CN117243900A - Injectable pharmaceutical composition containing aprepitant and preparation method thereof - Google Patents

Injectable pharmaceutical composition containing aprepitant and preparation method thereof Download PDF

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Publication number
CN117243900A
CN117243900A CN202310285606.3A CN202310285606A CN117243900A CN 117243900 A CN117243900 A CN 117243900A CN 202310285606 A CN202310285606 A CN 202310285606A CN 117243900 A CN117243900 A CN 117243900A
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China
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aprepitant
pharmaceutical composition
sodium
polyethylene glycol
surface stabilizer
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CN202310285606.3A
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Inventor
邹平
齐宜广
刘磐
容柏豪
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Jiangsu Huiju Pharmaceutical Co ltd Guangzhou Branch
Jiangsu Huiju Pharmaceutical Co ltd
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Jiangsu Huiju Pharmaceutical Co ltd Guangzhou Branch
Jiangsu Huiju Pharmaceutical Co ltd
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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
    • 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
    • A61K31/535—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Abstract

The invention discloses an injectable pharmaceutical composition, which comprises aprepitant, a surface stabilizer and deflocculant, wherein the deflocculant is one or more than two selected from citrate, tartrate, phosphate or carbonate. The pharmaceutical composition containing aprepitant provided by the invention can be injected and administrated, the preparation has good stability, can be stored and transported at normal temperature, can greatly reduce the production, storage and transportation costs, has little auxiliary material consumption, has small irritation at injection sites when a patient uses the preparation, is not easy to cause hypersensitivity reaction, and is safer.

Description

Injectable pharmaceutical composition containing aprepitant and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an injectable pharmaceutical composition containing aprepitant and a preparation method thereof.
Background
Aprepitant (Aprepitant) is an NK1 receptor antagonist developed and marketed by the company Merck Sharp & Dohme, U.S. and approved by the FDA in 2003 for oral administration, under the trade name Emend, and is used clinically to prevent acute and delayed nausea and vomiting occurring during primary and repeat therapies of highly emetic antitumor chemotherapy. Aprepitant is used clinically in combination with a glucocorticoid and a 5-HT3 antagonist, suitable for patients older than 6 months, for: 1. acute and delayed nausea and vomiting associated with initial and repeated courses of high emetic cancer chemotherapy (HEC), including high doses of cisplatin; 2. initial and repeated processes of moderate emetic cancer chemotherapy (MEC) associated nausea and vomiting have the chemical structure:
aprepitant is a selective high affinity antagonist of the human substance P neurokinin 1 (NK 1) receptor. The 5-hydroxytryptamine receptor 3 (5-HT 3), dopamine receptor and glucocorticoid receptor have low or no affinity for other existing medicines for treating nausea and vomiting (CINV) caused by chemotherapy and nausea and vomiting (PONV) after operation. Preclinical studies have shown that NK1 receptor antagonists can inhibit emesis induced by cytotoxic chemotherapeutic drugs such as cisplatin. Preclinical and human Positron Emission Tomography (PET) studies of aprepitant have shown that aprepitant can cross the blood brain barrier and occupy the NK1 receptor in the brain. Aprepitant inhibits cisplatin-induced acute and delayed emesis and enhances the antiemetic activity of the 5-HT3 receptor antagonists ondansetron and the glucocorticoid dexamethasone on cisplatin-induced emesis.
The aprepitant bulk drug is white to off-white crystalline solid, has a molecular weight of 534.43 and is difficult to dissolve in water. According to the Japanese IF file information of aprepitant capsules, the solubility of Shi Arui pieces of aprepitant in water at room temperature is 0.00055mg/mL, the aprepitant is slightly soluble in ethanol, isopropyl acetate and acetonitrile, belongs to low-solubility and low-permeability medicines, and the biopharmaceutical classification is class IV. Poor water solubility results in slow and incomplete dissolution of the drug and low bioavailability. To improve the bioavailability of the drug, the moesadong company uses the nanocrystalline technology to improve the bioavailability, and the absolute bioavailability of the oral capsule developed by the moesadong company is only 60 to 65 percent, and the maximum blood concentration (C) is required to be reached in about 4 hours max ) Is unfavorable for patients to take effect rapidly before or after chemotherapy, resulting in severely limited clinical application scenarios.
