CN112168788B - Aprepitant micelle sterile freeze-dried preparation for intravenous injection and preparation method thereof - Google Patents
Aprepitant micelle sterile freeze-dried preparation for intravenous injection and preparation method thereof Download PDFInfo
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- 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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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an aprepitant micelle sterile freeze-dried preparation for intravenous injection and a preparation method thereof, and belongs to the technical field of medicines. The aprepitant micelle sterile lyophilized preparation for intravenous injection comprises aprepitant, methoxypolyethylene glycol-derivatized phospholipid and a pharmaceutically acceptable lyophilization protectant. The invention selects methoxy polyethylene glycol-derivatized phospholipid as a solubilizer, increases the solubility of aprepitant and improves the bioavailability. Meanwhile, the aprepitant micelle sterile freeze-dried preparation does not contain irritant components such as ethanol and the like, does not contain Tween sensitizing components, and improves the clinical use safety. The composition can be administered by intravenous injection, is convenient for patients with dysphagia and poor oral absorption, and can be used for treating acute and delayed nausea and emesis caused by antineoplastic agent.
Description
Technical Field
The invention relates to an aprepitant preparation for intravenous injection and a preparation method thereof, wherein the aprepitant preparation is composed of aprepitant and methoxy polyethylene glycol-derivatized phospholipid, can improve solubility of aprepitant, prolong elimination half-life period and improve bioavailability, and belongs to the technical field of medicines.
Background
Tumor resistance is a complex therapeutic process that not only kills cancer cells, but also improves the cachexia status of the patient, strengthens the body, focuses on the mental perception of the patient, and is amenable to treatment. Nausea and vomiting caused by the antitumor drugs seriously affect the health and treatment effect of patients. More than 75% of chemotherapeutic drugs have emetogenic properties and the incidence of emesis is as high as 90% (Ann Oncol,2015.26(6): 1081-90.). In addition, some small molecule targeted drugs are also moderate-strength emetics such as imatinib (J. Clin. Oncology, 2014.19(3): 263-273.). Nausea and vomiting caused by these antineoplastic agents are the most common adverse effects. It can cause metabolic disorders, impaired body function, malnutrition, and significantly affect the quality of life and the effectiveness of chemotherapy in patients.
Nausea and vomiting caused by antineoplastic drugs are regulated by two key pathways. Central (brain) and peripheral (gastrointestinal) pathways. Acute emesis is a reaction occurring within 0-24 hours of chemotherapy and is mainly regulated and controlled by peripheral (gastrointestinal) pathways; delayed emesis occurs within 24-120 hours after chemotherapy and is mainly regulated by central pathways. Currently, there are many drugs that can inhibit acute reactions, such as 5-hydroxytryptamine receptor (5-HT)3) Antagonists, and the like. There remains a need for agents that effectively modulate central pathways to inhibit delayed nausea and vomiting. The NK-1 receptor antagonist aprepitant passes through a blood brain barrier, occupies an NK-1 receptor in the brain with high selectivity and high affinity,thus inhibiting chemotherapy-induced emesis at the central level (drug evaluation, 2016.13(10): 21-52.).
Aprepitant is a highly selective antagonist of the human substance P neurokinin 1(NK-1) receptor and is useful in the treatment of chemotherapy drug-induced (adult) acute and delayed nausea and vomiting. The pharmacological actions can be divided into the following two groups. Firstly, aprepitant has strong selectivity on NK-1 receptor and can treat the existing drug targets such as 5-HT3The dopamine receptor and the glucocorticoid receptor have low or no affinity, and are convenient for drug combination. Therefore, related clinical guidelines at home and abroad recommend drug combinations as a first line of treatment. Secondly, aprepitant can cross blood brain barrier and act on central NK-1 receptor, so that the curative effect of aprepitant on delayed emesis is obviously superior to that of 5-HT3Antagonists (drug evaluation, 2016.13(10): 21-52.). Currently, aprepitant is marketed in the form of oral capsules (trade name: Emend) and emulsions for intravenous injection (trade name: CINVANTI).
