solution preparation for injection and a preparation method thereof, and the ropivacaine long-acting solution preparation for injection is prepared from ropivacaine, a slow-release carrier and an alcohol solvent, so that the ropivacaine long-acting solution preparation for injection can play a short-term role, can generate local continuous anesthesia or postoperative analgesic efficacy exceeding 72 hours after single administration, can reduce the repeated times of single administration, reduce toxicity and improve patient compliance.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

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

Wherein the active ingredient comprises at least one of ropivacaine, ropivacaine hydrochloride or ropivacaine mesylate, preferably ropivacaine. Under the same concentration and dosage, ropivacaine has smaller cardiovascular and central nervous toxicity than bupivacaine, and the local infiltration anesthesia time is 2-3 times longer than the bupivacaine with the same concentration.

The slow release carrier comprises sucrose acetate isobutyrate; in some embodiments, the slow release carrier comprises sucrose acetate isobutyrate and other glycerides; preferably, the weight ratio of the sucrose acetate isobutyrate to the glycerate is 20:1-5:1; still further, the glycerides include at least one of medium chain triglycerides, tricaprylin, dioleate, triacetin, monoacetate, monooleate, monolinoleate, monolaurate, dipalmitate, monodecylate, and the like; more preferably, the slow release carrier is a composition composed of sucrose acetate isobutyrate and medium chain triglyceride in a mass ratio of 20:1-5:1.

The alcohol solvent described herein includes at least one of benzyl alcohol, ethanol, propylene glycol, polyethylene glycol (preferably polyethylene glycol 200 to 600, such as PEG200, PEG400, PEG 600), glycerol (glycerin), chlorobutanol, 1, 3-butanediol, and isopropylene glycol. The inventor finds that the alcohol solvent has good solubility on the ropivacaine serving as an active ingredient, the ropivacaine hydrochloride or the ropivacaine mesylate, is beneficial to improving the effect of the drug, and particularly has higher drug concentration under lower volume. The slow-release carrier has high viscosity, and has high sterilization requirement in the subsequent use process, and the stability and the drug effect of the preparation are improved by adopting an alcohol solvent. Preferably, the alcohol solvent comprises at least one of benzyl alcohol and ethanol, and the inventor finds that the benzyl alcohol has weak anesthetic effect, which is beneficial to improving the anesthetic effect of the medicine to a certain extent; in addition, benzyl alcohol has antiseptic effect, and can improve stability of the preparation.

Furthermore, the inventor also finds that the sustained-release carrier adopted by the invention has good safety, belongs to biodegradable in-situ gel matrix materials, belongs to small molecular substances, is not crystallized, but exists in a high-viscosity and hydrophobic liquid form, and can form a solution with the viscosity similar to that of vegetable oil after being dissolved by a small amount of organic solvent (about 15% -30%), in particular to an alcohol solvent adopted by the application, thus being easy for subcutaneous and intramuscular injection. More unexpectedly, after the sustained release carrier is dissolved by the alcohol solvent, the obtained ropivacaine long-acting solution preparation for injection can quickly release the drug at the early stage, is favorable for the purpose of quick anesthesia, and the release speed of the drug at the later stage can be delayed by adding the alcohol solvent, so that the ropivacaine long-acting solution preparation for injection can obtain the effect of taking short-term effect and durable analgesic effect of single administration into consideration.

Furthermore, the inventor also discovers that when a combined solvent of benzyl alcohol and ethanol is adopted, the release rate of the medicine can be further delayed, and the slow release effect is more obvious. Wherein, the mass ratio of benzyl alcohol to ethanol is preferably 0.8:1-5:1, and is preferably 3:1-5:1. Further, the ropivacaine long-acting solution preparation for injection is in a dosage range of 50-500 mg, preferably 50-200 mg, calculated by ropivacaine.

Furthermore, the inventor also found that when the sustained release carrier contains glycerate, the release rate of active ingredients such as ropivacaine can be further accelerated, but the rapid anesthesia is facilitated without causing sudden release.

Further, the ropivacaine long-acting solution preparation for injection comprises, by mass, 2.5-20% of active ingredients, 40-87.5% of slow release carriers and 10-40% of alcohol solvents; preferably, the active ingredient is 4-10%, the slow release carrier is 60-80%, and the alcohol solvent is 10-30%.

