CN113616796B - Pain-relieving anti-inflammatory compound slow-release preparation - Google Patents

Pain-relieving anti-inflammatory compound slow-release preparation Download PDF

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CN113616796B
CN113616796B CN202110800886.8A CN202110800886A CN113616796B CN 113616796 B CN113616796 B CN 113616796B CN 202110800886 A CN202110800886 A CN 202110800886A CN 113616796 B CN113616796 B CN 113616796B
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inflammatory
poloxamer
release preparation
analgesic
preparation
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CN113616796A (en
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钟正明
张勇
秦小强
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Jiangsu Kanghe Biological Pharmaceutical Co ltd
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention provides an analgesic and anti-inflammatory compound slow-release preparation, which comprises a local anesthetic, a non-steroidal anti-inflammatory drug and a slow-release agent consisting of poloxamer 407 and poloxamer 188. The compound slow-release preparation is a dual-action combined product consisting of local anesthetic and low-dose non-steroidal anti-inflammatory drug, is specially used for treating postoperative pain and inflammation by single administration at an operation site, and has obvious advantage in drug effect. The nonsteroidal 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, thereby recovering and enhancing the permeation efficacy of the local anesthetic, and the drug effect is as long as 4-5 days.

Description

Pain-relieving anti-inflammatory compound slow-release preparation
Technical Field
The invention relates to a compound sustained-release pharmaceutical preparation with analgesic and anti-inflammatory effects.
Background
The surgical amount and the surgical crowd in China are increased year by year, and the related medicine demand amount presents a rapid growth potential. Reducing opioid abuse is a major trend, but most patients are still using large amounts of opioid to treat postoperative pain. There is an urgent clinical need for safe, effective and non-addictive drugs to reduce opioid use and improve rehabilitation experience.
Regional anesthesia is considered an adjunct to multi-mode analgesia regimens. The existing local anesthetic action duration and administration methods in the market have drawbacks. The status and the demand of the long-acting local anesthetics in domestic and foreign guidelines are increasingly highlighted. At present, no long-acting analgesic product of local anesthetics for 72 hours exists in China. The sales amount of local anesthetic drug in public hospitals in China in 2019 is 19.48 hundred million yuan, which is increased by 9.03 percent in the same proportion, and the local anesthetic drug in China is increased stably in the last 5 years. The main varieties of local anesthetic drugs are ropivacaine, dyclonine and lidocaine.
Ropivacaine is a novel long-acting amide local anesthetic developed by the company astla, sweden, first marketed in the netherlands in 1996 and FDA approval in the united states for 24 months in the same year 9, and marketed in the united kingdom in 1997, so far in tens of countries. Ropivacaine has the characteristics of low toxicity and long action time, has dual functions of anesthesia and analgesia, and is widely used for various surgical anesthesia.
Dacromet is an emerging force in local anesthetics in recent years, and is one of the most rapid varieties of local anesthetics. The commercial sales of dyclonine city public hospitals in 2019 were 3.94 billion yuan, which all contributed by dyclonine hydrochloride mucilage in Yangtze pharmaceutical industry. Dyclonine has surface anesthesia effect on mucous membrane, and has the characteristics of strong penetrating power and lasting effect
The lidocaine has the characteristics of quick response, strong and durable effect, strong penetrating power, large safety range and the like, has no vasodilation effect, and hardly has irritation to tissues. Can be used for various local anesthetics, in particular to conduction anesthesia and epidural anesthesia, and is called as an all-purpose anesthetic.
In addition, common analgesic drugs for postoperative pain are:
opioid (a): morphine, fentanyl, sufentanil, oxycodone, and the like;
(II) acetaminophen and non-steroidal anti-inflammatory drugs;
(III) tramadol;
(IV) local anesthetics: bupivacaine, levobupivacaine, ropivacaine, chloroprocaine;
and (fifth) others: ketamine, gabapentin, pregabalin.
The following cases exist for the above-mentioned several local anesthetics, respectively:
bupivacaine has long action time and low price, is widely used for postoperative analgesia, but excessive medicines are easy to cause central nervous system and heart toxicity;
the pharmacological properties of levobupivacaine are similar to bupivacaine, but the heart toxicity of levobupivacaine is lower than that of bupivacaine;
the ropivacaine has the remarkable characteristics of 'motor feel separation', namely the concentration (0.0625-0.15%) of the drug for producing effective analgesia has relatively weak blocking effect on motor nerves, and the toxicity of the ropivacaine is lower than that of bupivacaine and levobupivacaine;
the chloroprocaine has rapid onset of action, has a certain phenomenon of "motor sensory separation" at low concentration, and should be free of preservative (nitrite) when used for subarachnoid anesthesia, and the dosage should be lower than 60mg.
