阅读说明：本技术 一种止痛抗炎复方缓释制剂 (Pain-relieving and anti-inflammatory compound sustained-release preparation ) 是由 钟正明 张勇 秦小强 于 2021-07-15 设计创作，主要内容包括：本发明提供一种止痛抗炎复方缓释制剂,其包含局部麻醉剂、非甾体抗炎药、以及由泊洛沙姆407和泊洛沙姆188组成的缓释剂。本发明的止痛抗炎复方缓释制剂是一款非阿片类止痛药,由局部麻醉剂和低剂量非甾体抗炎药组成的双重作用组合产品,专门用于在手术部位单次给药治疗术后疼痛和炎症,其药效有明显优势。其中的非甾体抗炎药不但具有抗炎、作用,而且能够抑制酸性环境的形成,使pH值正常化,从而恢复并增强局部麻醉药的渗透功效,药效长达4～5天之久。(The invention provides an analgesic and anti-inflammatory compound sustained-release preparation, which comprises a local anesthetic, a non-steroidal anti-inflammatory drug and a sustained-release agent consisting of poloxamer 407 and poloxamer 188. The pain-relieving anti-inflammatory compound sustained-release preparation is a non-opioid analgesic, is a dual-action combined product consisting of a local anesthetic and a low-dose non-steroidal anti-inflammatory drug, is specially used for treating postoperative pain and inflammation by single administration at an operation part, and has obvious advantages in drug effect. The non-steroidal anti-inflammatory drug not only has anti-inflammatory and anti-inflammatory effects, but also can inhibit the formation of an acidic environment and normalize the pH value, so that the penetration effect of the local anesthetic is recovered and enhanced, and the drug effect lasts for 4-5 days.)

1. An analgesic anti-inflammatory compound sustained release preparation, which comprises a local anesthetic, a non-steroidal anti-inflammatory drug and a sustained release agent consisting of poloxamer 407 and poloxamer 188.

2. The analgesic anti-inflammatory compound sustained-release formulation of claim 1, wherein the local anesthetic may be selected from one or more of ropivacaine, bupivacaine, lidocaine, procaine and dyclonine.

3. The analgesic anti-inflammatory compound sustained-release formulation of claim 1 or 2, wherein the non-steroidal anti-inflammatory drug is one or more selected from the group consisting of meloxicam, aspirin, acetaminophen, indomethacin, naproxen, naproxone, diclofenac, ibuprofen, nimesulide, rofecoxib and celecoxib.

4. An analgesic anti-inflammatory compound sustained release formulation according to any one of claims 1 to 3, wherein the formulation is a semi-fluid formulation.

5. The analgesic anti-inflammatory compound sustained-release preparation according to any one of claims 1 to 4, wherein the viscosity of the analgesic anti-inflammatory compound sustained-release preparation at room temperature is 2000 to 3000mPA.S, and the viscosity at 35 to 38 ℃ is 10000 to 15000 mPA.S.

6. The analgesic and anti-inflammatory compound sustained-release preparation according to any one of claims 1 to 5, wherein the content of poloxamer 407 is 18-26 wt% and the content of poloxamer 188 is 2-6 wt%.

7. The analgesic anti-inflammatory compound sustained-release preparation according to any one of claims 1 to 6, wherein the content of the local anesthetic is 1 to 6 wt%, preferably 2 to 5 wt%; the content of the non-steroidal anti-inflammatory drug is 0.05-0.5 wt%, preferably 0.1-0.2 wt%.

8. The analgesic anti-inflammatory compound sustained-release formulation according to any one of claims 1 to 7, wherein the formulation further comprises a solvent and optionally a cosolvent.

9. The analgesic anti-inflammatory compound sustained-release preparation according to claim 8, wherein the solvent is phosphate buffer, wherein the phosphate buffer is preferably 0.05 to 0.2mol/L, pH ═ 7 to 8 KH₂PO₄And (4) buffer solution.

10. The analgesic anti-inflammatory compound sustained-release preparation according to claim 8, wherein the cosolvent is dimethyl sulfoxide.

Technical Field

The invention relates to a compound sustained-release pharmaceutical preparation with analgesic and anti-inflammatory effects.