Further, according to mass percentage, the ropivacaine long-acting solution preparation for injection comprises 4-10% of ropivacaine, 60-80% of a composition of sucrose acetate isobutyrate and medium chain triglyceride, and 10-30% of a combined solvent of benzyl alcohol and ethanol; wherein, the mass ratio of the sucrose acetate isobutyrate to the medium chain triglyceride is 20:1-5:1, and the mass ratio of the benzyl alcohol to the ethanol is 0.8:1-5:1.

The term "medium chain triglyceride" as used herein means a mixture of saturated triglycerides having a content of caprylic acid glyceride and capric acid glyceride of not less than 95%, which is commercially available.

Further, a single administration of the ropivacaine long-acting solution formulation for injection results in an analgesic efficacy of more than 72 hours. Further preferably, a single administration of the ropivacaine long-acting solution formulation for injection results in an analgesic efficacy exceeding or up to 96 hours.

On the other hand, the invention provides a preparation method of the ropivacaine long-acting solution preparation for injection, which is obtained by mixing a slow-release carrier, an alcohol solvent and active ingredients, then filling and sealing and sterilizing.

Further, the preparation steps are as follows:

1) Dissolving the active ingredient in an alcoholic solvent;

2) Dissolving a slow release carrier in a mixed solution of an active ingredient and an alcohol solvent to obtain uniform liquid medicine; preferably, the slow release carrier is dissolved in a mixed solution of the active ingredient and an alcohol solvent after being preheated to a flowable state at 40-60 ℃; the slow release carrier is preheated to be beneficial to the faster dissolution;

3) Packaging the uniform liquid medicine, and sterilizing to obtain the ropivacaine long-acting solution preparation for injection.

Further, the preparation steps are as follows:

1) Adding the active ingredient into an alcohol solvent, sealing and mechanically stirring at a speed of 100-400 rpm for 10-30 min;

2) Adding the slow release carrier into the solution obtained in the step 1), and mechanically stirring for 10-30min at a speed of 100-400 rpm to form uniform liquid medicine;

3) And (3) passing the liquid medicine obtained in the step (2) through a sterilizing filter membrane, filling and sealing the liquid medicine in a packaging material under the protection of nitrogen, and performing hot press sterilization at 120-130 ℃ for 15-30 minutes to obtain the product.

Further, the packaging material is selected from any one of penicillin bottles, ampoule bottles, fillable syringes and cartridge bottles.

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

compared with the existing ropivacaine hydrochloride injection or ropivacaine mesylate injection, the ropivacaine long-acting solution preparation for injection has obvious slow release characteristics, and the ropivacaine long-acting solution preparation for injection prepared by the invention can continuously exert the effect of local anesthesia or postoperative analgesia for more than 72 hours (the embodiment of the invention still has the effect of local anesthesia or postoperative analgesia in 96 hours);

compared with the traditional ropivacaine polycystic liposome, ropivacaine PLGA microspheres and other microspheres, and ropivacaine nanospheres, the preparation process of the invention adopts the traditional process of mechanical stirring, the preparation process is greatly simplified, the cost is low, and the ampoule bottle packaging terminal sterilization can be adopted, so that the use of a sterile process is avoided, the solution property is stable, the long-term storage can be realized, and the product effectiveness and the safety are ensured.

Compared with the existing ropivacaine temperature-sensitive gel, the ropivacaine long-acting solution preparation for injection prepared by the invention is insensitive to temperature, and can avoid quality change caused by environmental temperature change in the process of residence and use; in addition, the polyethylene glycol derivatization polylactic acid-glycolic acid polymer and the like required for preparing the temperature-sensitive gel have complex quality control, higher cost and high viscosity, and are required to be produced by adopting a sterile process.

The ropivacaine long-acting solution preparation for injection provided by the invention is in a common solution state before injection; the injection site is contacted with local body fluid of a human body after injection, the viscosity of the slow-release carrier system is rapidly increased along with the continuous diffusion of the solution preparation and the continuous permeation of the body fluid, and a drug reservoir with controllable viscosity is formed at the injection site, so that the injection pain can be reduced, the administration site is not severely stimulated, and meanwhile, the drug is slowly released in local tissues, so that the local continuous anesthesia or postoperative pain relieving effect exceeding 72 hours is generated.

