Injectable composition of aprepitant

Abstract

The present invention relates to an injectable composition comprising aprepitant and at least one pharmaceutically acceptable excipient. The invention further relates to processes for preparing such injectable compositions and to their use in the prevention or treatment of emesis, including but not limited to chemotherapy- induced or postoperative nausea and vomiting.

Description

[0001]

[0002] “INJECTABLE COMPOSITION OF APREPITANT”

[0003] Related Applications:

[0004] This Complete Cognate Application claims the priority benefit of Indian Provisional Application No. 202421075827, filed on October 7, 2024, entitled “INJECTABLE COMPOSITION OF APREPITANT”, and Indian Provisional Application No. 202521018626, filed on March 3, 2025, entitled “INJECTABLE COMPOSITION OF APREPITANT”. Each of these applications is hereby incorporated by reference in its entirety.

[0005] FIELD OF INVENTION

[0006] The present invention relates to injectable pharmaceutical compositions comprising aprepitant and pharmaceutically acceptable excipients. The invention particularly relates to compositions suitable for parenteral administration, processes for their preparation, and their use in the prevention or treatment of emesis, including but not limited to chemotherapy-induced or postoperative nausea and vomiting.

[0007] BACKGROUND OF INVENTION

[0008] Aprepitant is a substance P / neurokinin 1 (NKl) receptor antagonist that acts as a well-established anti emetic agent. It is widely used, particularly for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). Aprepitant is typically a white to off-white crystalline solid with a molecular weight of approximately 534.43 and exhibits very low aqueous solubility. While sparingly soluble in certain organic solvents, such as ethanol and isopropyl acetate, and slightly soluble in acetonitrile, its aqueous insolubility results in formulation challenges, especially for non-oral dosage forms.

[0009] Aprepitant is commercially available in the United States as a capsule under the brand name Emend®. The oral formulation is limited by poor bioavailability, which creates a need for alternative dosage forms with enhanced delivery characteristics.

[0010] Injectable dosage forms are generally recognized to offer higher bioavailability and a more rapid onset of action. However, the development of injectable formulations with aprepitant is complicated by its low solubility in water.

[0011] Although aprepitant's prodrug, fosaprepitant, is available as a lyophilized powder for reconstitution (marketed as Emend® for injection), this arrangement introduces additional manufacturing complexity and cost, as well as requiring reconstitution steps prior to administration. More recently, an emulsion injection of aprepitant (Cinvanti®) has become available; however, this formulation is characterized by relatively high osmolality (around 630-635 mosmol / kg) and high viscosity (10.2- 11.3 cps according to the approved labeling). While rapid intravenous administration (bolus over 2 minutes) is possible, such elevated osmolality and viscosity can adversely impact patient comfort and safety, potentially resulting in vein irritation, pain on injection, tissue damage, and reduced patient compliance.

[0012] OBJECT OF THE INVENTION

[0013] An object of the invention is to provide an injectable pharmaceutical composition comprising aprepitant and one or more pharmaceutically acceptable excipients.

[0014] Another object of the invention is to provide injectable compositions comprising aprepitant in combination with excipients selected from long chain triglycerides, medium chain triglycerides, emulsifiers, solvents, tonicity adjusting agents, pH adjusting agents, and water, in any suitable proportions or combinations.

[0015] A further object of the invention is to provide processes for preparing injectable compositions comprising aprepitant and excipients as described herein.

[0016] Another object of the invention is to provide injectable aprepitant compositions with properties, such as osmolality and viscosity, optimized for improved patient comfort and safety.

[0017] A further object of the invention is to provide compositions and methods suitable for the prevention or treatment of emesis, including but not limited to chemotherapy-induced nausea and vomiting, by parenteral administration of aprepitant.

[0018] SUMMARY OF THE INVENTION

[0019] There remains a need for injectable aprepitant compositions that address the existing challenges described herein, by providing acceptable osmolality and viscosity while maintaining manufacturing, storage, and administration advantages. The present invention provides such an injectable aprepitant composition, offering improved patient comfort, safety, and suitability for clinical use.

[0020] The invention demonstrates significant and unexpected advantages over prior art injectable and oral forms of aprepitant, achieving clinically relevant outcomes by solving well-recognized formulation obstacles and advancing patient care parameters. The injectable compositions of aprepitant described herein uniquely maintain osmolality and viscosity within the range optimized for intravenous administration, addressing key safety and comfort concerns encountered with existing commercial emulsions, which typically exhibit elevated osmolality (e.g., around 630-635 mOsm / kg) and viscosity (10.2-11.3 cps). The inventive compositions, in contrast, deliver osmolality in the range of 240-360 mOsm / kg and viscosity between 2-3.5 cps, levels that are unexpectedly both lower and synergistic in minimizing vein irritation, pain upon injection, and tissue damage, as well as improving infusion characteristics. The compositions further display highly stable physicochemical properties — retaining a uniform globule size (with D90 less than 200 nm), ensuring robust aseptic fdtration and sterility, and consistently remaining free of precipitate or particulate matter — features directly linked to extended physical and chemical shelf life. These physicochemical improvements are maintained during rigorous stability testing, with data supporting at least 24 months of storage without significant degradation or impurity increase, and retention of high drug assay values and minimal related substances in real-world commercial packaging. As a result, the compositions easily adapt to a range of clinically desirable container formats, such as vials, prefilled syringes, or infusion bags, and can be administered without concern for in-line filtration or reconstitution — properties which directly translate to enhanced ease of use for healthcare providers and reduced error risk.