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. The bupivacaine liposome injection is the latest dosage form in the bupivacaine preparation products on the market, and compared with other bupivacaine preparations, the bupivacaine liposome injection has the advantages that a single injection can be maintained for 72 hours, and other bupivacaine preparations need to be administered for multiple times within 24 hours.
The local anesthetic is mainly used for postoperative analgesia treatment through 3 major types such as intrathecal medication, peripheral nerve block, local infiltration and the like. Although local anesthetics are mixed with many drugs for clinical analgesia, except for glucocorticoids, the intensity of action and the analgesic time are uncertain and cannot be accepted or recommended clinically (see the department of anesthesia of the Chinese medical society, the consensus of post-operative analgesic specialists).
Disclosure of Invention
Therefore, the present invention aims to develop an analgesic and anti-inflammatory drug which is long-acting and has a single administration duration of 3 to 7 days, in order to avoid opioids or drugs with great toxic and side effects in the analgesic drugs after size surgery. The administration mode can be that the wound is evenly smeared by a needleless injector after operation, and the wound tissue is sutured after completion.
The inventors of the present invention have found through extensive studies that inflammation plays a key role in pain management, but current local anesthetics do not address this problem. Amide local anesthetics such as ropivacaine, bupivacaine, and lidocaine can increase the threshold of nerve action potential, slow down the conduction of nerve impulses, and reduce the rate of action potential increase, thereby blocking the generation and conduction of nerve impulses. Chloroprocaine is a short-acting ester local anesthetic, has low lipophilicity and weak penetrating power to mucous membrane. The acidic environment associated with inflammation results in less drug penetration through the nerve membrane and reduced anesthetic action. Typically, surgical injuries result in an immediate drop in pH, and the acidic environment will remain for many days as inflammatory cytokines are released and inflammation begins, largely affecting the analgesic effect of local anesthetics. The inventors of the present invention have unexpectedly found that non-steroidal anti-inflammatory drugs have not only anti-inflammatory, antirheumatic, analgesic, antipyretic and anticoagulant effects, but also inhibit the formation of an acidic environment, normalize the pH, and thereby restore and enhance the osmotic efficacy of local anesthetics.
Based on the findings, 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.
In the pain-relieving and anti-inflammatory compound slow-release preparation, the effect of the acid environment caused by inflammation on the pain-relieving effect of the local anesthetic is inhibited by adopting the combination of the local anesthetic and the non-steroidal anti-inflammatory drug, and the combination of poloxamer 407 and poloxamer 188 is adopted as the slow-release agent, so that the pharmaceutical preparation quickly turns into gel in situ at body temperature and the drug 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, namely, is liquid at temperature and becomes gel 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 foods and medicines. Poloxamer 188 has average molecular weight of 7680-9510, is easy to dissolve in water, is commonly used as lubricant of emulsion, ointment and suspension in the pharmaceutical field, solubilizer and dispersing agent of tablet or capsule, can also be used as carrier of solid dispersing agent, and has stronger surface activity and gel effect.
The pain-relieving and inflammation-resisting compound slow-release preparation provided by the invention, wherein the local anesthetic can be selected from one or more of ropivacaine, bupivacaine, lidocaine, procaine and dyclonine. The analgesic and anti-inflammatory compound sustained release preparation of the invention is particularly effective for ropivacaine because ropivacaine is very sensitive to a reduced pH and the efficacy of ropivacaine is significantly reduced when the pH is acidic.
The pain-relieving anti-inflammatory compound sustained release preparation provided by the invention, wherein the non-steroidal anti-inflammatory drug can be selected from one or more of meloxicam, aspirin, acetaminophen, indomethacin, naproxen, diclofenac, ibuprofen, nimesulide, rofecoxib and celecoxib.
The compound slow release preparation for relieving pain and resisting inflammation, which is disclosed by the invention, is preferably a semi-fluid preparation. Preferably, the viscosity of the compound sustained release preparation for relieving pain and resisting inflammation is 2000-3000 mPa.S at room temperature (about 25 ℃), and the viscosity of the compound sustained release preparation for relieving pain and resisting inflammation is 10000-15000 mPa.S at 35-38 ℃.
The compound slow-release preparation for relieving pain and resisting inflammation, which is disclosed by the invention, wherein the content of poloxamer 407 in the preparation is 18-26wt% and the content of poloxamer 188 in the preparation is 2-6 wt%.
The analgesic and anti-inflammatory compound sustained-release preparation according to the invention, wherein the content of the local anesthetic in the preparation can be 1-6wt%, preferably 2-5wt%. The non-steroidal anti-inflammatory drug may be present in the formulation in an amount of 0.05 to 0.5wt%, preferably 0.1 to 0.2wt%.