The ropivacaine long-acting solution preparation for injection provided by the invention is colorless and clear, does not have sudden release phenomenon, has more stable drug release effect, is slowly released while being rapidly anesthetized, has longer slow release effect, increases the compliance of patients for drug administration, and also reduces side effects caused by repeated drug administration. In addition, the ropivacaine long-acting solution preparation for injection is similar to the commercial ropivacaine hydrochloride preparation under the condition of stability test.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described, and it is apparent that the drawings in the description below are only one embodiment of the present invention, and other embodiments may be obtained according to these drawings by those skilled in the art.

Figure 1 a graph showing the release profile of ropivacaine in physiological saline for a long-acting solution formulation for injection according to the present application.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail below by referring to the accompanying drawings and examples. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments herein fall within the scope of the protection of the present application.

The reagents used in this application are all conventional in the art and are commercially available.

Example 1

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

The preparation method is as follows:

screening ropivacaine through an 80-mesh sieve for later use;

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

preheating 56g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the preheated sucrose acetate isobutyrate into the ropivacaine solution, and mechanically stirring the mixture at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

and after the detection content of the uniform liquid medicine is qualified, filling the obtained liquid medicine in a 2mL ampoule bottle under the protection of nitrogen, and performing hot press sterilization for 20 minutes at 121 ℃ to finish the process.

Example 2

A ropivacaine long-acting solution formulation for injection comprising the following components:

3.4g of ropivacaine, 56g of sucrose acetate isobutyrate, 10g of injection-grade benzyl alcohol and 12g of injection-grade ethanol.

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

Adding 3.4g ropivacaine into 10g injection grade benzyl alcohol and 12g ethanol, sealing, and mechanically stirring at 300rpm for 20min to completely dissolve;

and after the detection content of the uniform liquid medicine is qualified, filling the obtained liquid medicine in a 2mL ampoule bottle under the protection of nitrogen, and performing hot press sterilization at 121 ℃ for 20 minutes.

Example 3

A ropivacaine long-acting solution formulation for injection comprising the following components: 4g of ropivacaine, 52g of sucrose acetate isobutyrate, 4g of medium chain triglyceride and 24g of injection-grade benzyl alcohol.

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

preheating 52g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, then adding the sucrose acetate isobutyrate and 4g of medium chain triglyceride into the ropivacaine solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 4

A ropivacaine long-acting solution formulation for injection comprising the following components: 4g of ropivacaine, 48g of sucrose acetate isobutyrate, 8g of medium chain triglyceride and 24g of injection-grade benzyl alcohol.

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

preheating 48g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the preheated sucrose acetate isobutyrate and 8g of medium chain triglyceride into the ropivacaine solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 5

A ropivacaine long-acting solution formulation for injection comprising the following components: 4g of ropivacaine, 55g of sucrose acetate isobutyrate, 11g of medium chain triglyceride, 12g of injection-grade benzyl alcohol and 4g of injection-grade ethanol.

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

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

preheating 55g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the sucrose acetate isobutyrate and 11g of medium chain triglyceride into the ropivacaine solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 6

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

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

Adding 2g of ropivacaine into 24g of injection-grade benzyl alcohol, and mechanically stirring at a speed of 100-400 rpm for 10-30min in a closed manner until the ropivacaine is completely dissolved;

preheating 50g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the preheated sucrose acetate isobutyrate into the ropivacaine solution, and mechanically stirring the solution for 10 to 30min at a speed of 100 to 400rpm to form uniform liquid medicine;

Example 7

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

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

15g of ropivacaine is added into 30g of injection-grade benzyl alcohol, and is mechanically stirred for 10-30min at a speed of 100-400 rpm in a closed manner until the ropivacaine is completely dissolved;

preheating 35g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the preheated sucrose acetate isobutyrate into the ropivacaine solution, and mechanically stirring the mixture at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 8

A ropivacaine long-acting solution formulation for injection comprising the following components: 8.3g of ropivacaine hydrochloride, 72g of sucrose acetate isobutyrate, 8g of glyceryl monoacetate, 7.5g of injection-grade benzyl alcohol and 2.5g of ethanol.

