CN111053738A - Clopidogrel injection, preparation method and application - Google Patents
Clopidogrel injection, preparation method and application Download PDFInfo
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- CN111053738A CN111053738A CN201910985982.7A CN201910985982A CN111053738A CN 111053738 A CN111053738 A CN 111053738A CN 201910985982 A CN201910985982 A CN 201910985982A CN 111053738 A CN111053738 A CN 111053738A
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- clopidogrel
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- block copolymer
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Abstract
The invention discloses an injection of clopidogrel, a preparation method and application thereof, wherein the injection of clopidogrel adopts a micelle nano system as a drug carrying system. The mPEG-PLA block copolymer and clopidogrel are prepared into a micelle nano system by a film dispersion method. The clopidogrel injection can realize the advantages of high solubility, quick release, quick drug effect and the like, and can be applied to the preparation of drugs for treating platelet aggregation related diseases and drugs for treating diseases with pharmacological effect on clopidogrel.
Description
Technical Field
The invention relates to a pharmaceutical dosage form, a preparation method and application, in particular to an injection dosage form of clopidogrel, a preparation method and application.
Background
Acute Coronary Syndrome (ACS) is a common serious cardiovascular disease, and is a group of clinical syndromes pathologically based on rupture or erosion of coronary atherosclerotic plaques, followed by complete or incomplete occlusive thrombosis, including Unstable Angina (UA), acute ST elevation myocardial infarction (STEMI), and acute non-ST elevation myocardial infarction (NSTEMI). Angina pectoris occurs when the blood flow to the coronary arteries fails to meet the metabolic needs of the myocardium, causing acute and transient ischemia and hypoxia to the myocardium. Coronary atherosclerosis can cause stenosis of one or more vascular lumens and insufficient blood supply to cardiac muscle, and once blood supply is rapidly reduced or interrupted, acute myocardial infarction ((AMI)) can occur when cardiac muscle is severely and durably subjected to acute ischemia for more than 20-30 minutes.
At present, Percutaneous Coronary Intervention (PCI) is the first choice for treating ACS, ACS patients are treated in time in a proper mode, the fatality rate can be greatly reduced, complications can be reduced, and the prognosis of the patients is improved. The goal of PCI reperfusion therapy in acute myocardial infarction is to restore optimal blood flow to the infarct-related artery, to ensure adequate blood supply to the ischemic but viable myocardium, and to reduce infarct size and mortality.
The essence of the development of acute coronary syndrome is a thrombotic event, while in ACS patients treated with PCI, platelets are highly activated, mediating thrombus formation, which is the pathophysiological basis for anti-platelet pretreatment in ACS patients. The risk of thrombosis in the stent is the highest in the early stage of PCI operation of a patient, the risk is in a trend of gradually decreasing along with the lapse of time, the active inhibition of platelet aggregation before the PCI operation is an important link, the risk of thrombosis in the stent can be reduced, and the recovery of blood flow after the PCI operation and the reperfusion of cardiac muscle are facilitated. Therefore, anti-platelet therapy during PCI perioperative plays an extremely important role in reducing the risk of ischemic events, reducing the risk of serious cardiovascular events and improving clinical prognosis.
Clopidogrel belongs to BCS II medicament, has low dissolution and high permeability, is used as a second generation thienopyridine antiplatelet medicament and irreversibly inhibits P2Y12Adenosine Diphosphate (ADP) platelet membrane receptor, an inactive prodrug, requires oxidation by the hepatocyte cytochrome P450(CYP) system to produce clopidogrel H4-thiol, a recognized sole active metabolite. It has been used in combination with aspirin to prevent acute coronary healdsThe standard of care for cardiovascular events in synergetics (ACS) and/or Percutaneous Coronary Intervention (PCI) patients, and still the most widely used P2Y12A receptor inhibitor. Although there is more efficient P2Y12Receptor inhibitors such as prasugrel and ticagrelor all showed superior effects to clopidogrel in reducing recurrent ischemic events, but these oral formulations may cause delayed absorption and may cause more bleeding events.