Oral capsules suffer from the following disadvantages. First, bioavailability is not high, about 65% (International Journal of Nanomedicine,2007.2(1): 13-18.). Secondly, gastrointestinal side effects are high. The medicine is NK-1 receptor high selective antagonist, and NK-1 receptor is distributed in central nervous system and periphery (gastrointestinal system). Since the oral capsule inhibits NK-1 receptors in the stomach and intestine, side effects of the stomach and intestine such as hiccup and constipation occur (J. Clin. therapy, 2018.16(9): 14-28.). Third, clinical use is limited. Some patients with tumors have dysphagia, such as high-grade esophageal tumors in China. In addition, patients with advanced tumors are mostly in a cachexia state and have poor gastrointestinal absorption capacity, while aprepitant is just a poorly absorbed drug of BCS IV (Int J Pharm,2004.285(1-2):135-46.), resulting in poor oral bioavailability. Fourth, children are restricted in use. Three-phase clinical studies by Merck showed that The drug could be administered to children, but at doses adjusted (The Lancet Oncology,2015.16(4): 385-394). The current dosage form specification is only suitable for adults. If aprepitant is prepared into freeze-dried powder for injection, the aprepitant can be conveniently divided into doses, and is suitable for patients of different ages.
Emulsions for intravenous injection also have certain drawbacks. Firstly, the emulsion for injection is easily phagocytized by a reticuloendothelial system, is enriched in organs such as liver, spleen and the like, and reduces the concentration of a target site drug, resulting in reduced bioavailability (Chinese patent CN 102018670B). Secondly, aprepitant emulsion for injection (trade name CINVANTI) adopts ethanol as a co-emulsifier. Ethanol is volatile, resulting in a decrease in oil/water interfacial tension, affecting emulsion stability. If the medicine is developed into a freeze-dried powder preparation for injection, the stability of the preparation is improved, and the storage life is prolonged. Thirdly, ethanol is used as a solubilizer for the injection emulsion. Clinical intravenous injection of ethanol may cause adverse reactions such as pain at injection site, neuritis and the like (Chinese patent CN 109364023A).
Therefore, the development of a new injection dosage form is still expected by those skilled in the art, and is beneficial to more patients, especially people with dysphagia or poor oral absorption, and part of children patients. Aprepitant is a BCS IV (four types in a biological pharmacy classification system) drug, is difficult to dissolve and absorb and has low bioavailability. Therefore, the key for solving the problems is to select a safe solubilizer to improve the solubility of aprepitant, avoid phagocytosis of a reticuloendothelial system and improve the bioavailability. Polyethylene glycol-derivatized phospholipids are phospholipid compounds modified by polyethylene glycol (PEG), and phospholipid molecules are directionally arranged in an aqueous solution to form a stable core-shell micelle structure. The PEG shell has better hydrophilicity, can shield the reticuloendothelial system from identifying and absorbing the medicament, prolongs the in vivo circulation time and improves the bioavailability of the medicament (China journal of the pharmaceutical industry 2011, 42(7): 535-537). Tween is selected as a solubilizer, but the excipients are easy to cause local and systemic anaphylactic reactions (Adv Ther,2018.35: 754-. Compared with tween, the polyethylene glycol-derived phospholipid has better biocompatibility. Phosphatidylethanolamine is a representative substance of such derivatized phospholipids. The phosphatidylethanolamine has been marketed in Germany, China, Japan, the United states and Canada respectively, and the clinical use for injection shows good safety. The invention selects methoxypolyethylene glycol-derivatized phospholipid as a solubilizer. The Log P of aprepitant is 5.2, the aprepitant has fat solubility, the phospholipid part of methoxyl polyethylene glycol derivatization phospholipid also has fat solubility, the aprepitant and the phospholipid part form micelles through self-assembly by a similar compatible principle, PEG on the surfaces of the micelles can prevent RES phagocytosis, the elimination half-life period is prolonged, and the bioavailability is improved.