The injection has obvious clinical advantages of administration before chemotherapy, has high bioavailability and quick action after administration, benefits cancer chemotherapy patients in the maximum range, and can further improve the curative effect of the medicine. However, aprepitant is hardly soluble in water (0.00055 mg/mL), and is difficult to dissolve and develop into a true solution type conventional injection, and poor solubility becomes an obstacle which is difficult for formulation staff to surmount.
Development of injectable formulations should overcome a number of difficulties due to poor solubility of aprepitant. With a hard effort, the company of moesaton, 2010, developed aprepitant as a prodrug fosaprepitant meglumine to increase solubility, and finally developed as a freeze-dried powder injection, with the trade name of EMEND (fosaprepitant meglumine for injection). However, the prodrug injection has more defects: 1) The prodrug has poor stability and is easy to be converted into aprepitant, and the bulk drug needs to be stored at the temperature of minus 20 ℃; 2) The freeze-dried fosaprepitant meglumine injection is still poor in stability and needs to be stored at 2-8 ℃; 3) The poor stability of fosaprepitant meglumine leads to high cost of production, storage, transportation and storage of raw material medicines and production, transportation and storage of preparations compared with common injection which can be produced and stored at normal temperature, thus leading to high medication cost of patients and huge waste of social medical resources; 4) The prescription of the fosaprepitant meglumine injection contains a large amount of Tween 80 (58 percent of the dosage of the active ingredient), the injection site of a patient is often painful and strong when the fosaprepitant meglumine injection is used, and clinical data show that the incidence rate (3.0 percent) of adverse reaction at the injection site of fosaprepitant meglumine is higher than that of an oral aprepitant control group (0.5 percent); 5) The fosaprepitant meglumine is easy to be converted into aprepitant in water and separated out, and potential safety hazards exist for patients when the fosaprepitant meglumine is used.
The HERON company tries to develop aprepitant into fat emulsion injection, and finally develops the fat emulsion injection successfully after many years of efforts, and the aprepitant fat emulsion injection is approved to be marketed by the American FDA in 2017, and has the trade name of CINVANTI and the specification of 18mL:130mg. The preparation contains lecithin 2.6g, ethanol 0.5g, sodium oleate 0.1g, soybean oil 1.7g and sucrose 1g. The injection still has more defects: 1) The dosage of the auxiliary materials in the preparation is 5.9g which is 45 times of that of the active ingredients, and the dosage of the auxiliary materials in the preparation is large, so that the medicine is easy to produce hypersensitivity after intravenous injection and harm the health of patients; 2) Sodium oleate has certain irritation, and symptoms such as pain at the administration part are easy to occur after intravenous administration; 3) The emulsion is a thermodynamically unstable system, and the preparation still needs to be stored at 2-8 ℃; 4) In addition, the preparation has larger liquid medicine volume, brings certain inconvenience to clinical use and is inconvenient and quick to use.
Aiming at the defects of the products on the market, the injection which has the advantages of good safety (small irritation of the administration part, difficult occurrence of hypersensitivity and the like), small medicine volume, convenient use and normal-temperature storage and transportation is still required to be developed, and is used for improving the use safety of patients, reducing the production, storage and transportation costs, facilitating the clinical use and saving the medical cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides the aprepitant nanocrystalline injection which has good stability, small auxiliary material consumption, small stimulation to patients and safer and the preparation method thereof, can greatly reduce the production, storage and transportation costs and promote the clinical application of the aprepitant nanocrystalline injection.
