CN108619525B - Netupidem-mPEG-PLA nanoparticle and preparation method and application thereof - Google Patents
Netupidem-mPEG-PLA nanoparticle and preparation method and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, and particularly relates to a nano-particle of Netupidem-mPEG-PLA, a preparation method and an application thereof. The technical problem to be solved by the invention is to provide a novel method to solve the problem of poor water solubility of Netupidan, the Netupidan is wrapped by an amphiphilic mPEG-PLA dual-block polymer, and a self-assembly method is adopted to prepare the Netupidan-mPEG-PLA nanoparticle. The nano-particles of Netupidem-mPEG-PLA have the advantages of good water solubility, uniform granularity, freeze-drying, redissolution, easy absorption, intravenous injection and the like.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a nano-particle of Netupidem-mPEG-PLA, a preparation method and an application thereof.
Background
At present, chemotherapy is a way for prolonging the life of patients with malignant tumors, and the life quality of the patients is seriously affected due to various adverse reactions in the chemotherapy. From the biological evolution point of view, emesis belongs to a mechanism for protecting the human body, can be influenced by the self state of a patient, cannot be completely controlled, and can only be alleviated. With the renewal of antiemetics, the combination of a compound such as Netupitant and palonosetron in antiemetic therapy, nausea and vomiting in nearly 98.5% of patients can be substantially completely alleviated.
Netupidem is a new drug, a selective antagonist of the human P-substance/neurokinin-1 (NK-1) receptor, while NK-1 is a natural neurotransmitter in the brain that causes emesis. As an NK-1 receptor blocker, netupitant is currently in clinical trials to effectively prevent nausea and vomiting during the acute and delayed phases of cancer chemotherapy (within 25-120 hours of initiating chemotherapy). Akynzeo capsules, developed by Hesinn corporation approved by FDA in the U.S. 10 months and 10 months in 2014, are marketed in the U.S. as a compound of netupitant and palonosetron to prevent nausea and vomiting during chemotherapy of patients. However, the poor water solubility of netupitant limits its use in pharmaceutical formulations, particularly in the form of solutions such as injectable formulations.
A Methoxy polyethylene glycol-polylactic acid (Methoxy polyethylene glycol) -poly (lactic acid), mPEG-PLA for short) diblock polymer is a degradable amphiphilic polymer with good biocompatibility and has important application in the field of biomedicine. Drug loading with PEG or PLA delivery vehicles has received U.S. FDA approval for clinical use in the 90's of the 20 th century. The mPEG-PLA copolymer contains hydrophilic block PEG and hydrophobic block PLA, can be self-assembled into nano-particles in aqueous solution, and has good application prospect in medicines and gene transfer systems. At present, paclitaxel formulations coated with mPEG-PLA diblock polymer nanoparticle carriers have been applied to clinical treatment of breast cancer in korea and europe, and have also entered phase II clinical trials in the united states.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a new method for wrapping netupitant so as to obviously improve the water solubility of the netupitant. The inventor finds that a novel water-soluble degradable nanoparticle, namely, a netupitant-mPEG-PLA nanoparticle, can be prepared by using an amphiphilic mPEG-PLA diblock copolymer to modify netupitant and using a self-assembly method. The nano-particles of Netupidem-mPEG-PLA have good water solubility, and can form various solution preparations, such as injections and the like.
The amphiphilic mPEG-PLA copolymer adopted in the invention is chemically named methoxy polyethylene glycol-polylactic acid, which is called mPEG-PLA for short. The methoxy polyethylene glycol-polylactic acid nano-particles have amphipathy, good biodegradability and biocompatibility, increase the circulation time and bioavailability of the drug in blood, and sustained release and targeted delivery, thereby increasing the drug effect and reducing the side effect. The mPEG-PLA nano-particle can be used as a carrier of chemical drugs, gene drugs, proteins, vaccines and the like.