Background

The operation amount and the operation population of China increase year by year, and the demand of related medicines is on the rise rapidly. The reduction of opioid abuse is a major trend, but most patients are still using large amounts of opioid for the treatment of postoperative pain. Clinically, there is an urgent need for safe, effective and non-addictive drugs to reduce opioid use and improve the rehabilitation experience.

Regional anesthesia is considered an adjunct to the multimodal analgesia protocol. The duration of action and the method of administration of the local anesthetic agents available on the market are deficient. The status and the demand of long-acting local anesthetics in domestic and foreign guidelines are increasingly highlighted. At present, no local anesthetic long-acting analgesic product for 72 hours is available in China. The sale amount of local anesthetic drugs sold in domestic public hospitals in cities in 2019 is 19.48 billion yuan, the year-on-year increase is 9.03%, and the increase is stable in the last 5 years. The main classes of local anesthetic drugs are ropivacaine, dyclonine and lidocaine.

Ropivacaine is a new long-acting amide local anesthetic developed by the swedish aste dragline company, first marketed in the netherlands in 1996, and obtained FDA approval in the united states 24/9/1997 in the same year, marketed in the uk in 1997, and has been marketed in several dozen countries to date. Ropivacaine has the characteristics of low toxicity and long action time, has the dual effects of anesthesia and analgesia, and is widely used for various surgical anesthesia.

Dyclonine is a new power in local anesthetics in recent years and is one of the most rapid-increasing varieties of local anesthetics. The sale of the urban public standing hospital of dyclonine in 2019 is 3.94 hundred million yuan, which is totally contributed by dyclonine hydrochloride mucilage in Yangziang pharmaceutical industry. The dyclonine has topical anesthetic effect on mucosa, and has the advantages of strong penetrating power and long-lasting effect

Lidocaine has the characteristics of quick response, strong and durable action, strong penetrating power, larger safety range and the like, has no function of expanding blood vessels, and hardly has irritation to tissues. Can be used for various local anesthetics, especially for conduction anesthesia and epidural anesthesia, and is called as general anesthetic.

In addition, the analgesic drugs commonly used for postoperative pain are:

(one) opioid: morphine, fentanyl, sufentanil, oxycodone, and the like;

(ii) acetaminophen and non-steroidal anti-inflammatory drugs;

(III) tramadol;

(IV) local anesthetics: bupivacaine, levobupivacaine, ropivacaine, chloroprocaine;

(V) others: ketamine, gabapentin, pregabalin.

The local anesthetics are as follows:

bupivacaine has long action time and low price, is widely used for postoperative analgesia, but the toxicity of the central nervous system and the heart is easily caused by excessive medicine;

levobupivacaine has similar pharmacological properties to bupivacaine, but has less cardiotoxicity than bupivacaine;

ropivacaine is remarkably characterized by 'motion-sensation separation', namely, the concentration (0.0625-0.15%) of the drug for generating effective analgesia has relatively weak effect on motor nerve blocking, and the toxicity of the ropivacaine is lower than that of bupivacaine and levobupivacaine;

the chloroprocaine has rapid onset of action and certain 'motion feeling separation' phenomenon at low concentration, and does not contain a preservative (nitrite) when being used for subarachnoid space anesthesia, and the dosage is lower than 60 mg.

At present, the bupivacaine preparation clinically used at home and abroad mainly comprises: bupivacaine hydrochloride injection, levobupivacaine hydrochloride injection, compound bupivacaine injection and bupivacaine liposome injection EXPAREL. Among them, the bupivacaine liposome injection is the latest formulation among the marketed bupivacaine preparation products, and has the advantage that a single injection can last for 72 hours compared with other bupivacaine preparations, and the other bupivacaine preparations need to be administrated for multiple times within 24 hours.

The local anesthetic is mainly used for postoperative analgesia treatment through 3 types such as intraspinal medication, peripheral nerve block, local infiltration and the like. Although local anesthetics are mixed with many drugs for clinical analgesia, the local anesthetics, except glucocorticoids, have uncertain action intensity and analgesia time and cannot be adopted or recommended clinically (see the general knowledge of the anesthesia expert after daily surgery of the Chinese medical society).