To achieve the above object, in a first aspect of the present invention, there is provided an injectable pharmaceutical composition comprising aprepitant, a surface stabilizer and a deflocculant, wherein the deflocculant is selected from one or more of citrate, tartrate, phosphate (such as sodium dihydrogen phosphate or disodium hydrogen phosphate) or carbonate.
Although the addition of the surface stabilizer to the aprepitant nanocrystalline injection composition can improve the dispersibility and stability of aprepitant particles in the preparation process, the nanocrystalline preparation is suspension type liquid and is a thermodynamically unstable system, and the phenomenon of Ostwald ripening can occur in the long-term storage process to cause aggregation and sedimentation, which hinders the clinical application of the nanocrystalline preparation. The deflocculant is added in the invention, so that the dispersibility and stability of the preparation process can be improved, and the subsidence of aprepitant particles can be inhibited, thereby improving the stability of aprepitant nanocrystals in the long-term storage process.
According to some embodiments of the invention, the mass ratio of aprepitant to deflocculant is 1 (0.001-1), preferably 1 (0.001-0.1), more preferably 1 (0.001-0.05), most preferably 1 (0.001-0.01).
According to some embodiments of the invention, the surface stabilizer comprises a primary surface stabilizer and a secondary surface stabilizer, wherein the primary surface stabilizer is selected from anionic surfactants, preferably sodium deoxycholate, sodium cholate and sodium dodecyl sulfate, more preferably sodium deoxycholate, sodium cholate; the secondary surface stabilizer is selected from nonionic or zwitterionic surfactants, preferably polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, tween 80, poloxamer, polyethylene glycol 15-hydroxystearate and lecithin; more preferably polyethylene glycol, poloxamer. The polyethylene glycol may have an average molecular weight of 200 to 7000, preferably 400 to 4000. In some embodiments, the polyethylene glycol is selected from one or more of polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000.
According to some embodiments of the invention, the deflocculant is selected from one or more of sodium citrate, sodium tartrate, sodium phosphate, sodium carbonate, potassium phosphate, potassium carbonate, preferably sodium citrate and sodium tartrate.
According to some embodiments of the invention, the mass ratio of aprepitant to the surface stabilizer is 1 (0.01-10), preferably 1 (0.05-5), more preferably 1 (0.1-4), most preferably 1 (0.15-3.6).
According to some embodiments of the invention, the mass ratio of aprepitant to the primary surface stabilizer is 1 (0.05-0.4), preferably 1 (0.06-0.36), more preferably 1 (0.075-0.32).
According to some embodiments of the invention, the mass ratio of aprepitant to the secondary surface stabilizer is 1 (0.1-3.2), preferably 1 (0.12-2.8), more preferably 1 (0.15-2.5).
According to some embodiments of the invention, the mass ratio of the primary surface stabilizer to the secondary surface stabilizer is 1 (2-10), preferably 1 (2-8).
According to some embodiments of the invention, the surface stabilizer comprises sodium deoxycholate and polyethylene glycol. Preferably, the mass ratio of the sodium deoxycholate to the polyethylene glycol is 1 (2-10), more preferably, the mass ratio of the sodium deoxycholate to the polyethylene glycol is 1 (2-8).
According to some embodiments of the invention, the mass ratio of aprepitant to sodium deoxycholate is 1 (0.05-0.4), preferably 1 (0.06-0.36), more preferably 1 (0.075-0.32).
According to some embodiments of the invention, the mass ratio of aprepitant to polyethylene glycol is 1 (0.1-3.2), preferably 1 (0.12-2.8), more preferably 1 (0.15-2.5).
According to some embodiments of the invention, the primary surface stabilizer is sodium deoxycholate and the secondary surface stabilizer is polyethylene glycol, and the deflocculant is selected from sodium citrate, sodium tartrate and phosphate, preferably sodium citrate.
According to some embodiments of the invention, the pharmaceutical composition further comprises a liquid medium selected from the group consisting of water, vegetable oil, ethanol, t-butanol and ethylene glycol, preferably water.