Netupidem used in the present invention has a Chinese cultural name of 2- [3,5-bis (trifluoromethyl) phenyl group]-N, 2-dimethyl-N- [4- (2-methylphenyl) -6- (4-methylpiperazin-1-yl) pyridin-3-yl]Propionamide; english chemical name is 2- [3,5-bis (trifluoromethyl 1) phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyIpiperazin-l-yl)pyridin-3-yI]propanoamide; molecular weight 578.60; molecular formula C30H32F6N4O; CAS accession number: 290297-26-62, is a novel medicine for preventing nausea and vomiting caused by acute and delayed chemotherapy of cancer patients.
The first technical problem to be solved by the invention is to provide a preparation method of a netupitant-mPEG-PLA nanoparticle solution, which is prepared by taking the following raw materials according to the following proportioning relation:
raw materials: netupidem, mPEG-PLA copolymer; wherein the mass ratio of the Netupitant to the mPEG-PLA copolymer is 0.01-0.25;
solvent: at least one of dichloromethane, chloroform, acetone, tetrachloromethane, ethanol, methanol, diethyl ether, petroleum ether, pentane, ethyl acetate or cyclohexane;
hydration solution: at least one of water, isotonic solution or buffer solution;
the preparation method comprises the following steps: respectively dissolving the mPEG-PLA copolymer and the netupitant in a solvent, uniformly mixing, evaporating the solvent to dryness, adding a proper amount of hydration solution, and slightly shaking until the hydration is complete, wherein the obtained solution is the netupitant-mPEG-PLA nanoparticle solution.
Preferably, in the method for preparing a nano-particle solution of netupitant-mPEG-PLA, the mass ratio of netupitant to mPEG-PLA copolymer is 0.25.
Preferably, in the method for preparing the netupitant-mPEG-PLA nanoparticle solution, the mPEG-PLA copolymer is 80 parts, and the netupitant is 20 parts.
Preferably, in the method for preparing the netupitant-mPEG-PLA nanoparticle solution, the isotonic solution is at least one of normal saline, 5% glucose solution or 0.149mol/L sodium bicarbonate solution.
Preferably, in the preparation method of the netupitant-mPEG-PLA nanoparticle solution, the buffer solution is at least one of a phosphate buffer solution, an acetic acid-sodium acetate buffer solution, a citric acid-sodium citrate buffer solution, a disodium hydrogen phosphate-citric acid buffer solution, or a phthalic acid-hydrochloric acid buffer solution.
The invention also provides a Netupidan-mPEG-PLA nanoparticle solution prepared by the preparation method of the Netupidan-mPEG-PLA nanoparticle solution.
The invention also provides the nano-particles of the Netupidan-mPEG-PLA, and the nano-particles of the Netupidan-mPEG-PLA are obtained by drying the transparent liquid Netupidan-mPEG-PLA nano-particle solution.
The Netupitant-mPEG-PLA nano-particles obtained by the invention have uniform particle size, the average particle size of 58nm +/-10 nm and the average potential of-0.57 +/-0.21 mV, are neutral and stable in aqueous solution, and can be redissolved after being freeze-dried.
The invention also provides application of the Netupidan-mPEG-PLA nanoparticle solution or the Netupidan-mPEG-PLA nanoparticle in preparation of an NK-1 receptor blocker.
The invention also provides application of the Netopiramate-mPEG-PLA nanoparticle solution or the Netopiramate-mPEG-PLA nanoparticle in preparation of a medicine for preventing, treating or relieving nausea and vomiting caused by chemotherapy.
The method adopts a self-assembly mode to wrap the Netupitant by the mPEG-PLA, so that the water solubility of the Netupitant is obviously improved, when the ratio of the Netupitant to the PEG-PLA is 0.25, the solubility of the prepared Netupitant-mPEG-PLA nano particles in an aqueous solution is about 20mg/mL, the solubility of the Netupitant raw material drug in the water is only 0.00285mg/mL, and the water solubility of the Netupitant-mPEG-PLA nano particles is at least 70 times of that of the raw material drug, so that the water solubility of the Netupitant is greatly improved. Because the water solubility of the netupitant is extremely poor, the currently marketed Akynzeo capsule is a compound capsule of the netupitant and the palonosetron, and the method of wrapping the nano particles by mPEG-PLA to form self-assembly not only effectively and remarkably improves the water solubility of the netupitant, but also can prepare the drug into solution preparations such as injection and the like to realize intravenous injection, so that the drug reaches the body in the form of the nano particles through intravenous injection, the netupitant can be absorbed more easily, the release of the drug can be controlled, and the slow release effect in the body can be achieved.