The clopidogrel with the consistent dose is administered before the PCI operation, so that the incidence rate of cardiovascular events can be obviously reduced, the main cardiovascular prognosis of patients after the PCI operation can be obviously improved, and ischemia after the operation can be improved, however, the clopidogrel still has the following problems that ① tablets have slow effect, and generate an anti-platelet aggregation effect about 6 hours after administration, which is a main defect of the clopidogrel applied to the PCI of acute myocardial infarction emergency, ② has irreversible anti-platelet aggregation effect, the recovery time of platelet function is long (5-7 days), other treatment effects of the patients can be influenced, and the administration of the clopidogrel for patients who are subjected to Coronary Artery Bypass Graft (CABG) is stopped for at least 5-7 days.
Therefore, treatment of patients suffering from ACS who require PCI surgery within ninety minutes after hospitalization is difficult to achieve an anti-platelet aggregation effect for this brief period of time when clopidogrel tablets are used. In addition, when faced with an emergency Acute Coronary Syndrome (ACS) situation, the clinician must decide whether to begin clopidogrel therapy in the emergency room prior to percutaneous coronary intervention or to delay clopidogrel therapy until after percutaneous coronary intervention can clear the coronary anatomy. The risk of potential ischemic events is reduced if treatment is initiated early. However, if treatment is initiated early and angiography indicates the need for coronary artery bypass grafting, the patient's risk of bleeding increases.
Oral clopidogrel has practical and clinical limitations in acute settings, mainly due to the slow onset of action of oral formulations that do not achieve the desired antiplatelet efficacy within an optimal time frame. The prevention of thrombosis and bleeding risk in stents is a pair of contradictions, so a balance point must be found, the balance point lies in the development of clopidogrel injection formulations, and the injection drugs have the characteristic of faster onset and can overcome the limitations in the acute treatment environment.
The low solubility of clopidogrel in water at neutral pH makes the development of a highly bioavailable and physically stable drug product very difficult, especially when intravenous dosage forms need to be developed. Today, there are many methods for preparing intravenous formulations of poorly water soluble drugs. These methods include drug nanoparticle suspension; forming a complex with cyclodextrin and its derivatives; various co-solvent systems are used; salts are formed with strong acids in low pH solutions, and the like. However, for nanosuspension systems, where the drug nanoparticles are more susceptible to catalytic degradation due to higher exposure to aqueous media, for co-solvent systems, precipitation, injection pain and phlebitis may be caused; cyclodextrins and their derivatives may cause potential nephrotoxicity and bradycardia, and blood pressure drops. In summary, each of the above listed methods has its inherent limitations and is insufficient to formulate clopidogrel injection dosage forms as a biocompatible carrier with sufficient stability, minimal side effects and adequate pharmacokinetic profile.
Injectable forms of clopidogrel can significantly impact the management paradigm of critically ill patients suffering from ACS. Clopidogrel for injection alters the need for a loading dose administration of clopidogrel before the anatomy of the coronary arteries is known. Thus, the absence of a clopidogrel loading dose does not increase the risk of bleeding if cardiac surgery is decided. If the anatomy suggests optimal treatment by percutaneous coronary intervention, an injectable formulation of clopidogrel can be used at this point to exert a rapid inhibition of platelet aggregation. The injectable formulation will make clopidogrel suitable only for the appropriate patients, not those most suitable for cardiac surgery.
Therefore, development of an injection of clopidogrel is urgently needed to realize rapid release of clopidogrel, enter liver for metabolism in a large amount, rapidly generate active metabolites and realize an anti-platelet aggregation effect so as to cope with clinical acute thrombosis treatment conditions.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide an injection of clopidogrel with good solubility, quick release and quick drug effect.
The invention also aims to provide a preparation method of the injection of the clopidogrel.
The last purpose of the invention is to provide the application of the injection preparation of the clopidogrel.
The technical scheme is as follows: the invention provides an injection of clopidogrel, which adopts a micelle nano system as a drug carrying system.
Further, the drug delivery system is a micelle nano system formed by mPEG-PLA block copolymer.
Further, the mPEG-PLA block copolymer is synthesized by adopting a ring-opening polymerization mode.
Further, the mPEG-PLA block copolymer and clopidogrel are prepared into a micelle nano system by a film dispersion method.