The preparation method is as follows:

ropivacaine hydrochloride is sieved by a 80-mesh sieve for standby.

8.3g ropivacaine hydrochloride is added into 7.5g injection-grade benzyl alcohol and ethanol 2.5g mixed solvent, and the mixture is sealed and mechanically stirred at the speed of 100 rpm to 400rpm for 10min to 30min until the ropivacaine hydrochloride is completely dissolved;

preheating 72g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the sucrose acetate isobutyrate and 8g of glyceryl monoacetate into the ropivacaine hydrochloride solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

and after the detection content of the uniform liquid medicine is qualified, filling the obtained liquid medicine in a 2mL ampoule bottle under the protection of nitrogen through a sterilizing filter membrane, and performing hot press sterilization at 121 ℃ for 20 minutes.

Example 9

A ropivacaine long-acting solution formulation for injection comprising the following components: 8.3g of ropivacaine mesylate, 72g of sucrose acetate isobutyrate, 8g of medium chain triglyceride and 10g of injection grade ethanol.

The preparation method is as follows:

ropivacaine mesylate was sieved through an 80 mesh screen for use.

8.3g of ropivacaine mesylate is added into 10g of ethanol solvent, and is sealed and mechanically stirred at the speed of 100 rpm to 400rpm for 10min to 30min to be completely dissolved;

preheating 72g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, then adding the sucrose acetate isobutyrate and 8g of medium chain triglyceride into the ropivacaine mesylate solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 10

A ropivacaine long-acting solution formulation for injection comprising the following components: 8.3g of ropivacaine mesylate, 72g of sucrose acetate isobutyrate, 8g of glycerol dioleate and 10g of glycerol.

The preparation method is as follows:

ropivacaine mesylate was sieved through an 80 mesh screen for use.

8.3g of ropivacaine mesylate is added into 10g of glycerol solvent, and is sealed and mechanically stirred at the speed of 100 rpm to 400rpm for 10min to 30min to be completely dissolved;

preheating 72g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the sucrose acetate isobutyrate and 8g of glycerol dioleate into the ropivacaine mesylate solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

Example 11

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

The preparation method is as follows:

ropivacaine is sieved by a 80-mesh sieve for standby.

Adding 5g of ropivacaine into 24g of polyethylene glycol 600, sealing and mechanically stirring at a speed of 100-400 rpm for 10-30min until the ropivacaine is completely dissolved;

preheating 50g of sucrose acetate isobutyrate in a water bath at 50 ℃ for 30min, adding the preheated sucrose acetate isobutyrate and 8g of medium chain triglyceride into the ropivacaine solution, and mechanically stirring at a speed of 100-400 rpm for 10-30min to form uniform liquid medicine;

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

Ropivacaine hydrochloride 0.15g, pluronic F127.3 g, pluronic F68.5 g, water for injection 10mL

The pharmaceutical composition is taken as a content, and the content is filled in an ampoule bottle.

The preparation method comprises the following steps:

ropivacaine hydrochloride is sieved by a 80-mesh sieve for standby. Adding 2.3g of pluronic F127 and 0.5g of pluronic F68 into 10ml of water for injection, and stirring in a water bath at 4 ℃ for 10-30min until the pluronic F68 is completely dissolved; adding 0.15g ropivacaine hydrochloride into the pluronic solution, and mechanically stirring for 10min to form uniform liquid medicine; and after the intermediate detection content is qualified, filling the obtained liquid medicine into 2ml ampoule bottles 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

Taking the medicinal composition as a content, freeze-drying the content at the temperature of-40 ℃ for 12 hours, and packaging the content in a penicillin bottle.

The preparation method comprises the following steps:

ropivacaine is sieved by a 80-mesh sieve for standby. Micronizing ropivacaine with jet mill, D ₉₀ Less than 5 μm. Taking 0.25g of Tween, 1.2g of mannitol and 0.25g of crosslinked carboxymethylAdding sodium cellulose into 25ml water, stirring in water bath at 50deg.C for 10-20min to dissolve completely; adding 0.05g of micronized ropivacaine into the mannitol solution, and mechanically stirring for 10min to form a suspension; after the intermediate is qualified in detection content, the intermediate is packaged in 10ml penicillin bottles, and is freeze-dried at the temperature of 40 ℃ below zero for 12 hours, and then a rubber plug is added, and a cover is rolled.