Disclosure of Invention

Therefore, the invention aims to develop a long-acting analgesic and anti-inflammatory drug with one-time administration duration of 3 to 7 days in order to avoid using opioids or drugs with large toxic and side effects in analgesic drugs after major and minor surgeries. The administration mode can be that the wound is evenly smeared by adopting a syringe without a needle head at the wound after the operation, and the suture is performed after the application is finished.

The inventors of the present invention have conducted extensive studies to find that inflammation plays a key role in pain management, however, current local anesthetics do not solve this problem. Amide local anesthetics such as ropivacaine, bupivacaine and lidocaine slow down the conduction of nerve impulses and reduce the rate of rise of action potential by increasing the threshold of nerve action potential, thereby blocking the generation and conduction of nerve impulses. Chloroprocaine is a short-acting ester local anesthetic with low lipophilicity and weak penetration to mucous membranes. The acidic environment associated with inflammation results in less drug penetration through the nerve membrane and reduced anesthesia. Usually, surgical injury causes an immediate decrease in pH, and with the release of inflammatory cytokines and the onset of inflammation, the acidic environment will remain for many days, largely affecting the analgesic effect of local anesthetics. The inventors of the present invention have unexpectedly found that the non-steroidal anti-inflammatory drug not only has anti-inflammatory, antirheumatic, analgesic, antipyretic and anticoagulant effects, but also can inhibit the formation of acidic environment and normalize pH value, thereby recovering and enhancing the penetration efficacy of local anesthetic.

Based on the above findings, the present invention provides an analgesic anti-inflammatory compound sustained-release preparation comprising a local anesthetic, a non-steroidal anti-inflammatory drug, and a sustained-release agent consisting of poloxamer 407 and poloxamer 188.

In the pain-relieving and anti-inflammatory compound sustained-release preparation, the influence of an acidic environment caused by inflammation on the pain-relieving effect of a local anesthetic is inhibited by adopting the combination of the local anesthetic and a non-steroidal anti-inflammatory drug, and the combination of poloxamer 407 and poloxamer 188 is adopted as the sustained-release agent, so that the medicinal preparation is quickly changed into gel in situ at body temperature, and the medicament is slowly released.

Wherein poloxamer 407 is composed of about 70% ethylene oxide and 30% propylene oxide, has an average molecular weight of 11500, a melting point of 56 ℃, and has a special reverse thermal gelation effect, i.e., liquid at warm temperatures and gels at body temperature. Poloxamer 407 has the characteristics of good slow release effect, low toxicity, high bioavailability and the like, and is widely applied to the fields of food and medicines. Poloxamer 188 has an average molecular weight of 7680-9510, is easily dissolved in water, is commonly used as a lubricant of emulsion, ointment and suspension in the pharmaceutical field, a solubilizer and a dispersant of tablets or capsules, and can also be used as a carrier of solid dispersant, and has strong surface activity and gel effect.

The analgesic anti-inflammatory compound sustained-release preparation according to the present invention, wherein the local anesthetic may be selected from one or more of ropivacaine, bupivacaine, lidocaine, procaine and dyclonine. The compound sustained-release preparation for relieving pain and diminishing inflammation is particularly effective to ropivacaine because ropivacaine is very sensitive to the reduced pH value and the efficacy of ropivacaine is obviously reduced when the pH value is acidic.

The analgesic anti-inflammatory compound sustained-release preparation according to the present invention, wherein the non-steroidal anti-inflammatory drug may be one or more selected from the group consisting of meloxicam, aspirin, acetaminophen, indomethacin, naproxen, naproxone, diclofenac, ibuprofen, nimesulide, rofecoxib and celecoxib.

The analgesic anti-inflammatory compound sustained-release preparation according to the present invention, wherein the preparation is preferably a semi-fluid preparation. Preferably, the viscosity of the pain-relieving and anti-inflammatory compound sustained-release preparation at room temperature (about 25 ℃) is 2000-3000 mPA.S, and the viscosity of the pain-relieving and anti-inflammatory compound sustained-release preparation at 35-38 ℃ is 10000-15000 mPA.S.

The pain-relieving and anti-inflammatory compound sustained-release preparation disclosed by the invention is characterized in that the content of poloxamer 407 is 18-26 wt%, and the content of poloxamer 188 is 2-6 wt%.