The preparation method of the clopidogrel injection comprises the following steps:
(1) synthesis of mPEG-PLA Block copolymer: mixing mPEG and lactide, heating, cooling after mPEG and lactide are completely melted, adding a stannous octoate toluene solution as a catalyst, magnetically stirring and uniformly mixing, removing toluene and residual moisture in vacuum, heating, reacting under the protection of nitrogen, cooling to room temperature after reaction is finished, adding a proper amount of dichloromethane into a reactant for dissolving, precipitating with low-temperature anhydrous ether, carrying out vacuum filtration to obtain a white filter cake, and carrying out vacuum drying on the purified product at room temperature for later use;
(2) synthesizing a polymer micelle system for encapsulating clopidogrel: accurately weighing clopidogrel and mPEG-PLA block copolymer, performing ultrasonic treatment with methanol until the clopidogrel and mPEG-PLA block copolymer are completely dissolved, performing rotary evaporation until the solvent is completely volatilized, completely forming a film, then performing hydration, and passing the film.
Further, the mass ratio of mPEG to lactide in the step (1) is 1: 1.
Further, the mass ratio of the clopidogrel to the mPEG-PLA block copolymer in the step (2) is 1: 1-5.
The clopidogrel injection is used for preparing a medicament for treating diseases related to platelet aggregation.
The clopidogrel injection is used for preparing a medicament for treating diseases with pharmacological effect on clopidogrel.
The micelle nano system is a novel drug-loading system prepared by taking a molecular polymer as a material, a nano core-shell structure is spontaneously formed by an amphiphilic copolymer material in a water-soluble solution, a core is a hydrophobic group and can be used as a storage of a drug with low solubility in water, a shell of a micelle is a hydrophilic group, the drug encapsulated in the micelle is protected from contacting with water, the polymer micelle solution is not easily damaged in the process of diluting or concentrating the solution, the encapsulated drug can be well protected, and the stability of the drug is improved.
Compared with other drug carrier materials, the polymer micelle serving as a carrier drug delivery system has low toxicity, inherent self-assembly performance, higher safety and easier preparation. The micelle as a drug carrier can not only increase the solubility of drugs with poor water solubility, but also reduce the use of auxiliary agents in injection and reduce the occurrence of adverse reactions such as allergy and the like.
mPEG-PLA polymers are one of the most potential carrier materials for current micellar drug delivery systems. The polyethylene glycol hydrophilic chain segment can prevent the drug carrier from being adhered to phagocyte cells in vivo, prolong the acting time of the drug in vivo, realize long circulation and play a good role in treatment. The polylactic acid can be completely biodegraded in vivo to generate carbon dioxide and water, the carbon dioxide and the water are not toxic or irritant to human bodies, and cannot be accumulated in vivo, and can be completely discharged out of the human bodies, and no toxic or side effect is caused to the human bodies. Therefore, the mPEG-PLA amphiphilic block copolymer not only can increase the solubility of insoluble drugs and realize larger drug loading, but also has good biocompatibility and biodegradability and does not generate accumulation. The micelle formed by mPEG-PLA can release drugs quickly, is mainly metabolized in the liver, can carry clopidogrel to the liver, is metabolized by liver medical enzyme to generate active metabolite, realizes the rapid platelet aggregation inhibition effect, and meets the requirements of clinical first aid.
Has the advantages that: the clopidogrel belongs to BCS II drugs, has low solubility and high permeability, and can increase the solubility thereof through a micelle nano system; on the premise that the drug-loading capacity of the mPEG-PLA block copolymer is large, compared with other nano systems, the micelle is possibly lack in stability, the drug can be released more quickly, and by utilizing the characteristic, the clopidogrel polymer micelle can realize quick drug release after entering blood circulation, so that the extremely quick platelet aggregation resisting effect is achieved; the micelle is mainly metabolized in the liver, and by means of the characteristic, clopidogrel is delivered to the liver, so that rapid biotransformation of P450 enzyme is realized, active metabolites are generated, and rapid antiplatelet activity is exerted.
Drawings
FIG. 1 is a nuclear magnetic spectrum of mPEG-PLA in the present invention;
FIG. 2 is a transmission electron microscope image of a micellar nanosystem encapsulating clopidogrel according to the present invention;
fig. 3 is an in vitro release profile of free clopidogrel and clopidogrel-encapsulated micellar nanosystems of the present invention.