Drawings
FIG. 1, (A) molecular structural formula of mPEG-PLA; (B) molecular structural formula of netupitant;
FIG. 2 is a schematic diagram of the self-assembly of Netupidem-mPEG-PLA nanoparticles;
FIG. 3, property profile of Netupidan-mPEG-PLA nanoparticles:
(A) a particle size distribution map of the netupitant-mPEG-PLA nanoparticles;
(B) a potential profile of the netupitant-mPEG-PLA nanoparticles;
(C) scanning transmission electron microscope images of the nano-particles of Netupidem-mPEG-PLA;
(D) appearance of nano-particles of netupitant-mPEG-PLA; the control is a mixed solution of a single raw material drug of netupitant dispersed in an aqueous solution (Wt ═ 20 mg/mL).
Detailed Description
Because of the poor water solubility of netupitant, the inventors have made extensive experimental studies to solve the problem of poor water solubility of netupitant, and attempted to modify or modify netupitant in various ways, for example, to make it hydrochloride salt, which is intended to improve the water solubility.
However, as a result of finding that the hydrochloride salt of netupitant is not dissolved, it was not possible to efficiently improve the water solubility of netupitant by the method of preparing the hydrochloride salt of netupitant as the hydrochloride salt of netupitant. The inventors have then made various attempts to make other modifications or adaptations to them without success. Finally, a large number of experiments show that the nano-particles of the netupitant-mPEG-PLA prepared by wrapping the netupitant with the mPEG-PLA in a self-assembly mode have good water solubility, and the method is an excellent method for effectively improving the water solubility of the netupitant.
The preparation method of the Netupidem-mPEG-PLA nanoparticle solution comprises the following steps of:
raw materials: netupidem, mPEG-PLA copolymer; wherein the mass ratio of the Netupitant to the mPEG-PLA copolymer is 0.01-0.25;
solvent: at least one of dichloromethane, chloroform, acetone, tetrachloromethane, ethanol, methanol, diethyl ether, petroleum ether, pentane, ethyl acetate or cyclohexane;
hydration solution: at least one of water, isotonic solution or buffer solution;
the preparation method comprises the following steps: respectively dissolving the mPEG-PLA copolymer and the netupitant in a solvent, uniformly mixing, evaporating the solvent to dryness, adding a proper amount of hydration solution, and slightly shaking until the hydration is complete, wherein the obtained solution is the netupitant-mPEG-PLA nanoparticle solution.
The invention also provides a Netupidan-mPEG-PLA nanoparticle solution prepared by the preparation method of the Netupidan-mPEG-PLA nanoparticle solution.
The invention also provides the nano-particles of the Netupidan-mPEG-PLA, and the nano-particles of the Netupidan-mPEG-PLA are obtained by drying the transparent liquid Netupidan-mPEG-PLA nano-particle solution.
The invention also provides application of the Netupidan-mPEG-PLA nanoparticle solution or the Netupidan-mPEG-PLA nanoparticle in preparation of an NK-1 receptor blocker.
The invention also provides application of the Netopiramate-mPEG-PLA nanoparticle solution or the Netopiramate-mPEG-PLA nanoparticle in preparation of a medicine for preventing, treating or relieving nausea and vomiting caused by chemotherapy.
The inventor invents that if the mass ratio of the netupitant to the mPEG-PLA copolymer exceeds 0.25, the self-assembly effect of the nanoparticles is poor, and the medicament cannot be completely formed into the nanoparticles. Within the range of less than 0.25, the proportion relation of the two can be adjusted freely according to the concentration requirement.
Examples
Respectively dissolving 20mg of netupitant and 80mg of mPEG-PLA in 10mL of dichloromethane, mixing in a round-bottom flask, removing an organic reagent at 60 ℃ by using a rotary evaporator, adding 1mL of pure water at 60 ℃, and slightly shaking until hydration is complete to form a netupitant-mPEG-PLA nanoparticle solution. The Netupidan-mPEG-PLA nanoparticle solution is dried to obtain the Netupidan-mPEG-PLA nanoparticles.