Test example 1 Release degree measurement

Chromatographic conditions

Chromatographic column: agilent EC-C18 (4.6 nm. Times.150 nm,4 μm)

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

Sample injection amount: 20 μl of

Column temperature: 30 DEG C

Detection wavelength: 263nm

Example release measurement:

the ropivacaine long-acting solution preparation for injection described in examples 1-11 (dosage 50 mg) was taken, 200mL of physiological saline was used as dissolution medium according to the united states pharmacopeia test method, the rotation speed was 10r/min, the temperature was (37.+ -. 0.5) °c, 2mL was sampled at 2h,4h,6h,24h,48h,72h,96h, and immediately filtered through a 0.45 μm microporous filter membrane, the primary filtrate was discarded, and HPLC analysis was performed to calculate the cumulative release percentage of the drug.

Table 1 cumulative percent release of each example drug (n=3)

As can be seen from table 1, in examples 1-11 of the present application, the drug release rate reached more than 6% within 2 hours, which indicates that the ropivacaine long-acting solution for injection of the present application can rapidly release the drug; and after 6 hours, the drug showed a gentle and stable release trend, and at 96 hours, the cumulative release rate was lower than 80%, indicating that it had a sustained release profile exceeding 96 hours.

From the comparison of the example 1 and the example 2, when benzyl alcohol and ethanol are used as the mixed solvent, the release rate of the ropivacaine long-acting solution preparation for injection is further delayed, and the slow release effect is smoother; from example 1, example 3 and example 4, it can be seen that the introduction of the glycerate adjuvant can accelerate the drug release, and the inventors have found that the pre-drug release rate is accelerated but the burst release phenomenon is not caused as the content of the glycerate increases; the results are shown in FIG. 1.

From the above results, it can be seen that the ropivacaine long-acting solution for injection of the present application has long-acting slow-release effect, for example, in example 1, when one of the active ingredient, sucrose acetate isobutyrate and alcohol solvents is adopted, rapid release of the drug can be achieved and the sustained-release characteristic is achieved for over 96 hours; furthermore, the addition of the ethanol is favorable for further delaying the release rate of the medicine, and the addition of the glyceride is favorable for accelerating the release rate of the earlier-stage medicine; preferably, the ropivacaine long-acting solution for injection comprises 2.5-20% of active ingredients, 40-87.5% of slow release carrier and 10-40% of alcohol solvent by mass percent; more preferably, the ropivacaine long-acting solution formulation for injection comprises, in mass percent, from the viewpoint of medication saving and cost reduction: 4-10% of active ingredient, 60-80% of slow release carrier and 10-30% of alcohol solvent.

Comparative example release measurement:

2ml of the ropivacaine hydrochloride temperature-sensitive gel preparation for injection described in comparative example 1 was added to a 10ml EP tube, and the EP tube was placed in a constant temperature water bath (37.+ -. 0.5 ℃) for 5min to gel the solution. 5mL of physiological saline at 37 ℃ is added as a release medium, and the release medium is taken out after shaking in a 50r/min constant temperature vibrating box for 2h,4h,6h,24h,48h,72h and 96h respectively, and then the solution is replenished again. The sample was immediately filtered through a 0.45 μm microporous filter, the primary filtrate was discarded, HPLC analysis was performed, and the cumulative percent release of the drug was calculated. The cumulative release amount is calculated. Taking the ropivacaine long-acting dry suspension preparation described in comparative example 2, re-dissolving the ropivacaine long-acting dry suspension preparation with 3mL of physiological saline, and adding the ropivacaine long-acting dry suspension preparation into a dialysis bag. Taking 200mL of physiological saline as a dissolution medium, rotating at 10r/min and the temperature of (37+/-0.5) DEG C, sampling 2mL of physiological saline at 2h,4h,6h,24h,48h,72h and 96h, immediately filtering with a 0.45 mu m microporous filter membrane, discarding the primary filtrate, and carrying out HPLC analysis to calculate the cumulative release percentage of the medicine.