Disclosure of Invention
The invention aims to solve the technical problem of providing an intravenous injection preparation for increasing the solubility of aprepitant and improving the bioavailability so as to overcome the defects of the existing preparation such as oral capsules, intravenous injection emulsion and the like. The aprepitant micelle sterile freeze-dried preparation for intravenous injection provided by the invention does not contain irritant components such as ethanol and does not contain Tween sensitizing components, so that the clinical use safety is improved.
In order to solve the technical problem, the invention adopts the following technical scheme.
The first aspect of the invention provides the following technical scheme: methoxy polyethylene glycol-derivatized phospholipid is selected as a solubilizer to prepare an aprepitant micelle sterile lyophilized preparation for intravenous injection, which contains aprepitant, methoxy polyethylene glycol-derivatized phospholipid and a lyophilization protectant.
The mass ratio of aprepitant to methoxypolyethylene glycol-derivatized phospholipid in the aprepitant micelle sterile lyophilized preparation for intravenous injection is 1: 1 to 1: 20.
the phospholipid derived from methoxypolyethylene glycol is formed by connecting methoxypolyethylene glycol and phospholipid through covalent bonds, and the phospholipid part can be Phosphatidylethanolamine (PE), Distearoylphosphatidylethanolamine (DSPE), Dipalmitoylphosphatidylethanolamine (DPE), dioleoylphosphatidylethanolamine (dioleoylphosphatidylethanolamine), Phosphatidylcholine (PC), Phosphatidylinositol (PI), Phosphatidylserine (PS), diphosphatidylglycerol, condensed acid phospholipid, Lysophosphatidylcholine (LPC) and Lysoethanolamine Phospholipid (LPE).
The phospholipid in the methoxypolyethylene glycol-derivatized phospholipid of the invention is preferably distearoyl phosphatidyl ethanolamine.
In the methoxypolyethylene glycol-derivatized phospholipid, the molecular weight of methoxypolyethylene glycol (MPEG) is 500-50000, and the preferred molecular weight is 1000-10000.
As a preferred embodiment of the invention, the methoxypolyethylene glycol-derived phospholipid is methoxypolyethylene glycol 2000-distearoyl phosphatidyl ethanolamine (MPEG2000-DSPE), and the Chinese name of the domestic adjuvant filing system is PEPTED.
As a preferred embodiment of the invention, the weight ratio of aprepitant to phosphatidylethanolamine in the aprepitant micelle sterile lyophilized preparation for intravenous injection is 1: 1 to 1: 20, preferably 1: 5 to 1: 15.
as a preferred embodiment of the present invention, the lyoprotectant is at least one of mannitol, glucose, albumin, lactose, fructose, and sucrose.
According to the requirement, a pH regulator (hydrochloric acid, histidine or sodium hydroxide) can be added into the aprepitant micelle sterile freeze-dried preparation to regulate the pH value to 6.0-8.0.
According to the requirement, an osmotic pressure regulator (glucose, mannitol or sucrose) can be added into the aprepitant micelle sterile lyophilized preparation to regulate the osmotic pressure to human body isotonic.
Other pharmaceutically acceptable auxiliary agents can be added into the sterile lyophilized preparation of aprepitant micelle according to needs.
The aprepitant micelle sterile freeze-dried preparation for intravenous injection is white loose block or powder in appearance. In clinical use, the injection is diluted by glucose injection or sodium chloride injection and then is injected into the vein. After dilution, the appearance is light blue opalescent liquid; the particle size range is 10-100 nm, the encapsulation efficiency is more than 90%, the pH value is 6.0-8.0, the ZETA potential is-40 to-30 mV, and the osmotic pressure molar concentration is 290-310 mOsmol/kg.