Detailed Description
Example 1
(1) Synthesis and characterization of mPEG-PLA
10g of each of mPEG2000 and lactide is taken and placed in a 250mL two-necked bottle, the temperature is slowly increased to 135 ℃, and the temperature is reduced to 110 ℃ after the mPEG2000 and the lactide are completely melted. Adding 20% (v/v) of a toluene solution of stannous octoate (the adding amount of the stannous octoate is 0.25% of the total weight of the reactants) as a catalyst, magnetically stirring and uniformly mixing, removing toluene and residual water in vacuum until no bubbles are generated in the reaction solution, heating to 140 ℃, and reacting for 6 hours under the protection of nitrogen. After the reaction is finished, cooling to room temperature, adding a proper amount of dichloromethane into the reaction product for dissolving, precipitating with low-temperature anhydrous ether, and performing vacuum filtration to obtain a white filter cake. The purification is repeated for 3 times, the obtained product is dried in vacuum for 24 hours at room temperature, and the structure of the product is detected by nuclear magnetism, and the result is shown in figure 1.
(2) Synthesis of mPEG-PLA micelle nano system for encapsulating clopidogrel
Accurately weighing 20mg of clopidogrel and 100mg of mPEG-PLA in a penicillin bottle, ultrasonically dissolving the clopidogrel and the mPEG-PLA in a proper amount of methanol, transferring the dissolved clopidogrel into an eggplant-shaped bottle, rotatably evaporating the mixture at 40 ℃ until a solvent is volatilized, completely forming a film, adding 5mL of up water for hydration, and filtering the mixture through a 0.22 mu m filter membrane to obtain a clopidogrel micelle solution.
Example 2
Synthesizing the mPEG-PLA micelle nano system for encapsulating and loading clopidogrel: accurately weighing 40mg of clopidogrel and 100mg of mPEG-PLA in a penicillin bottle, ultrasonically dissolving the clopidogrel and the mPEG-PLA in a proper amount of methanol, transferring the clopidogrel into an eggplant-shaped bottle, rotatably evaporating the clopidogrel and the mPEG-PLA in the methanol at 40 ℃ until the solvent is volatilized, completely forming a film, adding 5mL of up water for hydration, and filtering the mixture through a 0.22 mu m filter membrane to obtain a clopidogrel micelle solution.
The experimental procedures and conditions for synthesis and characterization of mPEG-PLA were the same as in example 1.
Example 3
Synthesizing the mPEG-PLA micelle nano system for encapsulating and loading clopidogrel: accurately weighing 60mg of clopidogrel and 100mg of mPEG-PLA in a penicillin bottle, ultrasonically dissolving the clopidogrel and the mPEG-PLA in a proper amount of methanol, transferring the clopidogrel into an eggplant-shaped bottle, rotatably evaporating the clopidogrel and the mPEG-PLA in the methanol at 40 ℃ until the solvent is volatilized, completely forming a film, adding 5mL of up water for hydration, and filtering the mixture through a 0.22 mu m filter membrane to obtain a clopidogrel micelle solution.
The experimental procedures and conditions for synthesis and characterization of mPEG-PLA were the same as in example 1.
Example 4
Synthesizing the mPEG-PLA micelle nano system for encapsulating and loading clopidogrel: accurately weighing 80mg of clopidogrel and 100mg of mPEG-PLA in a penicillin bottle, ultrasonically dissolving the clopidogrel and the mPEG-PLA in a proper amount of methanol, transferring the clopidogrel into an eggplant-shaped bottle, rotatably evaporating the clopidogrel and the mPEG-PLA in the methanol at 40 ℃ until the solvent is volatilized, completely forming a film, adding 5mL of up water for hydration, and filtering the mixture through a 0.22 mu m filter membrane to obtain a clopidogrel micelle solution.
The experimental procedures and conditions for synthesis and characterization of mPEG-PLA were the same as in example 1.
Example 5
And measuring the particle size of the sample by using a Malvern particle size measuring instrument and adopting a dynamic light scattering method technology to measure the particle size of the drug-loaded micelle to be 20.7 nm. The morphology of the formed micelle was observed by TEM transmission electron microscopy, as shown in fig. 2, and the obtained particle size was substantially the same as that measured by dynamic laser light scattering.