The compound slow-release preparation for relieving pain and resisting inflammation, which is disclosed by the invention, further comprises a solvent and an optional cosolvent. Preferably, the solvent is phosphate buffer, preferably KH of 0.05-0.2 mol/L, pH =7-8 2 PO 4 Buffer solution (PB). Preferably, the co-solvent is dimethyl sulfoxide (DMSO).
The compound slow-release preparation for relieving pain and resisting inflammation is a dual-action combined product consisting of local anesthetic and low-dose non-steroidal anti-inflammatory drug, and can be used for treating postoperative pain and inflammation by single administration at an operation site.
The pain-relieving and inflammation-resisting compound slow-release preparation has obvious advantages in the aspect of safety for 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 provided by the invention can be simply coated on affected tissues without using a needle, is easy to manage and less invasive, avoids the number of needle punching, and reduces the risks of accidental intravascular puncture and accidental needle punching.
In addition, the analgesic and anti-inflammatory compound sustained-release preparation has obvious advantages. The pain trace data of c.richard Chapman shows that 63% of the samples have the expected negative slope for POP decomposition within 6 days (NRS drop to 4 on day 4) for the drug effect of the formulations of the present invention as long as 4 to 5 days relative to the traditional analgesic. The longest-acting local anesthetic currently marketed internationally is a drug which is analgesic for 72 hours (3 days) after surgery, such as bupivacaine liposome, and is estimated to meet the postoperative analgesic requirements of more than half of clinical patients. Some patients fail to prove that the pain intensity is reduced with time, the part of the population accounts for 37 percent (37 percent of samples have gentle or positive slopes), and the 4-5-day analgesic provided by the invention is hopeful to fill the demands of the part of the population to a certain extent.
Drawings
Embodiments of the present invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 shows the in vitro release of the compound analgesic and anti-inflammatory sustained release preparation prepared in example 4.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof.
Example 1
Preparation of compositions of poloxamer 407 and poloxamer 188
According to Table 1, the weighed poloxamer 407 and poloxamer 188 were slowly added to KH at pH7.0 of 0.1mol/L 2 PO 4 The buffer solution (room temperature) was gently shaken to avoid vigorous stirring until it was completely dissolved. And showed a colorless transparent liquid at room temperature.
The dissolved colorless transparent liquid is put into a water bath constant temperature box to measure the viscosity at different temperatures. Three sets of parallel experiments were performed.
TABLE 1
Figure BDA0003164433880000051
In the measuring process, the model of the viscometer probe is continuously adjusted along with the increase of the viscosity, so that the opening angle of the viscometer probe is between 30% and 70%, a relatively accurate viscosity result is conveniently obtained, and data show that the viscosity of the composition gradually increases along with the continuous increase of the temperature, and finally the semisolid state is achieved. For compositions of poloxamers 407 and 188 at different concentrations, see table 2 for specific values.
TABLE 2
Figure BDA0003164433880000052
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Figure BDA0003164433880000061
When the concentration of poloxamer 407 and 188 is respectively 18-26wt% and 2-6 wt%, the blank preparation is in semi-flowing state at room temperature, the viscosity is 2000-3000 mPA.S, and when the temperature is 35-38 ℃, the viscosity of the blank preparation is 10000-15000 mPA.S, and the blank preparation is in semi-solid state, so that the aim of preparation development and clinical medication requirements are met.
Example 2
Preparation of the pain-relieving and inflammation-resisting compound slow-release preparation (without cosolvent)
According to Table 3, the weighed poloxamers 407 and 188 were slowly added to KH at pH7.4 of 0.1mol/L 2 PO 4 The buffer solution (room temperature) was gently shaken to avoid vigorous stirring until it was completely dissolved. And showed a colorless transparent liquid at room temperature. Adding ropivacaine and meloxicam with different concentrations into the solution, heating to 80-90 ℃ to mix evenly, stirring for 30min, cooling to 2-8 ℃, subpackaging, and sterilizing at 121 ℃ for 12min.
TABLE 3 Table 3
Figure BDA0003164433880000071
After the sterilization of ropivacaine and meloxicam at different concentrations, the higher the main drug concentration, the lower the viscosity of the preparation, and at the same time, the solution is separated out after the preparation is kept stand for 48 hours at the temperature of 2-8 ℃ at the concentration of 8% and 4% of ropivacaine and 0.24% and 0.12% of meloxicam.