In a second aspect, the invention provides a preparation method of the aprepitant micelle sterile lyophilized preparation for intravenous injection, which comprises the following steps:
(1) dissolving aprepitant and methoxypolyethylene glycol-derivatized phospholipid in a proper amount of organic solvent;
(2) removing the organic solvent to form an aprepitant/methoxypolyethylene glycol-derivatized phospholipid composite membrane;
(3) placing the aprepitant/methoxypolyethylene glycol-derived phospholipid composite membrane prepared in the step (2) in a vacuum drying oven to remove residual organic solvent;
(4) and (4) adding water into the dried composite membrane in the step (3), and hydrating, whirling and shaking to obtain the aprepitant-entrapped micelle solution.
(5) Adding a proper amount of a freeze-drying protective agent and a pH regulator into the aprepitant micelle solution prepared in the step (4), and dissolving the aprepitant micelle solution;
(6) and (5) sterilizing the aprepitant micelle solution prepared in the step (5) by a 0.22-micrometer microporous filter membrane under an aseptic condition, and freeze-drying to remove water to prepare the aprepitant micelle aseptic freeze-dried preparation.
The organic solvent in step (1) of the method of the present invention is methanol, ethanol, chloroform, or a mixture thereof.
Step (2) of the process of the present invention is the removal of the organic solvent by reducing the pressure and/or the removal of the organic solvent under vacuum.
The aprepitant/methoxypolyethylene glycol-derivatized phospholipid composite membrane obtained in the step (3) is dried in a vacuum drying oven for 12-24 hours, and is dried in vacuum at the temperature of 20-40 ℃ to remove residual organic solvent.
In the step (4), the water is hydrated in a water bath at the temperature of 20-60 ℃ for 1-2 hours.
The vortex shaking time in the step (4) of the method is 1-5 minutes.
The pH value of the micellar solution prepared in the step (4) of the method is adjusted to 6.0-8.0.
The preparation method of the aprepitant micelle sterile freeze-drying preparation comprises the following steps: dissolving methoxy polyethylene glycol-derivatized phospholipid and aprepitant in an organic solvent in a round-bottom flask, volatilizing the organic solvent by using a rotary evaporator to enable the methoxy polyethylene glycol-derivatized phospholipid and the drug to form a layer of uniform film on the wall of the flask, adding deionized water, adding a freeze-drying protective agent after hydration and vortex shaking, filtering the obtained micelle solution with a 0.22 mu m microporous filter membrane for sterilization, and freeze-drying to remove water to finally prepare the aprepitant micelle sterile freeze-dried powder.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and it is intended that such terms and phrases be interpreted as having a more complete description and interpretation herein, unless otherwise expressly stated otherwise, unless expressly stated otherwise.
Advantageous technical effects
The invention mainly provides an intravenous injection preparation for increasing solubility of aprepitant and improving bioavailability, so as to overcome the defects of the existing preparation such as oral capsules, intravenous injection emulsion and the like. Aprepitant is a BCS IV medicament, is insoluble and difficult to absorb, and has low bioavailability. The oral capsule has low bioavailability and more gastrointestinal side effects, can not be used by patients with dysphagia of part of tumor patients, and can not be used by children with the existing dosage specification. Meanwhile, the marketed intravenous injection emulsion is easy to be phagocytized by a reticuloendothelial system, so that the bioavailability is reduced; adverse reactions such as pain and neuritis exist at the injection site.