According to some embodiments of the invention, the aprepitant is nanocrystalline. According to some embodiments of the invention, the aprepitant nanocrystal D 50 Less than 200nm, preferably less than 120nm, more preferably less than 100nm. The small particle size of the rapitant nanocrystalline is more beneficial to product stability and is also beneficial to improving the dissolution rate of the rapitant nanocrystalline.
According to some embodiments of the invention, the pharmaceutical composition comprises, in parts by weight:
1 part of aprepitant; 0.05 to 0.4 parts of primary surface stabilizer; 0.1 to 3.2 parts of a secondary surface stabilizer; 0.001-1 part of deflocculant and water.
According to some embodiments of the invention, the pharmaceutical composition comprises, in parts by weight:
1 part of aprepitant; 0.05 to 0.4 part of sodium deoxycholate; 0.1 to 3.2 parts of polyethylene glycol and 0.001 to 0.1 part of sodium citrate.
According to some embodiments of the invention, the pharmaceutical composition comprises, in parts by weight:
1 part of aprepitant; 0.06-0.36 part of deoxycholate sodium; 0.12 to 2.8 parts of polyethylene glycol and 0.001 to 0.05 part of sodium citrate.
According to some embodiments of the invention, the pharmaceutical composition comprises, in parts by weight:
1 part of aprepitant; 0.075 to 0.32 parts of sodium deoxycholate; 0.15 to 2.5 parts of polyethylene glycol and 0.001 to 0.01 part of sodium citrate.
According to some embodiments of the invention, the pharmaceutical composition comprises aprepitant, sodium deoxycholate, polyethylene glycol, deflocculant and water,
wherein the deflocculant is selected from one or more of sodium citrate, sodium tartrate and phosphate, and preferably sodium citrate; the aprepitant is a nanocrystal, D of the aprepitant nanocrystal 50 Less than 200nm, preferably less than 100nm; the weight ratio of aprepitant to deflocculating agent is 1 (0.001-0.05), preferably 1 (0.001-0.01); the weight ratio of aprepitant to sodium deoxycholate is 1 (0.06-0.36), preferably 1 (0.075-0.32); the weight ratio of aprepitant to polyethylene glycol is 1 (0.12-2.8), preferably 1 (0.15-2.5); the mass ratio of the sodium deoxycholate to the polyethylene glycol is 1 (2-10), preferably 1 (2-8).
In a second aspect of the invention, there is provided a process for preparing a pharmaceutical composition according to the first aspect of the invention comprising the steps of:
(1) Mixing a surface stabilizer with a solvent, adding the deflocculant to obtain a mixed solution, wherein the solvent is preferably water for injection;
(2) Adding aprepitant into the mixed solution in the step (1) to obtain an initial grinding solution;
(3) And (3) grinding the initial grinding liquid in the step (2) to obtain the pharmaceutical composition.
According to some embodiments of the invention, the rotational speed during milling in step (3) is in the range of 2000 to 3800RPM, and the milling media is zirconia beads and/or polystyrene beads.
In a third aspect of the invention there is provided an aprepitant suspension injection comprising a pharmaceutical composition according to the first aspect of the invention or a pharmaceutical composition prepared by a method according to the second aspect of the invention.
In a fourth aspect of the present invention, there is provided aprepitant freeze-dried powder injection comprising:
(1) A pharmaceutical composition according to the first aspect of the invention or a pharmaceutical composition prepared by a method according to the second aspect of the invention, and
(2) The freeze-drying protective agent is prepared from the components of the composition,
preferably, the lyoprotectant is selected from one or more than two of sucrose, lactose, mannitol, sorbitol, polyethylene glycol or trehalose.
According to some embodiments of the invention, the lyophilized powder is prepared by adding a lyoprotectant to the pharmaceutical composition according to the first aspect of the invention and freeze-drying.
According to some embodiments of the invention, the weight ratio of aprepitant to lyoprotectant is 1 (0-5.0), preferably 1 (0.01-3.0).