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

As can be seen from table 2, the ropivacaine hydrochloride thermosensitive gel preparation for injection in comparative example 1 has thermosensitive slow release characteristic, but the release rate exceeds 85% in 48 hours. The ropivacaine long-acting dry suspension preparation for injection in comparative example 2 has slow release characteristic, but the release rate of the ropivacaine long-acting dry suspension preparation for injection exceeds 85% after 48 hours. Neither has a long-acting release profile of 72 hours or more.

Test example 2 rat efficacy test

1. Mechanical foot-reduction reflex threshold measurement

Preparation of incision pain model: 6 SD rats are selected, 200-250 g of rats are fasted for 6 hours before operation and forbidden for 1 hour, the rats are put into a transparent glass cup which is soaked with about 0.3mL of isoflurane liquid cotton ball and has a volume of 1L, the transparent glass cup is covered, after consciousness is lost, left rear sole of the rats is disinfected by iodophor, an incision with a length of about 1cm is made from a position of 0.5cm at the proximal end of the sole to the toe according to the Brennan method, skin is cut, and plantar muscles are picked up by using ophthalmic forceps and cut longitudinally, but starting, stopping and attaching of the muscles are kept intact. After hemostasis by pressing, the skin is sutured with a fine needle, and corresponding drugs are respectively injected into the incisions in A, B groups at the suture skin, wherein,

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

B. groups of embodiments: the ropivacaine long-acting solution formulations of each example in table 3 were injected at 50mg/kg (calculated as ropivacaine) near the incision.

The whole operation process is about 5min, and is completed by the same person, the wound after operation is disinfected by iodophor and is smeared with a small amount of erythromycin ointment, and the rat is fed in a quiet, warm and strong light-proof environment.

Threshold measurement: mechanical pain measurements were performed on rats using 8 different scales of von frey fiber rods (2, 4, 6, 8, 10, 15, 26g, 64 g). A grid frame made of metal wires with the height of 30cm from a test bed is arranged at the bottom, a plurality of transparent organic glass boxes with the length of 20cm multiplied by 25cm are placed on the grid frame, and rats to be tested are placed in the grid frame to adapt to a period of time and are generally controlled to be more than 30 minutes. After the rats are calm, the sole of the rats is directly stimulated by von-Frey fibers through a wire mesh grid, so that the filaments are bent for 90 degrees for 5 seconds, and the rats are raised or licked to be positive. The initial stimulus intensity was 2g, the stimulus intensity was gradually increased, and each intensity was repeatedly applied 5 times at intervals of 5 minutes. If the positive reaction is more than or equal to 3 times, the strength is the upper limit strength, and the strength positive reaction rate (the positive reaction frequency/5) is calculated to be the upper limit strength positive rate. And the last force is the lower limit intensity, and the intensity positive reaction rate is calculated as the lower limit intensity positive rate.

According to the 50% positive response 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 footshrink reflex threshold of the rat. Each rat measured the mechanical foothold reflex threshold as a basic mechanical pain threshold 2h before surgery (before incision pain model establishment), and measured the change of the mechanical foothold reflex threshold 2h,4h, 10h, 24h,48h,72h,96h after surgery (after incision pain model establishment), respectively.

TABLE 3 average value comparison of mechanical foot-reduction reflex threshold values for rat pharmacodynamic test

As can be seen from table 3, there was no incision before surgery, so the effect of perceived pain in rats was not obvious, as reflected by a higher threshold; the drug effect of the ropivacaine hydrochloride solution group can be maintained for 4-10 hours only by single injection. Compared with the ropivacaine hydrochloride solution group, the ropivacaine hydrochloride long-acting solution for injection can maintain the anesthetic effect for more than 96 hours.

2 rat regional blocking pharmacodynamic experiments

Ropivacaine is used clinically at a recommended dose of 7.5-225 mg/person for regional blocks (e.g., peripheral nerve blocks and invasive anaesthesia). Assuming that the clinical dose to the target human body is 225 mg/human, the dose of the drug administered to rats is about 4 mg/rat in terms of body surface area method. The dosage of the ropivacaine for injection used in example 1 in this experiment was determined to be 4.8 mg/dose (i.e., 0.1 mL/dose) based on 48mg/mL of the ropivacaine long-acting solution for injection.