In order to solve the defects of the product, the invention selects methoxypolyethylene glycol-derivatized phospholipid as a solubilizer. The methoxy polyethylene glycol-derived phospholipid is an amphiphilic polymer formed by combining MPEG molecules and phospholipid molecules through covalent bonds, and the phospholipid molecules are directionally arranged in an aqueous solution to form a stable core-shell micelle structure. The MPEG shell causes repulsion between the particles; MPEG forms 'conformation cloud' on the surface of micelle to generate 'steric hindrance effect'; hydrophilic MPEG forms a hydrated film on the surface of micelle particles (journal of chinese medical industry 2004, 35(1): 55-58). The superposition of the three effects can shield the recognition and the uptake of the reticuloendothelial system to the micelle particles, prolong the in vivo circulation time and improve the bioavailability of the medicament. The phospholipid portion of the polyethylene glycol derivatized phospholipid contains a non-polar fatty acid, forming the hydrophobic core of the micelle. The Log P of aprepitant is 5.2, the aprepitant has hydrophobicity, and can form micelles by self-assembly with fatty acid of phospholipid through a similar compatible principle, and the MPEG on the surfaces of the micelles can prevent RES phagocytosis, prolong elimination half-life and improve bioavailability. The aprepitant micelle sterile freeze-dried preparation for intravenous injection does not contain irritant components such as ethanol and Tween sensitizing components, so that the clinical use safety is improved; the particle size range is 10-100 nm, and the encapsulation efficiency is more than 90%.
Drawings
Figure 1 is a rat pharmacokinetic profile of aprepitant micelles.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
Example 1:
dissolving 75mg of cultivated phosphatidylethanolamine and 15mg of aprepitant in 2mL of ethanol in a round-bottom flask, evaporating the ethanol by using a rotary evaporator under the condition of 50 ℃ water bath to form a layer of uniform film on the wall of the polymer and the drug, hydrating the film with 5mL of deionized water, standing the film for 30min to form micelles by full self-assembly, adding a proper amount of sodium hydroxide solution to adjust the pH value to 7.5, adding 0.9g of lactose, filtering and sterilizing the solution through a 0.22 mu m microporous membrane after dissolution, and freeze-drying the filtrate for 72 hours to remove water to finally prepare the aprepitant micelle sterile freeze-dried preparation.
Relevant properties of aprepitant micellar solution were determined:
particle size: the particle size is 17nm as determined by a dynamic light scattering method;
the drug encapsulation efficiency is as follows: 93.8% by high performance liquid chromatography;
pH value: 7.5.
example 2:
dissolving 150mg of cultivated phosphatidylethanolamine and 15mg of aprepitant in 3mL of ethanol in a round-bottom flask, evaporating the ethanol by using a rotary evaporator under the condition of 50 ℃ water bath to form a layer of uniform film on the wall of the polymer and the drug, hydrating the film with 10mL of deionized water, standing the film for 30min to form micelles by full self-assembly, adding a proper amount of sodium hydroxide solution to adjust the pH value to 7.5, adding 1.65g of lactose, filtering and sterilizing the solution through a 0.22 mu m microporous membrane after dissolution, and freeze-drying the filtrate for 72 hours to remove water to finally prepare the aprepitant micelle sterile freeze-dried preparation.
Relevant properties of aprepitant micellar solution were determined:
particle size: the particle size is 25nm as measured by a dynamic light scattering method;
the drug encapsulation efficiency is as follows: 94.5% by high performance liquid chromatography;
pH value: 7.4.
example 3:
in a round-bottom flask, dissolving 300mg of cultivated phosphatidylethanolamine and 15mg of aprepitant in 5mL of ethanol, evaporating the ethanol by using a rotary evaporator under the condition of 50 ℃ water bath to form a layer of uniform thin film on the wall of the polymer and the drug, then hydrating with 15mL of deionized water, standing for 30min to form micelles by sufficient self-assembly, adding a proper amount of sodium hydroxide solution to adjust the pH value to 7.5, adding 3.15g of lactose, filtering and sterilizing through a 0.22 mu m microporous membrane after dissolution, and freeze-drying the filtrate for 72 hours to remove water to finally prepare the aprepitant micelle sterile freeze-dried preparation.