In a fifth aspect of the invention there is provided the use of a pharmaceutical composition according to the first aspect of the invention or a pharmaceutical composition prepared by a method according to the second aspect of the invention in the manufacture of a medicament for the prevention and/or treatment of chemotherapy-induced nausea and vomiting, and/or post-operative nausea and vomiting.
Compared with the prior art, the invention has the following beneficial effects: the aprepitant is prepared into the injectable nano suspension injection by selecting the specific surface stabilizer and deflocculant, so that the stability of the aprepitant is greatly improved, the aprepitant can be stored and transported at normal temperature, the dosage of auxiliary materials is greatly reduced, and the production, storage and transportation costs can be greatly reduced; in addition, the injection site of the developed preparation is small in irritation and is not easy to cause hypersensitivity reaction when a patient uses the preparation, so that the preparation is safer; the medicine has small volume and convenient use.
Detailed Description
The present invention is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
Sodium deoxycholate is used as a primary surface stabilizer, polyethylene glycol 4000 is used as a secondary surface stabilizer, and monosodium citrate is used as a deflocculant to prepare aprepitant nanocrystalline suspension injection, wherein the specific prescription comprises the following components in percentage by weight:
prescription (100 pieces)
Aprepitant 13g
Deoxycholate sodium 0.98g
Polyethylene glycol 4000.9 g
Citric acid monosodium salt 0.04g
The water for injection is added to 500mL
The preparation process comprises the following steps:
(1) Preparing an initial grinding fluid: 3.9g of polyethylene glycol 4000, 0.98g of sodium deoxycholate and 0.04g of monosodium citrate are dissolved in water for injection and stirred until completely dissolved. 13g of aprepitant raw material medicine is added to be uniformly dispersed and then used as an initial grinding liquid.
(2) 50ml of yttrium stabilized grinding beads (grinding media) were added to the grinding chamber, and the initial grinding fluid was added to the grinding drum to start grinding at 3800RPM.
(3) And grinding for 4 hours, and sampling to test that the average particle size of the suspension is smaller than 200nm to obtain the aprepitant nano suspension.
(4) The nano suspension is further diluted to about 26mg/mL by water for injection, and the aprepitant nano suspension injection is prepared.
After the nano suspension injection is placed for 10 days at 40 ℃, indexes such as particle size, pH value, insoluble particles, related substances and the like are examined, and detection results are shown in table 1.
TABLE 1
The results show that the injection prepared by adopting sodium deoxycholate and polyethylene glycol 4000 as stabilizers and citric acid monosodium as deflocculating agent is placed for 10 days at 40 ℃, the particle size, the pH value, insoluble particles and related substances have no obvious change, and the preliminary shows that the sample stability is good.
Example 2
Sodium deoxycholate is used as a primary surface stabilizer, polyethylene glycol 400 is used as a secondary surface stabilizer, and monosodium citrate is used as a deflocculant to prepare aprepitant nanocrystalline suspension injection, wherein the specific prescription comprises the following components in percentage by weight:
prescription (100 pieces)
Aprepitant 13g
Deoxycholate sodium 0.98g
Polyethylene glycol 400.95 g
Citric acid monosodium salt 0.04g
The water for injection is added to 500mL
The preparation process comprises the following steps:
(1) Preparing an initial grinding fluid: 1.95g of polyethylene glycol 4000, 0.98g of sodium deoxycholate and 0.04g of monosodium citrate are dissolved in water for injection and stirred until completely dissolved. 13g of aprepitant raw material medicine is added to be uniformly dispersed and then used as an initial grinding liquid.
(2) 50ml of yttrium stabilized grinding beads (grinding media) were added to the grinding chamber, and the initial grinding fluid was added to the grinding drum to start grinding at 3800RPM.
(3) And grinding for 4 hours, and sampling to test that the average particle size of the suspension is smaller than 200nm to obtain the aprepitant nano suspension.
(4) The nano suspension is further diluted to about 26mg/mL by water for injection, and the aprepitant nano suspension injection is prepared.
After the nano suspension injection is placed for 10 days at 40 ℃, indexes such as particle size, pH value, insoluble particles, related substances and the like are examined, and detection results are shown in table 2.
TABLE 2
The results show that the injection prepared by adopting sodium deoxycholate and polyethylene glycol 400 as stabilizers and citric acid monosodium as deflocculating agent is placed for 10 days at 40 ℃, the particle size, the pH value, insoluble particles and related substances have no obvious change, and the preliminary shows that the sample stability is good.
Example 3
The type and amount of the surface stabilizer affect the particle size and stability of the final sample, and the test results are shown in Table 3.
TABLE 3 Table 3
The above experimental data show that the use of polyethylene glycol 4000 and polyethylene glycol 400 at various concentrations in combination with sodium deoxycholate enables nanocrystalline suspensions with average particle sizes of less than 200nm. Unexpectedly, using a combination of sodium deoxycholate and polyethylene glycol gives D compared to a combination of sodium deoxycholate with other stabilizers 50 Smaller (less than 150nm, less than 120nm, even less than 100 nm) nanocrystalline suspensions, and good solution stability after grinding. It was further found that when the mass ratio of sodium deoxycholate to polyethylene glycol is in the range of 1:2-8, the solution stability can be further improved. The results show that the stabilizer combination of sodium deoxycholate and polyethylene glycol is suitable for developing the nanocrystalline suspension injection.
Example 4
The ability of different deflocculant amounts to disperse nanocrystals was examined by particle size and property detection, and the results of the detection were shown in table 4 below, according to the minimum particle size recipe of example 3.
TABLE 4 Table 4
Experimental data indicate that no deflocculant is added to grind particle size D 50 Larger and poor solution stability after grinding; the adoption of the sodium citrate or the sodium tartrate as deflocculant can lead the average grain diameter of the nanocrystalline suspension to be less than 200nm, and the stability of the ground solution is good. D can be obtained by adding monosodium citrate as deflocculant 50 Smaller (less than 150nm, less than 120nm, even less than 100 nm) nanocrystalline suspensions, and further found that the weight ratio of aprepitant to deflocculant is 1:0.001-0.01, can further improve solution stability.
Example 5
Preparation of aprepitant suspension freeze-dried powder injection (wet grinding method)
Prescription (100 pieces)
Aprepitant 13g
Deoxycholate sodium 2.54g
Polyethylene glycol 400.95 g
Citric acid monosodium salt 0.08g
Sucrose 15g
The water for injection is added to 500mL
The preparation process comprises the following steps:
(1) Preparation of grinding media: 14.95g of polyethylene glycol 400, 2.54g of sodium deoxycholate and 0.08g of monosodium citrate are dissolved in water for injection and stirred until complete dissolution. 13g of aprepitant raw material medicine is added to be uniformly dispersed and then used as an initial grinding liquid.
(2) 50ml of yttrium stabilized grinding beads were added to the grinding chamber, and the initial grinding fluid was added to the grinding drum to start grinding at 3800RPM.
(3) And grinding for 4 hours, and sampling to test that the average particle size of the suspension is smaller than 200nm to obtain the aprepitant nano suspension.
(4) Dissolving sucrose (30%) into the nano suspension, further diluting to about 26mg/ml with water for injection, sterilizing, filtering, filling into penicillin bottles, and freeze-drying to obtain aprepitant freeze-dried powder injection. The lyophilization process conditions are shown in table 5.
TABLE 5
The appearance of the sample obtained after freeze drying is loose and porous white block, the porous white block is extremely easy to re-dissolve, the particle size of the nano suspension after re-dissolution is unchanged from that before freeze drying, and the stability of the sample after freeze drying at an acceleration of 40 ℃ for 6 months is examined, and the results are shown in table 6.
TABLE 6
The result shows that the aprepitant nano suspension freeze-dried powder injection has stability under the condition of high temperature of 60 ℃ for 30 days, and the result shows that the appearance of key quality attributes, the particle size, insoluble particles and related substances are unchanged, which indicates that the nano suspension injection has good stability and can be stored at normal temperature.
The suspension injection and the freeze-dried powder injection prepared by adopting the sodium deoxycholate, the polyethylene glycol and the deflocculant sodium citrate through the nanocrystalline technology have good stability, and the raw material medicaments and the finished products can be stored and transported at normal temperature, so that the production, storage and transportation costs can be greatly reduced. Compared with the fosaprepitant meglumine bulk drug which needs to be stored at the temperature of minus 20 ℃, the finished product needs to be stored at the temperature of 2-8 ℃ and has great advantages. Compared with the finished aprepitant fat emulsion injection, the finished aprepitant fat emulsion injection has better storage stability at the temperature of 2-8 ℃, and saves the storage, transportation and use costs in the process of drug production and circulation.
The suspension injection prepared by the nanocrystalline technology contains less auxiliary materials, the auxiliary material dosage can be 0.02-0.45 g/branch, for example, the auxiliary material dosage of example 2 is 0.03 g/branch, and the auxiliary material dosage of example 5 is 0.33 g/branch. Compared with the aprepitant fat emulsion injection on the market, the dosage of auxiliary materials can be greatly reduced. As shown in Table 7, the dosage of the auxiliary materials of the aprepitant fat emulsion injection is 5.9 g/branch.
TABLE 7 prescription composition of marketed aprepitant fat emulsion injection (CINAVANTI)
Component name Dosage (g/branch) Action
Aprepitant 0.13 Active ingredient
Egg yolk lecithin 2.6 Surface active agent
Soybean oil 1.7 Oil phase
Oleic acid sodium salt 0.1 Surface active agent
Ethanol 0.5 Cosolvent
Sucrose 1 Osmotic pressure regulator
Water for injection 12 Solvent(s)
The technical scheme of the invention is not limited to the specific embodiment, and all technical modifications made according to the technical scheme of the invention fall within the protection scope of the invention.

Claims (17)

1. An injectable pharmaceutical composition comprises aprepitant, a surface stabilizer and a deflocculant,
wherein the deflocculant is one or more than two selected from citrate, tartrate, phosphate or carbonate.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio of aprepitant to deflocculant is 1 (0.001-1), preferably 1 (0.001-0.1), more preferably 1 (0.001-0.05), most preferably 1 (0.001-0.01).
3. The pharmaceutical composition according to claim 1 or 2, wherein the surface stabilizer comprises a primary surface stabilizer and a secondary surface stabilizer, wherein the primary surface stabilizer is selected from the group consisting of anionic surfactants, preferably sodium deoxycholate, sodium cholate and sodium dodecyl sulfate; the secondary surface stabilizer is selected from nonionic or zwitterionic surfactants, preferably polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, tween 80, poloxamer, polyethylene glycol 15-hydroxystearate and lecithin;
the deflocculant is selected from one or more of sodium citrate, sodium tartrate, sodium phosphate (such as sodium dihydrogen phosphate or disodium hydrogen phosphate), sodium carbonate, potassium phosphate and potassium carbonate, preferably sodium citrate and sodium tartrate.
4. A pharmaceutical composition according to any of claims 1 to 3, wherein the mass ratio of aprepitant to the surface stabilizer is 1 (0.01-10), preferably 1 (0.05-5), more preferably 1 (0.1-4), most preferably 1 (0.15-3.6).
5. The pharmaceutical composition according to any one of claims 3 to 4, wherein the mass ratio of aprepitant to primary surface stabilizer is 1 (0.05-0.4), preferably 1 (0.06-0.36), more preferably 1 (0.075-0.32);
and/or the mass ratio of aprepitant to the secondary surface stabilizer is 1 (0.1-3.2), preferably 1 (0.12-2.8), more preferably 1 (0.15-2.5).
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the surface stabilizer comprises sodium deoxycholate and polyethylene glycol, preferably the mass ratio of sodium deoxycholate to polyethylene glycol is 1 (2-10), more preferably the mass ratio of sodium deoxycholate to polyethylene glycol is 1 (2-8).
7. The pharmaceutical composition according to claim 6, wherein the mass ratio of aprepitant to sodium deoxycholate is 1 (0.05-0.4), preferably 1 (0.06-0.36), more preferably 1 (0.075-0.32);
and/or the mass ratio of aprepitant to polyethylene glycol is 1 (0.1-3.2), preferably 1 (0.12-2.8), more preferably 1 (0.15-2.5).
8. The pharmaceutical composition according to any one of claims 1 to 7, further comprising a liquid medium selected from the group consisting of water, vegetable oil, ethanol, t-butanol and ethylene glycol, preferably water.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein aprepitant is nanocrystalline and aprepitant D 50 Less than 200nm, preferably less than 120nm, more preferably less than 100nm.
10. The pharmaceutical composition according to any one of claims 3 to 9, comprising, in parts by weight:
1 part of aprepitant; 0.05 to 0.4 parts of primary surface stabilizer; 0.1 to 3.2 parts of a secondary surface stabilizer; 0.001-1 part of deflocculant and water.
11. The pharmaceutical composition according to any one of claims 1 to 10, comprising, in parts by weight:
1 part of aprepitant; 0.05 to 0.4 part of sodium deoxycholate; 0.1 to 3.2 parts of polyethylene glycol and 0.001 to 0.1 part of sodium citrate; or alternatively
1 part of aprepitant; 0.06-0.36 part of deoxycholate sodium; 0.12 to 2.8 parts of polyethylene glycol and 0.001 to 0.05 part of sodium citrate; or alternatively
1 part of aprepitant; 0.075 to 0.32 parts of sodium deoxycholate; 0.15 to 2.5 parts of polyethylene glycol and 0.001 to 0.01 part of sodium citrate.
12. A process for preparing a pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of:
(1) Mixing a surface stabilizer with a solvent, adding the deflocculant to obtain a mixed solution, wherein the solvent is preferably water for injection;
(2) Adding aprepitant into the mixed solution in the step (1) to obtain an initial grinding solution;
(3) And (3) grinding the initial grinding liquid in the step (2) to obtain the pharmaceutical composition.
13. The method according to claim 12, wherein the rotational speed during milling in step (3) is 2000 to 3800RPM and the milling media is zirconia beads and/or polystyrene beads.
14. Aprepitant suspension injection comprising a pharmaceutical composition according to any one of claims 1 to 11 or a pharmaceutical composition prepared by the method of any one of claims 12 to 13.
15. An aprepitant freeze-dried powder injection, comprising:
(1) A pharmaceutical composition according to any one of claims 1 to 11 or a pharmaceutical composition prepared by a method according to any one of claims 12 to 13, and
(2) The freeze-drying protective agent is prepared from the components of the composition,
preferably, the lyoprotectant is selected from one or more than two of sucrose, lactose, mannitol, sorbitol, polyethylene glycol or trehalose.
16. The aprepitant freeze-dried powder injection according to claim 15, wherein the weight ratio of aprepitant to the lyoprotectant is 1 (0-5.0), preferably 1 (0.01-3.0).
17. Use of a pharmaceutical composition according to any one of claims 1 to 11 or a pharmaceutical composition prepared by a method according to any one of claims 12 to 13 in the manufacture of a medicament for the prevention and/or treatment of chemotherapy-induced nausea and vomiting, and/or post-operative nausea and vomiting.
CN202310285606.3A 2022-06-17 2023-03-22 Injectable pharmaceutical composition containing aprepitant and preparation method thereof Pending CN117243900A (en)

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CN2022106899398 2022-06-17

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