Example 6: evaluation of in vitro Release of clopidogrel micelles
0.5mL of clopidogrel micelle and 0.5mL of clopidogrel serving as a raw material drug are placed in a dialysis bag (5.0cm multiplied by 2.5cm, the intercepted relative molecular weight is 3500), the two ends are tied, and the clopidogrel micelle and the clopidogrel serving as the raw material drug are respectively added into 20mL of release media, wherein the release media are physiological saline containing 0.5 percent of polysorbate 80, and each of the three portions is parallel to each other, and the release conditions of the clopidogrel micelle and the clopidogrel serving as the raw material. Taking 1mL of release medium and supplementing an equal volume of fresh release medium at the same time for 0.5, 1, 2, 4, 6, 8, 12 and 24 hours respectively, sampling 10 mu L of sample after the sample passes through a 0.22 mu m filter membrane, measuring according to chromatographic conditions, recording peak area, calculating the release amount of CHS at each time point, and drawing a release curve, wherein the result is shown in figure 3. As shown in figure 3, the clopidogrel bulk drug is released quickly, is released completely in 4 hours basically, enters a plateau phase, is released quickly in the prophase (within 0.5 hour) of the clopidogrel micelle to generate burst release, is released slowly compared with a free drug, and is slowed down to some extent. Due to the unstable micelle structure, the sustained release effect gradually disappears along with the prolonging of time, the drug release speed is accelerated, and the cumulative release amount of the clopidogrel micelle is up to the release of free drugs after 6 hours, so that the clopidogrel micelle is basically completely released and reaches the plateau stage. Compared with free drugs, the drug release of the clopidogrel micelle is slowed, but the overall phase difference is not very large, so that the rapid drug release of the clopidogrel can be realized, and particularly, the clopidogrel micelle has a little phase difference compared with the free clopidogrel in a short time range of 0.5h, so that the aim of clinical first aid can be fulfilled.
Claims (9)
1. An injection formulation of clopidogrel, characterized in that: the micelle nano system is adopted as a drug-carrying system.
2. The injectable dosage form of clopidogrel according to claim 1, characterized in that: the drug delivery system is a micelle nano system formed by mPEG-PLA segmented copolymer.
3. The injectable dosage form of clopidogrel according to claim 2, characterized in that: the mPEG-PLA block copolymer is synthesized by adopting a ring-opening polymerization mode.
4. The injectable dosage form of clopidogrel according to claim 3, characterized in that: the mPEG-PLA segmented copolymer and clopidogrel are prepared into a micelle nano system by a film dispersion method.
5. The process for preparing an injection formulation of clopidogrel according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
(1) synthesis of mPEG-PLA Block copolymer: mixing mPEG and lactide, heating, cooling after mPEG and lactide are completely melted, adding a stannous octoate toluene solution as a catalyst, magnetically stirring and uniformly mixing, removing toluene and residual moisture in vacuum, heating, reacting under the protection of nitrogen, cooling to room temperature after reaction is finished, adding a proper amount of dichloromethane into a reactant for dissolving, precipitating with low-temperature anhydrous ether, carrying out vacuum filtration to obtain a white filter cake, and carrying out vacuum drying on the purified product at room temperature for later use;
(2) synthesizing a polymer micelle system for encapsulating clopidogrel: accurately weighing clopidogrel and mPEG-PLA block copolymer, performing ultrasonic treatment with methanol until the clopidogrel and mPEG-PLA block copolymer are completely dissolved, performing rotary evaporation until the solvent is completely volatilized, completely forming a film, then performing hydration, and passing the film.
6. The method for preparing an injection formulation of clopidogrel according to claim 5, characterized in that: the mass ratio of mPEG to lactide in the step (1) is 1: 1.
7. The method for preparing an injection formulation of clopidogrel according to claim 5, characterized in that: the mass ratio of the clopidogrel to the mPEG-PLA block copolymer in the step (2) is 1: 1-5.
8. Use of the clopidogrel injection formulation of claim 1 for the preparation of a medicament for the treatment of platelet aggregation-related diseases.
9. Use of the clopidogrel injection formulation of claim 1 for the preparation of a medicament for treating a disease having a pharmacological effect on clopidogrel.
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