Relevant properties of aprepitant micellar solution were determined:
particle size: the particle size is 28nm as measured by a dynamic light scattering method;
the drug encapsulation efficiency is as follows: 95.3% by high performance liquid chromatography;
pH value: 7.5.
example 4:
the aprepitant micelle sterile lyophilized formulation prepared in example 1 was subjected to a three-month accelerated test at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60%. + -. 5%, and the results are shown in Table 1 below.
TABLE 1 aprepitant micelle freeze-dried powder acceleration test
The relevant detection results in table 1 show that all indexes of the aprepitant micelle sterile lyophilized preparation have no significant change in the three-month accelerated test process, which indicates that the preparation has good stability.
Example 5:
12 SD rats were randomly divided into 2 groups of 6 rats, and fasted for 12 hours before administration and freely ingested. One group of the aprepitant micelle sterile lyophilized preparations prepared in example 1 is injected in tail vein at a dose of 14mg/kg, the other group is injected with commercial aprepitant emulsion (commercial product CINVANTI) at the same dose, and the two groups of the aprepitant micelle sterile lyophilized preparations are dissolved and diluted respectively by using glucose injection as a solvent. Rat blood was collected at 0.03, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 12 hours after dosing, respectively. The samples were immediately centrifuged at 13125 Xg for 10min to separate the plasma. Treating plasma sample with acetonitrile precipitated protein, separating with Cortex C18+ chromatographic column, and purifying with methanol-10 mmol. multidot.L-1Ammonium acetate as mobile phase, adopting electrospray ion source, and labeling internal standard d with stable isotope4Aprepitant was used as an internal standard for aprepitant, and plasma aprepitant concentrations were analyzed by LC-MS/MS, with results shown in figure 1.
Fig. 1 shows that the aprepitant micelles prepared in example 1 have similar peak concentrations to the aprepitant emulsion sold in the market, but the elimination half-life and AUC of the aprepitant micelles are significantly increased, so that the bioavailability of the drug is improved.
While the present disclosure has been described in terms of a detailed general description and several examples, it will be appreciated that modifications, additions, permutations and certain sub-combinations thereof may be made based thereon. Therefore, modifications, additions, substitutions and sub-combinations based on the patentable core content of the invention are intended to be within the scope of the invention as claimed.
Claims (10)
1. An aprepitant micelle sterile lyophilized preparation for intravenous injection, which is characterized by comprising aprepitant, methoxypolyethylene glycol-derivatized phospholipid and a pharmaceutically acceptable lyophilization protectant, wherein the mass ratio of aprepitant to methoxypolyethylene glycol-derivatized phospholipid is 1: 1 to 1: 20, the methoxypolyethylene glycol-derived phospholipid is formed by connecting methoxypolyethylene glycol and phospholipid through covalent bonds, the molecular weight of the methoxypolyethylene glycol in the methoxypolyethylene glycol-derived phospholipid is 2000,
the phospholipid part of the methoxypolyethylene glycol-derivatized phospholipid is selected from phosphatidylethanolamine, distearoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, diphosphatidylglycerol, lysophosphatidylcholine or lysoethanolamine phospholipid.
2. The aprepitant micelle sterile lyophilized formulation of claim 1, wherein the mass ratio of aprepitant to methoxypolyethylene glycol derivatized phospholipid is 1: 5 to 1: 15.
3. the sterile lyophilized formulation of aprepitant micelle of claim 1 wherein the methoxypolyethylene glycol derivatized phospholipid is methoxypolyethylene glycol 2000-distearoylphosphatidylethanolamine.
4. The sterile lyophilized aprepitant micelle preparation as claimed in claim 1, wherein the sterile lyophilized aprepitant micelle preparation further comprises a pharmaceutically acceptable pH regulator and an osmotic pressure regulator.
5. The sterile lyophilized aprepitant micelle preparation according to claim 1, wherein the sterile lyophilized aprepitant micelle preparation is in a sterile lyophilized powder form.