The analgesic and anti-inflammatory compound sustained-release preparation provided by the invention can be used for preparing an analgesic and anti-inflammatory compound sustained-release preparation, wherein the content of the local anesthetic in the preparation can be 1-6 wt%, preferably 2-5 wt%. In the preparation, the content of the non-steroidal anti-inflammatory drug can be 0.05-0.5 wt%, and preferably 0.1-0.2 wt%.

The analgesic and anti-inflammatory compound sustained-release preparation further comprises a solvent and an optional cosolvent. Preferably, the solvent is phosphate buffer, and the phosphate buffer is preferably 0.05-0.2 mol/L, pH ═ 7-8 KH₂PO₄Buffer solution (PB). Preferably, the co-solvent is dimethyl sulfoxide (DMSO).

The pain-relieving anti-inflammatory compound sustained-release preparation is a non-opioid analgesic, is a dual-action combined product consisting of a local anesthetic and a low-dose non-steroidal anti-inflammatory drug, and can be used for treating postoperative pain and inflammation by single administration at an operation part.

The pain-relieving anti-inflammatory compound sustained-release preparation has obvious advantages in the aspect of safety of patients: it is easy to administer and can remain at the surgical site after administration while releasing the active ingredient; the release of the active ingredient is controlled by the diffusion of the polymer and is not affected by the environment. Compared with other injections, the preparation of the invention can be simply coated on affected tissues without using a needle, is easy to manage and less invasive, avoids the times of acupuncture and reduces the risks of accidental intravascular puncture and accidental acupuncture.

In addition, the analgesic and anti-inflammatory compound sustained-release preparation has obvious advantages in drug effect. The effect of the formulation of the invention was as long as 4-5 days compared to the conventional analgesics, and the pain trace data of c.richard Chapman showed that 63% of the samples had the expected negative slope to POP decomposition within 6 days (NRS decreased to 4 at day 4). The currently internationally marketed local anesthetic drug with the longest effect is a drug for analgesia lasting for 72 hours (3 days) after operation, such as bupivacaine liposome, and is estimated to meet postoperative analgesia requirements of more than half clinical surgical patients. Some patients fail to prove that the pain intensity is reduced along with time, and the part of people accounts for 37 percent (37 percent of samples have gentle or positive slope).

Drawings

Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:

FIG. 1 shows the in vitro release of the analgesic and anti-inflammatory compound sustained-release preparation prepared in example 4.

Detailed Description

The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

Example 1

Preparation of a composition of Poloxamer 407 and Poloxamer 188

According to the table 1, the weighed poloxamer 407 and poloxamer 188 were slowly added to 0.1mol/L KH of pH7.0₂PO₄In the buffer (room temperature), gently shaking to avoid vigorous stirring until it is completely dissolved. It appeared as a colorless transparent liquid at room temperature.

And (3) putting the dissolved colorless transparent liquid into a water bath thermostat, and measuring the viscosity at different temperatures. Three parallel experiments were performed.

TABLE 1

In the measuring process, the type of the probe of the viscometer is continuously adjusted along with the increase of the viscosity, so that the opening angle of the probe of the viscometer is between 30 and 70 percent, which is convenient for obtaining a relatively accurate viscosity result, and the data show that the viscosity of the composition gradually increases along with the continuous increase of the temperature, and finally reaches a semi-solid state. For compositions of different concentrations of poloxamers 407 and 188, see table 2 for specific values.

TABLE 2

When the concentrations of poloxamer 407 and poloxamer 188 are respectively 18-26 wt% and 2-6 wt%, the blank preparation is in a semi-flowing state at room temperature, the viscosity is 2000-3000 mPA.S, and when the temperature is 35-38 ℃, the blank preparation is 10000-15000 mPA.S, and is in a semi-solid state, so that the purposes of preparation development and clinical medication requirements are met.

Example 2

Preparing the pain-relieving and anti-inflammatory compound sustained-release preparation (without cosolvent)

According to Table 3, the weighed poloxamer 407 and 188 was slowly added to 0.1mol/L KH of pH7.4₂PO₄In the buffer (room temperature), gently shaking to avoid vigorous stirring until it is completely dissolved. It appeared as a colorless transparent liquid at room temperature. Adding ropivacaine and meloxicam with different concentrations into the solution, heating to 80-90 deg.C for mixing, stirring for 30min, cooling to 2-8 deg.C, packaging, and sterilizing at 121 deg.C for 12 min.