Example 3
Preparation of the pain-relieving and inflammation-resisting compound slow-release preparation (containing cosolvent)
According to Table 4, the poloxamers 407 and 188, respectively, were slowly added to KH at pH7.4 of 0.1mol/L 2 PO 4 Slightly shaking the buffer solution (PB), uniformly mixing, uniformly dividing into 16 parts, sequentially marking as experiments 1-16 parts, respectively placing 16 parts of the preparation in a water bath at 90 ℃ for heating for 10min, adding four parts of the preparation into the weighed meloxicam, ropivacaine and DMSO, and adopting PB to fix the volume to a required volume; heating and stirring for 10min, cooling to 2-8deg.C, packaging, and sterilizing at 121deg.C for 12min. Wherein, the concentration of DMSO is 10-20%, ropivacaine is 4%, meloxicam is 0.12%, and orthogonal test is carried out. (the contents are all mass percent content)
TABLE 4 Table 4
Figure BDA0003164433880000072
Figure BDA0003164433880000081
Orthogonal experiments were performed according to 16 prescriptions under the experimental design, experiments 5 and 6, experiments 9 and 10 were semi-fluid at room temperature, viscosity was about 1000mpa.s, semi-fluid at 35-37 ℃ and viscosity was 5000mpa.s, i.e. the most preferred protocol was experiments 9 and 10, prescriptions were poloxamer 407 content 20%, poloxamer 188 content 4%, ropivacaine content 4%, meloxicam content 0.12%, DMSO content 20%, the rest 10mmol/L, ph7.4 PB buffer.
Comparative examples 1 and 2
A compound sustained release preparation was prepared in a similar manner to example 3, in which the cosolvent was 10wt% DMSO, 10wt% meglumine, and 10wt% PEG4000, respectively, according to table 5.
TABLE 5
Name of the name Experiment 1 (wt%) Experiment 2 (wt%) Experiment 3 (wt%)
Poloxamer 407 24 24 24
Poloxamer 188 4 4 4
Ropivacaine 4 4 4
Meloxicam preparation 0.12 0.12 0.12
DMSO 10 - -
Meglumine (meglumine) - 10 -
PEG4000 - - 10
PB Constant volume Constant volume Constant volume
Sterilizing the preparation containing different cosolvent, standing at 2-8deg.C for 48 hr, wherein the preparation solution (experiment 1) containing DMSO cosolvent has no precipitation of main medicine component; however, the formulation solutions (experiments 2 and 3) containing meglumine and PEG4000 co-solvent all had liquid drug precipitation, which did not meet the requirements of formulation development.
Example 4
Determination of in vitro Release Rate of sustained Release preparation
The dialysis bag method is the most commonly used method 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 current prescription weight. The embodiment adopts a dialysis bag method to examine the in-vitro release condition of the pain-relieving and inflammation-resisting compound slow-release preparation.
The preparation liquid medicine is prepared according to the following formula: PB buffer solution with poloxamer 407 content of 20%, poloxamer 188 content of 4%, ropivacaine content of 4%, meloxicam content of 0.12%, DMSO content of 20%, and rest 10mmol/L, pH 7.4.
In vitro release test study was performed by dialysis bag method, and drug release concentrations were detected by sampling at time points of 0h, 12h, 24h, 36h, 72h, 96h, 120h and 144h, respectively. The results are shown in figure 1, and the in vitro release curve shows that the compound preparation provided by the invention has obvious slow release effect.
The examples of the present invention are merely exemplary embodiments of the present invention, which are merely for explaining the present invention, and do not limit the scope of the present invention. Modifications, substitutions, changes, etc. which do not depart from the spirit of the invention will be readily apparent to those skilled in the art.

Claims (4)

1. An analgesic and anti-inflammatory compound slow-release preparation comprises a local anesthetic, a non-steroidal anti-inflammatory drug and a slow-release preparation consisting of poloxamer 407 and poloxamer 188, wherein the preparation further comprises a solvent and a cosolvent, the local anesthetic is ropivacaine, the non-steroidal anti-inflammatory drug is meloxicam, the solvent is phosphate buffer solution, and the cosolvent is dimethyl sulfoxide;
wherein the content of poloxamer 407 is 18-26wt%, the content of poloxamer 188 is 2-6wt%, the content of local anesthetic is 1-6wt%, and the content of the non-steroidal anti-inflammatory drug is 0.05-0.5wt%; the phosphate buffer solution is KH of 0.05-0.2 mol/L, pH =7-8 2 PO 4 Buffer solution.
2. The analgesic anti-inflammatory compound slow release formulation of claim 1 wherein said formulation is a semi-fluid formulation.
3. The analgesic and anti-inflammatory compound slow-release preparation according to claim 1 or 2, wherein the viscosity of the analgesic and anti-inflammatory compound slow-release preparation at room temperature is 2000-3000 mpa.s, and the viscosity at 35-38 ℃ is 10000-15000 mpa.s.
4. The analgesic anti-inflammatory compound sustained-release preparation according to claim 1 or 2, wherein the content of the local anesthetic is 2-5wt%; the content of the nonsteroidal anti-inflammatory drug is 0.1-0.2 wt%.
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