6. A method for preparing the aprepitant micelle sterile lyophilized preparation of any one of claims 1-5, comprising combining aprepitant with methoxypolyethylene glycol-derivatized phospholipid to form a micelle, and preparing the aprepitant micelle sterile lyophilized preparation for intravenous injection.
7. The method of claim 6, characterized in that said method comprises the steps of:
(1) dissolving aprepitant and methoxypolyethylene glycol-derivatized phospholipid in a proper amount of organic solvent;
(2) removing the organic solvent to form an aprepitant/methoxypolyethylene glycol-derivatized phospholipid composite membrane;
(3) placing the aprepitant/methoxypolyethylene glycol-derivatized phospholipid composite membrane prepared in the step (2) in a vacuum drying oven to remove residual organic solvent;
(4) adding water into the dried composite membrane in the step (3), hydrating, carrying out vortex shaking, and adding a pH regulator to obtain an aprepitant-entrapped micelle solution;
(5) adding a proper amount of freeze-drying protective agent into the aprepitant micelle solution prepared in the step (4), and dissolving the aprepitant micelle solution;
(6) and (5) sterilizing the aprepitant micelle solution prepared in the step (5) by a 0.22-micrometer microporous filter membrane under an aseptic condition, and freeze-drying to remove water to prepare the aprepitant micelle aseptic freeze-dried preparation.
8. The method of claim 7,
the organic solvent in the step (1) is selected from methanol, ethanol, chloroform or a mixture thereof;
step (2) removing the organic solvent by reducing pressure and/or removing the organic solvent under vacuum condition;
and (3) drying the aprepitant/methoxypolyethylene glycol-derivatized phospholipid composite membrane in a vacuum drying oven for 12-24 hours at the temperature of 20-40 ℃ to remove residual organic solvent.
9. The method according to claim 8,
the hydration in the step (4) is carried out in a water bath at the temperature of 20-60 ℃ for 1-2 hours;
the vortex shaking time in the step (4) is 1-5 minutes;
and (4) adding a pH regulator to regulate the pH value of the micelle solution to 6.0-8.0.
10. The method according to claim 8, wherein the prepared micelle solution is added with a proper amount of a lyoprotectant, and after dissolution, filtration sterilization and freeze drying, the sterile lyophilized aprepitant micelle preparation is prepared.
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| CN101138548B (en) * | 2006-09-06 | 2011-12-28 | 北京德科瑞医药科技有限公司 | Polyglycol derivatization phospholipid loaded vinorelbine nano-micelle preparations |
| CN101278913B (en) * | 2008-04-25 | 2010-08-18 | 中国科学院生物物理研究所 | Novel polyethylene glycol-phospholipid entrapped prostaglandin E1 micelle preparation |
| CN102525880B (en) * | 2010-12-31 | 2014-06-11 | 正大天晴药业集团股份有限公司 | Aprepitant solid dispersion composition |
| US20150010475A1 (en) * | 2011-12-30 | 2015-01-08 | Stc.Unm | Crlf-2 binding peptides, protocells and viral-like particles useful in the treatment of cancer, including acute lymphoblastic leukemia (all) |
| BR112014029176A2 (en) * | 2012-05-24 | 2017-06-27 | Innopharma Inc | injectable formulations of aprepitant |
| WO2014005606A1 (en) * | 2012-07-06 | 2014-01-09 | Pharmathen S.A. | Stable injectable pharmaceutical composition of neurokinin 1 receptor antagonist and process for preparation thereof |
| CN104414983B (en) * | 2013-08-28 | 2018-09-04 | 山东新时代药业有限公司 | A kind of injection fosaprepitant dimeglumine sterile lyophilized powder and its preparation process |
| CN104971049B (en) * | 2014-04-08 | 2019-05-21 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of lyophilized preparation and preparation method thereof containing Fosaprepitant |
| 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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| EP3478283A4 (en) * | 2016-06-29 | 2020-07-22 | Menlo Therapeutics Inc. | Use of neurokinin-1 antagonists to treat a variety of pruritic conditions |
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