The characterization map of the drug-loaded nanoparticles is shown in fig. 3. Wherein FIG. 3(A) is a particle size distribution diagram of the nanoparticle. Wherein the average particle diameter of the nanoparticles was found to reach 58nm, and fig. 3(B) is a potential distribution diagram of the nanoparticles. Wherein the average potential of the nanoparticles was-0.52 mV, and FIG. 3(C) is a transmission electron micrograph of the nanoparticles. The transmission electron microscope detection shows that the nano-particles have small particle size and uniform dispersion. Fig. 3(D) is a graph of an appearance control of the nanoparticles. The control is a single mixed solution of netupitant drug dispersed in an aqueous solution (Wt ═ 20 mg/mL). As can be seen from the figure, when netupitant is directly added to water, the drug is poorly soluble in water and tends to float on the surface of the aqueous solution, and some of the drug forms crystals in water. The nano-particles prepared by the method of the invention are clear and transparent in appearance, and have no drug crystallization.
Claims (8)
1. The preparation method of the nano-particle solution of Netupidem-mPEG-PLA is characterized by comprising the following steps: the raw materials are taken according to the following proportioning relation for preparation:
raw materials: netupidem, mPEG-PLA copolymer; wherein the mass ratio of the Netupitant to the mPEG-PLA copolymer is 0.01-0.25;
solvent: at least one of dichloromethane, chloroform, acetone, tetrachloromethane, ethanol, methanol, diethyl ether, petroleum ether, pentane, ethyl acetate or cyclohexane;
hydration solution: at least one of water, isotonic solution or buffer solution;
the preparation method comprises the following steps: respectively dissolving the mPEG-PLA copolymer and the netupitant in a solvent, then uniformly mixing, evaporating the solvent to dryness, and adding a proper amount of hydration solution until the hydration is complete to obtain the netupitant-mPEG-PLA nanoparticle solution.
2. The method for preparing a solution of nanoparticles of Netupidem-mPEG-PLA according to claim 1, characterized in that: the mass ratio of netupitant to mPEG-PLA copolymer was 0.25.
3. The method for preparing a solution of nanoparticles of Netupidem-mPEG-PLA according to claim 1, characterized in that: the isotonic solution is at least one of normal saline, 5% glucose solution or 0.149mol/L sodium bicarbonate solution.
4. The method for preparing a solution of nanoparticles of Netupidem-mPEG-PLA according to claim 1, characterized in that: the buffer solution is at least one of phosphate buffer solution, acetic acid-sodium acetate buffer solution, citric acid-sodium citrate buffer solution, disodium hydrogen phosphate-citric acid buffer solution or phthalic acid-hydrochloric acid buffer solution.
5. The Netupidan-mPEG-PLA nanoparticle solution prepared by the method for preparing the Netupidan-mPEG-PLA nanoparticle solution according to any one of claims 1 to 4.
6. The nano-particle of Netupidem-mPEG-PLA is characterized in that: obtained by drying the solution of nano-particles of Netupidan-mPEG-PLA according to claim 5.
7. Use of the solution of Netupidan-mPEG-PLA nanoparticles of claim 5 or the Netupidan-mPEG-PLA nanoparticles of claim 6 in the preparation of NK-1 receptor blockers.
8. Use of the netupitant-mPEG-PLA nanoparticle solution of claim 5 or the netupitant-mPEG-PLA nanoparticle of claim 6 in the preparation of a medicament for preventing, treating or alleviating chemotherapy-induced nausea and vomiting.
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| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
| CN105878250A (en) * | 2014-10-29 | 2016-08-24 | 北京乐嘉宝医药科技有限责任公司 | Aprepitant nano composition |
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| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
| CN105878250A (en) * | 2014-10-29 | 2016-08-24 | 北京乐嘉宝医药科技有限责任公司 | Aprepitant nano composition |
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| Recent advances in PeG–PLA block copolymer nanoparticles;Ren Zhong Xiao等;《International Journal of Nanomedicine》;20101125;第5卷;第1057-1065页 * |
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