TABLE 3

According to measurement, the higher the concentration of the main medicine is, the lower the viscosity of the preparation is, and meanwhile, the liquid medicine is separated out after the preparation is kept stand for 48 hours at the temperature of 2-8 ℃ under the concentration of 8% and 4% of ropivacaine and the concentration of 0.24% and 0.12% of meloxicam.

Example 3

Preparing the pain-relieving and anti-inflammatory compound sustained-release preparation (containing cosolvent)

According to Table 4, the weighed poloxamer 407 and 188 were slowly added to KH of 0.1mol/L pH7.4₂PO₄Slightly shaking and uniformly mixing the materials in a buffer solution (PB), evenly dividing the mixture into 16 parts, sequentially marking the 16 parts as experiments 1-16, respectively placing the 16 parts of preparations in a water bath at 90 ℃ to heat for 10min, adding the weighed meloxicam, ropivacaine and DMSO into the four parts of preparations, and fixing the volume to the required volume by adopting PB; respectively heating and stirring for 10min, mixing, cooling to 2-8 deg.C, packaging, and sterilizing at 121 deg.C for 12 min. Wherein the concentration of DMSO is 10-20%, the concentration of ropivacaine is 4%, and the concentration of meloxicam is 0.12%, and an orthogonal test is carried out. (the contents are all the mass percentage contents)

TABLE 4

Orthogonal experiments, experiments 5 and 6, experiments 9 and 10 were performed according to 16 sets of recipes under experimental design, with a viscosity of about 1000mpa.s in a semi-fluid state at room temperature and a viscosity of 5000mpa.s in a semi-solid fluid state at 35-37 ℃, i.e. experiments 9 and 10 are most preferred, with a PB buffer solution with a poloxamer 407 content of 20%, a poloxamer 188 content of 4%, a ropivacaine content of 4%, a meloxicam content of 0.12%, a DMSO content of 20%, and the remainder of 10mmol/L, ph 7.4.

Comparative examples 1 and 2

A compound sustained-release preparation was prepared according to table 5 in a similar manner to example 3, in which 10 wt% of DMSO, 10 wt% of meglumine, and 10 wt% of PEG4000 were used as co-solvents, respectively.

TABLE 5

Name (R)	Experiment 1 (wt%)	Experiment 2 (wt%)	Experiment 3 (wt%)
				Poloxamer 407	24	24	24
Poloxamer 188	4	4	4
				Ropivacaine	4	4	4
Meloxicam	0.12	0.12	0.12
				DMSO	10	-	-
Meglumine	-	10	-
				PEG4000	-	-	10
PB	Constant volume	Constant volume	Constant volume

Sterilizing the preparation containing different cosolvents, standing for 48h at 2-8 ℃, and analyzing the main drug-free component of the preparation liquid containing the DMSO cosolvent (experiment 1); however, the formulation solutions containing meglumine and PEG4000 cosolvent (experiments 2 and 3) all had drug solution precipitated, which did not meet the requirements for formulation development.

Example 4

Determination of in vitro Release Rate of sustained Release formulations

The dialysis bag method is the most commonly used method in the in vitro release, and can greatly reduce the difference of drug release behaviors caused by the difference of forms during injection, thereby providing conditions for the prescription renewal. In this example, the in vitro release of the analgesic and anti-inflammatory compound sustained-release preparation of the present invention was examined by a dialysis bag method.

The preparation liquid medicine is prepared according to the following prescription: 20% of poloxamer 407, 4% of poloxamer 188, 4% of ropivacaine, 0.12% of meloxicam, 20% of DMSO and the balance of 10mmol/L PB buffer solution with pH 7.4.

In vitro release test study is carried out by adopting a dialysis bag method, samples are taken at time points of 0h, 12h, 24h, 36h, 72h, 96h, 120h and 144h respectively, and drug release concentration is detected. The results are shown in fig. 1, and the in vitro release curve shows that the compound preparation of the invention has obvious sustained release effect.

The examples of the present invention are merely exemplary embodiments of the present invention, and are provided only for explaining the present invention, not for limiting the scope of the present invention. Modifications, substitutions, changes, etc. that may occur to those skilled in the art without departing from the spirit and scope of the present invention are intended to be covered by the present invention.