6 rats (male and female halves) were subcutaneously administered to one thigh, and 0.5h, 1h, 1.5h, 2h, 3h, 4h,6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 132h, 144h, 156h, 168h after the injection were stimulated with a silver needle (about 1cm from the injection site), and the rats were observed and recorded for the occurrence of a tingling reaction. Meanwhile, the non-administered thigh was stimulated with a silver needle, and rats were observed for a tingling response as a control. If all rats develop a stinging response at three consecutive time points, the experiment is ended and no further observations of the stinging response are made at subsequent time points. The experimental results of the analgesic effect at the injection site of the rat are shown in Table 4.

TABLE 4 Table 4

Note that: "v" indicates that analgesic effect is present; "×" indicates that no analgesic effect was present.

From the results in table 4, it can be seen that the area blocking effect of the ropivacaine long-acting solution preparation for injection can reach 96 hours or even longer, which indicates that the ropivacaine long-acting solution preparation for injection can reach the anesthetic effect of more than 96 hours.

Test example 3 influence factor test

The ropivacaine long-acting solution preparation for injection prepared in the examples 1-11 is packaged by a paper box and placed in a constant temperature box with the temperature of 60 ℃ for 10 days under the high humidity environment with 90% RH and the illumination condition; the ropivacaine long-acting solution preparation for injection prepared in examples 1-11 is packaged by a paper box and is stored in a constant temperature and humidity box with the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5% for 3 months.

Conclusion: the example product and the control product prepared by the invention are respectively placed under the conditions of high temperature of 60 ℃, high humidity of 90 percent RH and illumination; placing in a constant temperature and humidity box with the temperature of 40+/-2 ℃ and the relative humidity of 75+/-5 percent for preservation; the measurement results of related substances are basically consistent with the analysis results before experiments, the impurities of the product have no obvious change, the quality of the product is stable, and the preparation can keep good stability.

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

Claims

1. The ropivacaine long-acting solution preparation for injection is characterized by comprising an active ingredient, a slow release carrier and an alcohol solvent;

wherein the active ingredient is selected from at least one of ropivacaine hydrochloride or ropivacaine mesylate;

the slow release carrier is sucrose acetate isobutyrate; the alcohol solvent is benzyl alcohol and ethanol;

or, the slow release carrier is sucrose acetate isobutyrate and glycerate; the glyceride is at least one selected from medium chain triglyceride, tricaprylin, glycerol dioleate, glyceryl triacetate and glyceryl monoacetate; the alcohol solvent is at least one selected from benzyl alcohol, ethanol, propylene glycol, polyethylene glycol and glycerol;

the ropivacaine long-acting solution preparation for injection comprises the following components in percentage by mass: 4-10% of active ingredient, 60-80% of slow release carrier and 10-30% of alcohol solvent.

2. The ropivacaine long-acting solution preparation for injection according to claim 1, wherein when the alcohol solvent is benzyl alcohol and ethanol, the mass ratio of the benzyl alcohol to the ethanol is 0.8:1-5:1.

3. The ropivacaine long-acting solution formulation for injection according to claim 1, wherein when the slow release carrier is sucrose acetate isobutyrate and glycerate, the weight ratio of the sucrose acetate isobutyrate to the glycerate is 20:1-5:1.

4. The ropivacaine long-acting solution preparation for injection according to claim 1, wherein when the active ingredient is ropivacaine, the slow release carrier is sucrose acetate isobutyrate and medium chain triglycerides, and the alcohol solvent is benzyl alcohol and ethanol, the mass ratio of the sucrose acetate isobutyrate to the medium chain triglycerides is 20:1-5:1, and the mass ratio of the benzyl alcohol to the ethanol is 0.8:1-5:1.

5. The ropivacaine long-acting solution formulation for injection according to claim 1, wherein a single administration of said ropivacaine long-acting solution formulation for injection results in an analgesic efficacy of more than 72 hours.

6. A process for preparing a long-acting solution formulation of ropivacaine for injection according to any one of claims 1 to 5, characterized in that it is prepared by mixing a slow-release carrier, an alcoholic solvent and an active ingredient, then encapsulating and sterilizing.

7. The preparation method according to claim 6, wherein the preparation method comprises the following specific steps: