Pharmaceutical formulations comprising aprepitant

Abstract

The present disclosure provides pharmaceutical formulations including aprepitant that are suitable for intravenous administration, including lyophilized formulations, processes for the preparation thereof, and their use in the treatment or prevention of emesis.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING APREPITANT BACKGROUND1. Technical Field

[0001] The present disclosure is directed to pharmaceutical formulations comprising aprepitant that are suitable for intravenous administration, processes for the preparation thereof, and in some non-limiting embodiments, to their use in the treatment or prevention of nausea and vomiting associated with emetogenic cancer chemotherapy and / or postoperative nausea and vomiting.2. Technical Considerations

[0002] Aprepitant (1 ), or 5-[[(2R,3S)-2-[(1 R)-1 -[3,5bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one, is the active pharmaceutical ingredient (API) in branded pharmaceuticals Cinvanti® and Aponvie®.

[0003] Cinvanti® is indicated in combination with other antiemetic agents, in adults for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy (HEC) and moderately emetogenic cancer chemotherapy (MEC).Aponvie® is indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. Both products are provided as a 7.2 mg / mL injectable emulsion in a single-dose vial for intravenous use.

[0004] According to the label, each vial of Cinvanti® contains 130 mg aprepitant in 18 mL of emulsion and the following inactive ingredients: egg lecithin (2.6 g), ethanol (0.5 g), sodium oleate (0.1 g), soybean oil (1.7 g), sucrose (1 g), and sterile water for injection (12 g). For administration, the emulsion is injected without dilution (bolus injection) or diluted for intravenous infusion with 0.9% Sodium Chloride Injection, USP or 5% Dextrose for Injection, USP.

[0005] According to the label, each vial of Aponvie® contains 32 mg aprepitant in 4.4 mL of emulsion. The emulsion also contains the following inactive ingredients: dehydrated alcohol (0.13 g), egg lecithin (0.64 g), sodium oleate (0.02 g), soybean oil (0.42 g), sucrose (0.24 g), and water for injection (2.97 g). The recommended dose is 32 mg administered as a 30 second intravenous injection prior to induction of anesthesia.

[0006] Although aprepitant is also available in oral dosage forms, clearly, injectable formulations can be preferable in treating nausea and vomiting. Formulating aprepitant in a liquid formulation suitable for intravenous administration is challenging as the drug substance exhibits both low solubility and low permeability, falling into Class IV of the Biopharmaceutics Classification System (BCS).

[0007] Oil-in-water emulsion formulations of aprepitant enable sufficient solubilization of the drug substance for intravenous administration. However, other challenges arise with liquid emulsions associated with physical and chemical stability.

[0008] Injectable pharmaceutical formulations comprising aprepitant, including emulsions, are reported in, for example, US 2024 / 0156829 A1 , CN 117414334 A, CN 112168788 B, US 2021 / 0212933 A1 , WO 2014 / 206090 A1 and WO 2016 / 044784 A1 .

[0009] Existing injectable aprepitant formulations suffer from one or more disadvantages including, for example, instability, incorporation of alcohol solvent and / or high osmolality.

[0010] There exists a need to provide pharmaceutical formulations comprising aprepitant that address problems associated with known aprepitant formulations, and processes for the preparation thereof.SUMMARY

[0011] The present disclosure provides pharmaceutical formulations comprising aprepitant that are suitable for intravenous administration which possess a balance of desirable properties, and to processes for the preparation thereof.

[0012] In one non-limiting aspect, the present disclosure provides a lyophilized pharmaceutical formulation comprising aprepitant, a solubilizer comprising one or more phospholipids, and a bulking agent. As a solid, the lyophilized pharmaceutical formulation of the present disclosure does not elicit the same storage stability concerns as a liquid emulsion and can be conveniently reconstituted to afford a liquid formulation near to the time of administration.

[0013] In another non-limiting aspect, the present disclosure provides pharmaceutical formulations suitable for intravenous administration comprising aprepitant and a pharmaceutically acceptable excipient(s) that are substantially free of ethanol and / or a triglyceride.

[0014] Additionally provided are processes for the preparation of formulations comprising aprepitant and methods of use thereof.

[0015] Accordingly, in a first non-limiting aspect of the present disclosure, there is provided a lyophilized pharmaceutical formulation comprising aprepitant, a solubilizer comprising one or more phospholipids, and a bulking agent. In some non-limiting embodiments of the first non-limiting aspect, the weight ratio of the solubilizer to the amount of aprepitant is from about 5:1 to about 30:1. In some non-limiting embodiments of the first non-limiting aspect, the weight ratio of the bulking agent to the amount of aprepitant is from about 1.5:1 to about 15:1. In some non-limiting embodiments of the first non-limiting aspect, the solubilizer comprises a mixture of naturally occurring phospholipids. In some non-limiting embodiments of the first non-limiting aspect, the mixture of naturally occurring phospholipids is derived from egg or soybean. In some nonlimiting embodiments of the first non-limiting aspect, the phospholipid(s) comprises from about 50 wt% to about 90 wt% phosphatidylcholine. In some non-limiting embodiments of the first non-limiting aspect, the bulking agent is selected from the group consisting ofmannitol, lactose, glycerin, dextrose, glucose, glycine, arginine, sucrose and mixtures thereof. In some non-limiting embodiments of the first non-limiting aspect, the bulking agent is mannitol. In some non-limiting embodiments of the first non-limiting aspect, the formulation comprises from about 2 wt% to about 10 wt% aprepitant, from about 60 wt% to about 80 wt% egg phospholipids, and from about 5 wt% to about 35 wt% mannitol. In some non-limiting embodiments of the first non-limiting aspect, the formulation comprises about 5 wt% aprepitant, about 75 wt% egg phospholipids, and about 20 wt% mannitol. In some non-limiting embodiments of the first non-limiting aspect, the formulation comprises about 4 wt% aprepitant, about 64 wt% egg phospholipids, and about 32 wt% mannitol. In some non-limiting embodiments of the first non-limiting aspect, the formulation is substantially free of ethanol and a triglyceride. In some non-limiting embodiments of the first non-limiting aspect, the pH of the formulation is from about 6.5 to about 9. In some non-limiting embodiments of the first non-limiting aspect, the formulation is stable when stored at about 5°C, about 25°C / 60% RH or about 40°C I 75% RH for at least three months. In some non-limiting embodiments of the first non-limiting aspect, the formulation is reconstituted with a diluent to afford a reconstituted formulation having a concentration of aprepitant of from about 2 mg / mL to about 15 mg / mL. In some non-limiting embodiments of the first non-limiting aspect, the diluent is sterile water for injection or 5% dextrose. In some non-limiting embodiments of the first non-limiting aspect, the concentration of aprepitant is about 7.2 mg / mL. In some non-limiting embodiments of the first non-limiting aspect, the diluent is 5% dextrose and the concentration of aprepitant is about 5.8 mg / mL. In some non-limiting embodiments of the first non-limiting aspect, the reconstituted formulation is further diluted to afford an infusion formulation having a concentration of aprepitant of about 1.1 mg / mL.

[0016] In a second non-limiting aspect of the present disclosure, there is provided an article of manufacture comprising: (a) a container which holds a lyophilized formulation comprising aprepitant, a solubilizer comprising one or more phospholipids and a bulking agent; and (b) instructions for reconstituting the lyophilized mixture with a diluent to an aprepitant concentration in the reconstituted formulation of about 2 mg / mL to about 15 mg / mL. In some non-limiting embodiments of the second non-limiting aspect, the article of manufacture further comprises a second container holding a diluent. In some non-limiting embodiments of the second non-limiting aspect, the diluent is sterile water for injection or 5% dextrose. In some non-limiting embodiments of the second non-limiting aspect, the aprepitant concentration is about 5.8 mg / mL or about 7.2 mg / mL.

[0017] In a third non-limiting aspect of the present disclosure, there is provided a pharmaceutical formulation suitable for intravenous administration comprising aprepitant and a solubilizer comprising one or more naturally occurring phospholipids, wherein the formulation is substantially free of a triglyceride.

[0018] In a fourth non-limiting aspect of the present disclosure, there is provided a method for the treatment or prevention of emesis in a human subject in need thereof, comprising administering to the subject the formulation of the first, second or third aspects of the present disclosure. In some non-limiting embodiments of the fourth non-limiting aspect, the emesis is induced by cancer chemotherapy. In some non-limiting embodiments of the fourth non-limiting aspect, the chemotherapy is highly emetogenic cancer chemotherapy (HEC) or moderately emetogenic cancer chemotherapy (MEC). In some non-limiting embodiments of the fourth non-limiting aspect, the emesis is postoperative nausea and vomiting (PONV). In some non-limiting embodiments of the fourth non-limiting aspect, the administration effects a serum profile of aprepitant having a mean Cmax of greater than about 3000 ng / mL or an ALICt of greater than about 7000 ng / mL.

[0019] In a fifth non-limiting aspect of the present disclosure, there is provided a process for the preparation of the lyophilized pharmaceutical formulation of the first aspect comprising lyophilizing an aseptic mixture comprising aprepitant, ethanol, a solubilizer comprising one or more phospholipids, a bulking agent, and water for injection. In some non-limiting embodiments of the fifth non-limiting aspect, the aseptic mixture is prepared by a process comprising: a) combining aprepitant, the solubilizer, and ethanol and passing through a sterilization filter to afford a first phase; b) combining the bulking agent with water for injection, passing through a sterilization filter and adjusting the pH to a range from about 6.5 to about 9 to afford a second phase; and c) combining the first and second phase to afford a bulk solution. In some non-limiting embodiments of the fifth non-limiting aspect, the first phase is added to the second phase. In some non-limitingembodiments of the fifth non-limiting aspect, the bulk solution is lyophilized in individual containers to afford about 130 mg of aprepitant per container. In some non-limiting embodiments of the fifth non-limiting aspect, the aseptic mixture is prepared by a process comprising: a) combining aprepitant, the solubilizer, and ethanol to afford a first phase; b) combining the bulking agent with water for injection and adjusting the pH to a range from about 9 to about 11 to afford a second phase; c) combining the first and second phase to afford a bulk solution and adjusting the pH to a range from about 6.5 to about 9; and d) passing the bulk solution through one or more sterilization filters to afford an aseptic mixture.

[0020] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the disclosure in conjunction with the accompanying figures.DETAILED DESCRIPTION

[0021] Marketed forms of injectable aprepitant formulations are oil-in-water emulsion products. Pharmaceutical regulations, such as the United States Pharmacopeia (USP) govern the physical properties of oil-in-water emulsions such as mean droplet size and fat globule size, which must be maintained over the shelf life of the product. However, the droplet size of emulsions is subject to several thermodynamic forces which tend to cause growth of the droplet size and instability of the emulsion. To counteract these forces, a number of excipients, including emulsifiers such as lecithin and co-surfactants such as ethanol, are often used to physically stabilize the emulsion.

[0022] It has been discovered by the present inventors that aprepitant can be formulated and stored as a lyophilized solid cake for reconstitution. The cake can be conveniently reconstituted for administration, such as a bolus injection or an intravenous infusion. In some non-limiting embodiments, the lyophilized cake is substantially free of both ethanol and added oil and has a reduced excipient burden compared to branded products. In some non-limiting embodiments, the reconstituted and diluted formulations are isotonic for increased patient comfort. In some non-limiting embodiments wherein the aprepitant formulations of the present disclosure are substantially ethanol-free, any sideeffects and / or concerns associated with ethanol use including irritation, hypersensitivity, and other alcohol-related issues are eliminated.

[0023] The following description is provided to enable those skilled in the art to make and use the described aspects contemplated for carrying out the disclosure. Various modifications, equivalents, variations, and alternatives, however, will remain readily apparent to those skilled in the art. Any and all such modifications, variations, equivalents, and alternatives are intended to fall within the scope of the present disclosure.

[0024] As used herein, the singular form "a", "an", and "the" include plural references. For example, "an" excipient includes one or more excipients. The term “comprising” is open-ended and may be synonymous with “including”, “containing”, or “characterized by”. The term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. As used herein, the term “about” means “close to” and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, when the term “about” is used with respect to a numerical value, the value may vary within a reasonable range, such as within + / -10%, + / -5%, or + / -1 % of the stated value. It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “90 to 95” is intended to include any and all sub-ranges between and including the recited minimum value of 90 and the recited maximum value of 95, that is, all subranges beginning with a minimum value equal to or greater than 90 and ending with a maximum value equal to or less than 95, and all subranges in between, e.g., 90 to 94.3, or 92.5 to 95, or 91 to 94.

[0025] As used herein, the term “pharmaceutical formulation”, refers to a mixture of aprepitant, optionally a second active ingredient, and a pharmaceutically acceptable excipient(s). The pharmaceutical formulation facilitates administration of an active ingredient to a human subject. The pharmaceutical formulation is preferably administered parenterally in a form adapted to such a route, and in a dose effective for the treatment intended. For example, the pharmaceutical formulation is preferably in a form that issuitable for intravenous administration, including a lyophilized solid, a reconstituted liquid thereof and / or a diluted solution for intravenous administration.

[0026] As used herein, the term “emulsion”, refers to a dispersed colloidal system comprising or consisting of two immiscible liquid phases generally stabilized with one or more suitable agents.

[0027] The term “pharmaceutically acceptable excipient” as used herein means a diluent, carrier, and / or composition auxiliary, which is non-toxic and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the active agent. Each excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated. Non-limiting examples of materials which can serve as pharmaceutically acceptable excipients are presented in Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, Pa., 21 st Edition (2005), which describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions.

[0028] The term “substantially free of” refers to a condition that is not entirely absolute. Preferably, the term corresponds to an amount of ethanol or a triglyceride that is less than about 5 wt%, more preferably less than about 3 wt%, and most preferably less than about 1 wt% in a formulation of the present disclosure.

[0029] The terms “stable” and “stability” mean that the evolution of the product with time and / or under specific environmental conditions (i.e. , temperature, humidity, etc.) has no significant effects on its quality, safety and / or efficacy for a given time period. It can be measured by monitoring for changes in physical and chemical attributes such as appearance, pH, osmolality, droplet size, degradation products and other properties as indicated in Example 2 and / or 4. In some embodiments, stability is monitored under refrigerated (5°C ± 3°C), long-term (25°C ± 2°C / 60% RH ± 5% RH) and / or accelerated(40°C ± 2°C / 75% RH ± 5% RH) conditions for at least 12 months and 6 months, respectively.

[0030] As used herein, the term “Q.S.” (an abbreviation of the Latin phrase quantum satis) means an amount sufficient to achieve the intended purpose. For example, Q.S. indicates that the quantity of a component is adjusted as necessary to accomplish a specified function, such as pH adjustment, volume completion, or concentration attainment, without specifying an exact numerical value.

[0031] As used herein, the term “Cmax” refers to the maximum observed concentration of a drug in plasma or serum following administration of a pharmaceutical formulation, measured over a defined sampling period.

[0032] As used herein, the term “ALICt” refers to the area under the plasma concentration-time curve from time zero to the last measurable concentration, representing the extent of systemic drug exposure over a specified time interval.

[0033] As used herein, the term “wt%” (weight %) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weight unit, expressed as a percentage. For example, with respect to a formulation comprising a mixture of components, wt% refers to the ratio of the weight of a component (in mg) to the weight of the formulation (in mg), expressed as a percentage.

[0034] As used herein, the phrase “therapeutically effective amount” means that amount of aprepitant, or a pharmaceutically acceptable salt thereof, that will elicit a biological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing, or halting of progression of the condition or disease, including but not limited to nausea and vomiting associated with emetogenic cancer chemotherapies such as MEC and HEC and / or postoperative nausea and vomiting. For treatment of chemotherapy-induced nausea and vomiting (CINV), a typical parenteral dosage regimen may range from about 50 mg to about 200 mg aprepitant by a single intravenous infusion or injection given over a time ranging from, for example, one or more minutes and up to about 1 hour prior tochemotherapy. For treatment of postoperative nausea and vomiting (PONV), a typical parenteral dosage regimen may range from about 10 mg to about 100 mg aprepitant by a single intravenous infusion or injection given over a time ranging from, for example, one or more seconds to one or more minutes prior to introduction of anesthesia.

[0035] As used herein, the term “isotonic” refers to a formulation having an osmotic pressure essentially equivalent to human blood. Isotonic formulations will generally have an osmotic pressure from about 250 to about 350 mOsm / kg. Isotonicity can be measured using a vapor pressure or ice-freezing type osmometer, for example.

[0036] As used herein, the term "lecithin" refers to a complex mixture of acetoneinsoluble phosphatides, which consist chiefly of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidic acid, present in conjunction with various amounts of other substances such as triglycerides, fatty acids, and carbohydrates. Lecithins can be derived from various sources including egg yolk, soybean, and / or corn lecithin.

[0037] As used herein, the term “egg phospholipids”, refers to a mixture of naturally occurring phospholipids obtained from the yolk of eggs that comprises phosphatidylcholine, phosphatidylethanolamine and lysophosphatidylcholine. Egg phospholipids preferably comprise less than about 5 wt% of oil in the form of triglycerides.

[0038] As used herein, the term “soy phospholipids”, refers to a mixture of naturally occurring phospholipids obtained from soybean that comprises a mixture of naturally occurring phospholipids obtained from soybean that comprises phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol. Soy phospholipids preferably comprise less than about 5 wt% of oil in the form of triglycerides.

[0039] As used herein, the term “naturally occurring phospholipids” refers to phospholipids that are present in biological materials such as egg yolk, soybean, or other natural sources without synthetic chemical modification of their molecular structure. Some non-limiting examples of naturally occurring phospholipids may comprise, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidic acid (PA), lysophosphatidylcholine (LPC) andmixtures thereof. Naturally occurring phospholipids may be provided as crude mixtures (e.g., lecithin) or as purified fractions enriched in one or more phospholipid species. Such materials may contain minor amounts of triglycerides, fatty acids, and carbohydrates inherent to the source material. In some non-limiting embodiments, naturally occurring phospholipids are derived from egg yolk and comprise phosphatidylcholine as the major component together with phosphatidylethanolamine and lysophosphatidylcholine. In some non-limiting embodiments, purified naturally occurring phospholipids refers to a composition comprising one or more phospholipids obtained from a natural biological source, such as egg yolk or soybean, wherein the phospholipids have been subjected to purification processes to substantially remove non-phospholipid components including triglycerides, fatty acids, and carbohydrates. In some non-limiting embodiments, purified phospholipids may comprise phosphatidylcholine (PC) as the major component, optionally in an amount of from about 50 wt% to about 90 wt% of the phospholipid fraction; minor amounts of other naturally occurring phospholipids such as phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), and mixtures thereof; and less than about 5 wt% of oil in the form of triglycerides. Naturally occurring phospholipids do not comprise synthetically modified PEGylated phospholipids conjugated with polyethylene glycol chains.

[0040] As used herein, the term “reconstituted”, refers to a formulation which has been prepared by dissolving a lyophilized aprepitant formulation in a diluent such that the aprepitant is dispersed in the reconstituted formulation. The reconstituted formulation, which may be further diluted with additional diluent, is suitable for administration (e.g., intravenous administration) to a patient.

[0041] In some non-limiting embodiments of the present disclosure, there is provided a lyophilized pharmaceutical formulation comprising aprepitant, a solubilizer comprising one or more phospholipids, and a bulking agent.

[0042] In some non-limiting embodiments, the solubilizer may be a pharmaceutically acceptable amphiphilic substance(s) suitable for intravenous administration. The solubilizer may be lecithin, a phospholipid or a mixture of several phospholipids, which may be derived from a natural source, such as egg yolk or soy. The phospholipid(s) ispreferably selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof. Particularly suitable phospholipids are commercial preparations of purified phospholipids comprising, for example, Lipoid® products derived from egg yolk and / or soybean, such as Lipoid E80® and Lipoid S75® and the like. The relative weight of solubilizer is preferably in excess of the weight of aprepitant. In a non-limiting example, the amount of solubilizer relative to aprepitant, expressed as a weight ratio, may be from about 5:1 to about 30:1. Preferably, the amount of solublizer relative to aprepitant, expressed as a weight ratio, is from about from about 10:1 to about 20: 1 .

[0043] In some non-limiting embodiments, the bulking agent may be a pharmaceutically acceptable agent suitable for intravenous administration. The bulking agent may be selected from the group consisting of mannitol, lactose, glycerin, dextrose, glucose, trehalose, sorbitol, glycine, arginine, histidine, sucrose, polyvinylpyrrolidine, polyethylene glycol, hydroxypropyl [3-cyclodextrin, sodium chloride, starch derivatives, gelatin, albumin, and mixtures thereof. Preferably, the bulking agent is mannitol. The relative weight of bulking agent is preferably in excess of the weight of aprepitant. In a non-limiting example, the amount of bulking agent relative to aprepitant, expressed as a weight ratio, may be from about 1.5:1 to about 15:1. Preferably, the amount of bulking agent relative to aprepitant, expressed as a weight ratio, is from about 2:1 to about 6:1.

[0044] Within some non-limiting embodiments, the lyophilized formulation preferably comprises from about 2 wt% to about 10 wt% aprepitant, from about 60 wt% to about 80 wt% solubilizer ,and from about 5 wt% to about 35 wt% bulking agent. For example, the lyophilized formulation may comprise 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%,9 wt% or 10 wt% aprepitant; 60 wt%, 61 wt%, 62 wt%, 63 wt%, 64 wt%, 65 wt%, 66 wt%, 67 wt%, 68 wt%, 69 wt%, 70 wt %, 71 wt%, 72 wt%, 73 wt %, 74 wt%, 75 wt%, 76 wt%, 77 wt%, 78 wt%, 79 wt% or 80 wt% solubilizer; and 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%,10 wt%, 11 wt%, 12 wt%, 13 wt%, 14, wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt %,30 wt %, 31 wt%, 32 wt%, 33 wt%, 34 wt% or 35 wt% bulking agent. Preferably, the solubilizer is egg phospholipids and / or soy phospholipids and the bulking agent is mannitol.

[0045] In some non-limiting embodiments, the lyophilized formulation further comprises a stabilizer. In some non-limiting embodiments, the stabilizer acts as an antioxidant. Non-limiting examples of stabilizers comprise ethylenediaminetetraacetic acid (EDTA), alpha-tocopherol (e.g. vitamin E), ascorbic acid (e.g. vitamin C) and mixtures thereof.

[0046] Other pharmaceutically acceptable excipients such as buffers (e.g. sodium phosphate buffer), stabilizers and pH-adjusting agents as described generally, for example, in Remington The Science and Practice of Pharmacy 21 st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 41 ) may be added as required provided that they do not adversely affect the desired characteristics of the formulation.

[0047] In some non-limiting embodiments, the lyophilized formulation may be reconstituted with a diluent, preferably sterile water for injection (WFI) or 5% dextrose solution, to afford a reconstituted formulation having an aprepitant concentration of from about 2 mg / mL to about 15 mg / mL, preferably from about 5 mg / mL to about 8 mg / mL. Each 100 mL of 5% Dextrose Injection, USP, contains dextrose, hydrous 5 g in water for injection. Preferably, the lyophilized formulation is reconstituted to an aprepitant concentration of about 7.2 mg / mL aprepitant with sterile water or 5% dextrose and this reconstituted solution is administered by intravenous injection or further diluted with 5% dextrose to afford an infusion formulation. The aprepitant concentration in the infusion solution is preferably from about 0.5 mg / mL to about 2 mg / mL, more preferably the aprepitant concentration is about 1.1 mg / mL. Alternatively, the lyophilized formulation is reconstituted to an aprepitant concentration of about 5.8 mg / mL with 5% dextrose to afford a bolus formulation for administration. Advantageously, some non-limiting embodiments of the reconstituted and / or diluted solution of aprepitant are isotonic, having an osmolality from about 260 to about 320 mOsm / kg as shown in Table 7.

[0048] In some non-limiting embodiments, reconstitution generally takes place at room temperature although other temperatures may be employed as desired. The time required for reconstitution will depend, e.g., on the type of diluent and amount of excipient(s) and is preferably less than about 10 minutes. Preferably, the reconstituted formulation exhibits a globule size distribution of not more than about 5.0 pm.

[0049] In some non-limiting embodiments, the lyophilized formulation may be prepared by subjecting a bulk solution, preferably an aseptic bulk solution, to lyophilization. Preferably, the bulk solution is prepared by mixing of a first phase comprising a mixture of aprepitant, a solubilizer and ethanol with a second phase comprising a mixture of a bulking agent and sterile water for injection and adjusting the pH to a range from about 6.5 to about 9 to afford a bulk solution. Preferably, the first phase is prepared by mixing aprepitant, a solubilizer and ethanol at a suitable temperature, preferably at a temperature from about 25 °C to about 50 °C, for a suitable to time, to afford a solution that may be sterilized, preferably by passing through a suitable 0.2 pm filter. Preferably, the concentrations of aprepitant, ethanol and solubilizer in the first phase are from about 10 mg / mL to about 30 mg / mL, from about 300 mg / mL to about 600 mg / mL and from about 150 mg / mL to about 500 mg / mL, respectively. Preferably, the second phase is prepared by mixing a bulking agent in sterile water for injection, preferably at a temperature from about 25 °C to about 50 °C, for a suitable time, to afford a solution that may be sterilized, preferably by passing through a 0.2 pm filter. Preferably, the concentration of bulking agent in the second phase is from about 40 mg / mL to about 400 mg / mL. The pH of the second phase may be adjusted with an acid such as hydrochloric acid or a base such as sodium hydroxide to a range from about 9 to about 11 . Preferably, the first phase is added into the second phase, and the pH is adjusted with an acid such as hydrochloric acid or a base such as sodium hydroxide, to a range from about 6.5 to about 9, more preferably from about 7.9 to about 8.5, under aseptic conditions. If necessary, the bulk solution may be passed through one or more sterilizing filters prior to undergoing lyophilization in a suitable container. Preferably, the bulk solution is dispensed into individual vials in an amount to afford the desired commercial dose for reconstitution / dilution after lyophilization.

[0050] In another non-limiting embodiment of the present disclosure, an article of manufacture is provided which contains the lyophilized formulation of the present disclosure and provides instructions for its reconstitution and / or use. The article of manufacture comprises a container. Suitable containers include, for example, bottles, vials (e.g., dual chamber vials), syringes (such as dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic. The container holds the lyophilized formulation and the label on, or associated with, the container may indicate directions for reconstitution and / or use. For example, the label may indicate that the lyophilized formulation is reconstituted to aprepitant concentrations as described above. In some non-limiting embodiments, the label may further indicate that the formulation is useful or intended for intravenous administration. In some nonlimiting embodiments, the article of manufacture may further comprise a second container comprising a suitable diluent such as sterile water for injection or 5% dextrose. In some non-limiting embodiments, upon mixing of the diluent and the lyophilized formulation, the final aprepitant concentration in the reconstituted formulation will generally be from about 2 mg / mL to about 15 mg / mL, preferably about 5.8 mg / mL or about 7.2 mg / mL. In some non-limiting embodiments, the article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

[0051] In another non-limiting embodiment of the present disclosure, the lyophilized formulation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 0.1 mg / kg to about 10 mg / kg of body weight / day of aprepitant. Preferably, the lyophilized formulation is provided in a suitable container such as a vial comprising about 32 mg or about 130 mg of aprepitant. In some non-limiting embodiments, when the lyophilizate comprises 130 mg aprepitant, it is preferably reconstituted in the container with about 15 mL of a sterile diluent to afford a reconstituted formulation having a final volume of about 18 mL. From this vial, the required volume may be withdrawn and further diluted with sterile diluent for intravenous administration of a dose (e.g., 100 mg or 130 mg) to the patient as per thedosing requirements. Alternatively, the lyophilizate (e.g., 130 mg aprepitant) can be reconstituted in the container with about 20 mL of a sterile diluent to afford a reconstituted formulation having a final volume of about 22.5 mL. From this vial, the entire volume or a fraction thereof (e.g., 17.5 mL) can be withdrawn for bolus administration of a dose (e.g., 100 mg or 130 mg) to the patient as per the dosing requirements. In some non-limiting embodiments, when the lyophilizate comprises 32 mg aprepitant, it is preferably reconstituted in the container with a sterile diluent to afford a reconstituted formulation having a final volume of about 4.4 mL. From this vial, the entire volume or a fraction thereof can be withdrawn for bolus administration of a dose (e.g., 32 mg) to the patient as per the dosing requirements.EXAMPLES

[0052] The following non-limiting examples are illustrative of some of the aspects and embodiments of the disclosure described herein.Example 1 : Aprepitant Lyophilized Formulation A

[0053] A lyophilized pharmaceutical formulation for reconstitution having the composition shown in Table 1 was prepared according to the process described below. Variations of Formulation A, substituting the mannitol bulking agent with trehalose (500 mg), glycine (600 mg) or a mixture of PEG / mannitol (200 mg / 400 mg) are also expected to be useful.

[0054] The manufacturing procedure of aprepitant for injection involved preparation of a non-aqueous solution (First Phase) and an aqueous solution (Second Phase). The First Phase was mixed with the Second Phase solution at a 1 :2 ratio. The bulk solution wasfilled into vials and the lyophilization process initiated. After lyophilization, stoppering was done with nitrogen in the head space, followed by sealing.Preparation of First Phase (Non-Aqueous):1 ) Dispensed quantity of egg phospholipids into a suitable mixing vessel. 2) The indicated amount of ethanol was added to the above mixing vessel containing egg phospholipids and the mixture was stirred until dissolution.RPM:600 Stirring time: 30 min3) The indicated amount of aprepitant was added to the above and the mixture stirred at about 40 °C to achieve dissolution. RPM: 500 Stirring time: 15 min4) The above solution was filtered through a 0.2 pm polyethersulfone (PES) filter.5) The density and volume of the resulting solution were measured.Preparation of Second Phase (Aqueous):1 ) Sterile water for injection (6.5 L) was collected in a mixing vessel and purged with nitrogen until the dissolved oxygen (DO) was less than 5.0 ppm.2) The indicated amount of mannitol was added, the mixture was stirred until a clear solution was obtained, and the volume was made up to 7.0 L.3) The above solution was filtered through 0.2 pm PES filter.Addition of First Phase to Second Phase (1 :2 ratio)1 ) The Second Phase solution (7.0 L) was collected in the final mixing vessel in a sterile area, passing through 0.2 pm PES filter.2) The First Phase (3.5 L) was added slowly to the Second Phase mannitol solution and the mixture stirred until dissolution.3) The pH of the solution was adjusted with 0.2N NaOH solution to pH 8.1 (target range 7.9 to 8.3).4) The DO was checked to ensure it was less than 5.0 ppm.5) The above solution was filled into 30 mL vials with a target fill volume of 15.9 mL. Lyophilization, Stoppering & Sealing1 ) The filled vials were half-stoppered and loaded to a lyophilizer to initiate the lyophilization process according to the program in Table 5.2) After lyophilization, the chamber was back-filled with nitrogen and stoppering was done with nitrogen in the head space. 3) The vials were unloaded from the lyophilizer after stoppering and sealing and contained 130 mg of aprepitant / vial.Example 2: Stability of Lyophilized Aprepitant Formulation A

[0055] The stability of the lyophilized aprepitant formulation A of Example 1 (130 mg / container) was tested under the conditions shown in Table 6. The initial osmolality of a solution reconstituted with water to a concentration of 7.2 mg / mL ranged from 275 to 290 mOsm / kg of water. A solution reconstituted with 5% dextrose to a concentration of 5.8 mg / mL ranged from 500 to 510 mOsm / kg of water.Inference:

[0056] The evaluated test parameters (reconstitution time, water content of lyophilized cake, viscosity, particle size distribution, zeta potential, assay, acid value and free fatty acid content) remained within acceptable limits under the conditions tested. Hence, there was no degradation of the drug product, and the formulation was considered stable.Example 3: Osmolality of Reconstituted and Diluted Lyophilized Formulation A

[0057] The osmolality of reconstituted and diluted solutions of lyophilized Formulation A of Example 1 are shown in Table 7 in comparison to reference product as-is and diluted as shown for intravenous administration.Example 4: Aprepitant Lyophilized Formulation B

[0058] A lyophilized pharmaceutical formulation for reconstitution having the composition shown in Table 8 was prepared according to the process described below."Used for preparation of 0.2N sodium hydroxide for aqueous phase pH adjustment to 10.8+ / -0.1 and final bulk solution pH adjustment to 8.5+ / -0.1 ; **Used for preparation of 0.1 N HCI for aqueous phase pH adjustment to 10.8+ / -0.1 and final bulk solution pH adjustment to 8.5+ / -0.1.

[0059] The manufacturing procedure of aprepitant for injection involved preparation of a non-aqueous solution (First Phase) and an aqueous solution (Second Phase). The First Phase was mixed with the Second Phase solution at a 1 :2 ratio. The final bulk solution was aseptically filtered using a suitable filter. The bulk solution was filled into vials and the lyophilization process initiated. After lyophilization, stoppering was done with nitrogen in the head space, followed by sealing.Preparation of First Phase (Non-Aqueous):1 ) In a suitable manufacturing vessel, added 90% of the required ethanol.2) Added egg phospholipid to the ethanol-containing vessel and rinsed the dispensed egg phospholipid container with the remaining 5% ethanol.3) Stirred the solution at 300-1000 RPM until a clear yellow solution was obtained.4) Maintained the temperature of the solution at 45°C to 50°C while stirring at 300-1000 RPM.5) Slowly added the required quantity of aprepitant API into the manufacturing vessel and rinsed the aprepitant container with the remaining 5% ethanol while stirring at 300-1000 RPM until a clear light yellow to yellow colour solution was obtained.6) Added quantity sufficient of ethanol to makeup the alcohol quantity to 100% of batch quantity of ethanol.7) Maintained the temperature at 45°C.Preparation of Second Phase (Aqueous):1 ) Collected 25% of the batch size of Water for Injection (WFI) in a manufacturing vessel.2) Dispensed quantity of mannitol to be added into the manufacturing vessel and rinsed the dispensed container / polybag with a suitable volume of WFI and transferred the rinse to the vessel.3) Stirred the contents at 350-1000 rpm until a clear solution was obtained.4) Checked the initial pH of the solution and adjusted the pH to 10.8±0.1.5) Maintained the solution at 60°C to 70°C.Addition of First Phase to Second Phase1 ) Slowly added Phase II (aqueous solution) to Phase I (non-aqueous solution) with constant stirring at 300 to 1000 RPM at 45°C and stirred until a clear light yellow to yellow solution was obtained.2) Adjusted the pH to 8.5 ±0.1.3) Made up the volume to 100% of the batch size with WFI and stirred at 300 to 1000 RPM until a clear light yellow to yellow colour solution was obtained.4) Maintained the bulk solution temperature at 45°C.Filtration1 ) Maintained the bulk solution temperature at 45°C during filtration.2) Filtered the bulk solution twice (primary and secondary filtration) through Merck Durapore 0.2 pm Hydrophilic PVDF filters and collected the filtrate in a holding vessel.3) Used filtered nitrogen (0.22pm) for filtration.4) The bulk solution was filled into clean depyrogenated glass vials to a target fill volume of 10.45 mL.1 ) The filled vials were half-stoppered and loaded to a lyophilizer to initiate the lyophilization process.2) After lyophilization, the chamber was back-filled with nitrogen and stoppering was done with nitrogen in the head space.3) The vials were unloaded from the lyophilizer after stoppering and sealing and contained 130 mg of aprepitant / vial.Example 5: Stability of Lyophilized Aprepitant Formulation B

[0060] The stability of a lyophilized sample in accordance with formulation B of Example 4 (130 mg / container) and packaged in a 30 mL clear glass vial with a rubber stopper and aluminum seal was tested under the following ICH conditions: • Accelerated: 40 °C ± 2 °C / 75% RH ± 5% RH with testing at 0 and 3 months• Long-term: 25 °C ± 2 °C / 60% RH ± 5% RH with testing at 0 and 3 months• Refrigerated: 8 °C ± 3 °C with testing at 0 and 3 months

[0061] Samples were tested at the initial and subsequent time points for description, cake height, head space oxygen, reconstitution time, reconstitution solution appearance, water content, pH, viscosity, osmolality, particle size, zeta potential, assay, acid value, free fatty acid content, phosphatidylcholine content and related substances, including desfluoro aprepitant. The samples conformed with the acceptance criteria shown in Table 9 within the tested time points.Dawley Rats

[0062] A GLP-compliant pharmacokinetic study was conducted to evaluate the pharmacokinetic profile of test formulations T1 and T2 aprepitant for injection (130 mg / vial) with comparison to reference formulation R (Cinvanti® injectable emulsion 130 mg / 18 mL) when administered by single intravenous dose in Sprague Dawley Rats. The study design comprised of three groups (G1 to G3); each group comprised of 6 male animals. Test formulations T1 (Formulation A, Table 1 ) and T2 (Formulation B, Table 8) were prepared by reconstitution of each respective lyophilized cake with 15.5 mL water for injection to a concentration of 7.2 mg / mL, followed by dilution of a 7 mL aliquot to 50 mL with 5% dextrose solution to afford a final concentration of 1 mg / mL. The Reference formulation R was prepared by diluting a 7 mL aliquot to 50 mL with 5% dextrose to afford a final concentration of 1 mg / mL. Animals in groups G1 and G2 were administered test formulations T1 and T2 and those in group G3 were administered the reference formulation R. The formulations were administered through the intravenous route and the dose was maintained at 0.5 mg / rat. After single intravenous (bolus) administration of the test dose, blood (0.25 mL / time point) was withdrawn from the G1 , G2 and G3 animals. Subsequently, plasma was separated and sent for analysis.

[0063] Clinical signs, moribundity and mortality check was done during acclimatization, treatment and observation period. At the end of observation period (day 1 ), all animals were euthanized.

[0064] No clinical signs of evident toxicity, moribundity and mortality were observed in any of the treated animals throughout the observation period. All the animals showed normal body weight over the course of the study. In sample analysis, aprepitant concentration was detected in the collected rat plasma samples. In data analysis, the pharmacokinetic profile of T1 , T2 and R were as shown in Tables 9-11 .

[0065] The T2 formulation showed a 105.99% higher Cmax and a 28.36% higher ALICt compared to the reference.

Claims

What is claimed is:

1. A lyophilized pharmaceutical formulation comprising aprepitant, a solubilizer comprising one or more phospholipids, and a bulking agent.

2. The pharmaceutical formulation of claim 1 , wherein the weight ratio of the solubilizer to the amount of aprepitant is from about 5:1 to about 30:1 .

3. The pharmaceutical formulation of claim 1 or 2, wherein the weight ratio of the bulking agent to the amount of aprepitant is from about 1.5:1 to about 15:1.

4. The pharmaceutical formulation of any of claims 1 to 3, wherein the solubilizer comprises a mixture of naturally occurring phospholipids.

5. The pharmaceutical formulation of claim 4, wherein the mixture of naturally occurring phospholipids are derived from egg or soybean.

6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the phospholipid(s) comprises from about 50 wt% to about 90 wt% phosphatidylcholine.

7. The pharmaceutical formulation of any of claims 1 to 6, wherein the bulking agent is selected from the group consisting of mannitol, lactose, glycerin, dextrose, glucose, glycine, arginine, sucrose and mixtures thereof.

8. The pharmaceutical formulation of claim 7, wherein the bulking agent is mannitol.

9. The pharmaceutical formulation of any of claims 1 to 8, wherein the formulation comprises from about 2 wt% to about 10 wt% aprepitant, from about 60 wt% to about 80 wt% egg phospholipids and from about 5 wt% to about 35 wt% mannitol.

10. The pharmaceutical formulation of claim 9, wherein the formulation comprises about 4 wt% aprepitant, about 64 wt% egg phospholipids and about 32 wt% mannitol.11 . The pharmaceutical formulation of any of claims 1 to 10, wherein the formulation is substantially free of ethanol and a triglyceride.

12. The pharmaceutical formulation of any of claims 1 to 11 , having a pH of from about6.5 to about 9.

13. The pharmaceutical formulation of any of claims 1 to 11 , wherein the formulation is stable when stored at about 5°C, about 25°C / 60% RH or about 40°C I 75% RH for at least three months.

14. The pharmaceutical formulation of any of claims 1 to 13, that is reconstituted with a diluent to afford a reconstituted formulation having a concentration of aprepitant of from about 2 mg / mL to about 15 mg / mL.

15. The reconstituted formulation of claim 14, wherein the diluent is sterile water for injection or 5% dextrose.

16. The reconstituted formulation of claim 15, wherein the concentration of aprepitant is about 7.2 mg / mL.

17. The reconstituted formulation of claim 14, wherein the diluent is 5% dextrose and the concentration of aprepitant is about 5.8 mg / mL.

18. The reconstituted formulation of any of claims 14 to 17, wherein the reconstituted formulation is further diluted to afford an infusion formulation having a concentration of aprepitant of about 1 .1 mg / mL.

19. An article of manufacture comprising:(a) a container which holds a lyophilized formulation comprising aprepitant, a solubilizer comprising one or more phospholipids, and a bulking agent; and(b) instructions for reconstituting the lyophilized mixture with a diluent to an aprepitant concentration in the reconstituted formulation of about 2 mg / mL to about 15 mg / mL.

20. The article of manufacture of claim 18, further comprising a second container holding a diluent.21 . The article of manufacture of claim 19 or 20, wherein the diluent is sterile water for injection or 5% dextrose.

22. The article of manufacture of any of claims 19 to 21 , wherein the aprepitant concentration is about 5.8 mg / mL or about 7.2 mg / mL.

23. A pharmaceutical formulation suitable for intravenous administration comprising aprepitant and a solubilizer comprising one or more naturally occurring phospholipids, wherein the formulation is substantially free of a triglyceride.

24. A method for the treatment or prevention of emesis in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of the formulation of any of claims 1 to 18 and 23.

25. The method of claim 24, wherein the emesis is induced by cancer chemotherapy.

26. The method of claim 25, wherein the chemotherapy is highly emetogenic cancer chemotherapy (HEC) or moderately emetogenic cancer chemotherapy (MEC).

27. The method of claim 24, wherein the emesis is postoperative nausea and vomiting (PONV).

28. The method of any one of claims 24 to 27, wherein the administration effects a serum profile of aprepitant having a mean Cmax of greater than about 3000 ng / mL or an ALICt of greater than about 7000 ng / mL.

29. A process for the preparation of the lyophilized pharmaceutical formulation of any of claims 1 to 13 comprising lyophilizing an aseptic mixture comprising aprepitant, ethanol, a solubilizer comprising one or more phospholipids, a bulking agent and water for injection.

30. The process of claim 29, wherein the aseptic mixture is prepared by a process comprising: a) combining aprepitant, the solubilizer, and ethanol and passing through a sterilization filter to afford a first phase;b) combining the bulking agent with water for injection, passing through a sterilization filter and adjusting the pH to a range from about 6.5 to about 9 to afford a second phase; and c) combining the first and second phase to afford a bulk solution. 31 . The process of claim 30, wherein the first phase is added to the second phase.

32. The process of claims 30 or 31 , wherein the bulk solution is lyophilized in individual containers to afford about 130 mg of aprepitant per container.

33. The process of claim 29, wherein the aseptic mixture is prepared by a process comprising: a) combining aprepitant, the solubilizer, and ethanol to afford a first phase; b) combining the bulking agent with water for injection and adjusting the pH to a range from about 9 to about 11 to afford a second phase; c) combining the first and second phase to afford a bulk solution and adjusting the pH to a range from about 6.5 to about 9; and d) passing the bulk solution through one or more sterilization filters to afford an aseptic mixture.

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