[0021] Additionally, the invention dispenses with the need for aprepitant prodrugs (such as fosaprepitant), thus reducing cost, simplifying manufacturing, and removing complexity from the end-user experience. Unlike lyophilized products (which require additional reconstitution steps and present associated risks and costs), these ready-to-use emulsions meet direct clinical demand for efficiency and reliability in chemotherapy and postoperative settings. The combined effect of optimized viscosity and osmolality, extended stability under ICH conditions, optimal globule sizing, ready-to-administer format, and absence of administration-related pain or vein irritation constitute a constellation of secondary considerations: unexpected superiority in performance, improvements in patient compliance and comfort, reduction in adverse reactions, and commercial adoption prospects. The invention’s demonstrated ability to achieve these benefits — even in the absence of cosurfactants or co-emulsifiers and with a broad range of excipients and solvent systems — provides further evidence that the observed technical effect is not expected or routine, but arises from a unique combination and processing of ingredients. These surprising results and secondary indicia collectively supply robust support for overcoming a prima facie case of obviousness by highlighting advantages that are not predictable or suggested by the prior art and instead reflect inventive step and clinical significance.

[0022] The present invention provides an injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water.

[0023] The present invention also provides a method of treating a patient suffering from emesis (vomiting), the method comprising administering by injection the injectable composition described herein.

[0024] The present invention also provides a method of treating chemotherapy-induced nausea and vomiting by co-administering the injectable composition described herein with a 5-HT3 antagonist and dexamethasone.

[0025] The present invention also provides a process for preparing the injectable composition described herein, comprising dispersing aprepitant and lecithin in an oil phase, forming an emulsion with an aqueous phase comprising a tonicity adjusting agent and pH adjusting agent, homogenizing at 10,000 to 30,000 psi, and sterile fdtering or aseptic processing.

[0026] The present invention also provides a kit comprising the injectable composition described herein packaged in a sterile vial, prefdled syringe, or infusion bag.

[0027] The present invention also provides use of an injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water, for the manufacture of a medicament for the prevention or treatment of emesis or chemotherapy-induced nausea and vomiting.

[0028] The present invention also provides an injectable composition comprising aprepitant, soybean oil, lecithin, dimethylacetamide, sucrose, sodium oleate, and water, for use in the prevention or treatment of chemotherapy-induced nausea and vomiting.

[0029] The present invention also provides an injectable composition as described herein, for use in the treatment or prevention of emesis.

[0030] The present invention also provides use of the composition described herein for the manufacture of a medicament for the treatment of emesis in pediatric, elderly, or immune-compromised subjects.

[0031] The present invention also provides use of an injectable composition consisting essentially of aprepitant, lecithin, soybean oil, sucrose, sodium oleate, water, and optionally solvent, for the manufacture of a medicament for the treatment or prevention of emesis, wherein the composition does not contain a co-surfactant or co-emulsifier.

[0032] In summary, this invention represents a significant advancement in the field of parenteral antiemetics by providing a robust, stable, and patient-centric injectable aprepitant composition. Its combination of technological, pharmaceutical, and clinical advantages addresses longstanding challenges with existing therapies and is poised to set a new standard for the prevention and treatment of emesis in a variety of clinical contexts.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to injectable composition comprising aprepitant, a process of preparing the injectable composition comprising aprepitant and pharmaceutically acceptable excipients, and its use in the treatment emesis.

[0035] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0036] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In the present disclosure, 'about' is intended to encompass values within a range that a person skilled in the art would consider reasonably equivalent to the stated value, such as

[0037] ±10%, ±5%, ±1%, or as otherwise consistent with manufacturing or measurement variability. Also, the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0038] “Aprepitant” refers to any pharmaceutically suitable form of aprepitant, including but not limited to its free base, acid addition salts, hydrates, solvates, polymorphs, amorphous forms, crystalline forms, derivatives, prodrugs, esters, isomers, tautomers, and mixtures thereof, unless otherwise indicated by context. Aprepitant is designated chemically as 5-[[(2R,3S)-2-[(lR)-l-[3,5- bi s(trifluoromethyl)phenyl] ethoxy] -3 -(4-fluorophenyl) -4-morpholinyl] methyl] - l,2-dihydro-3H-l,2,4-triazol-3-one and a molecular weight of 534.43. The chemical structure is:

[0039] Aprepitant is available in the United States as a capsule dosage form under the brand name Emend®. It is observed that this oral dosage form exhibits poor bioavailability, and there was a need for a better dosage form to improve the same. It is well known that an injectable dosage form exhibits superior bioavailability and provides a better option. However, owing to the solubility concerns of aprepitant, it is a challenge to formulate aprepitant in an injectable dosage form. Aprepitant is available in its prodrug form Fosaprepitant and is approved in United States in an injectable dosage form Emend®. However, this formulation is a lyophilized powder which needs reconstitution, and also, synthesis of prodrug adds to the cost and complexity.

[0040] An emulsion formulation of aprepitant is also approved in the United States under the brand name Cinvanti®. It has been observed that this formulation has notably high osmolality levels around 630-635 mosmol / kg and relatively higher viscosity ranging from 10.2-11.3 cps. As per the approved pack insert, the formulation can be administered as a 2-minute intravenous bolus. Such high osmolality values and viscosity can have significant impact on patient comfort and safety. High osmolality can lead to vein irritation, pain upon injection, and tissue damage, while high viscosity can impede flow and increase the risk of complications. When present together, these attributes can magnify patient discomfort, reduce compliance, and jeopardize therapeutic outcomes.

[0041] “Injectable composition” refers to any sterile composition intended for administration by any parenteral route, including but not limited to intravenous, intramuscular, subcutaneous, intraperitoneal, intra-arterial, or intraspinal injection or infusion.

[0042] “Medium chain triglyceride” refers to triglycerides comprising fatty acids having chain lengths of from 6 to 12 carbon atoms. 'Long chain triglyceride' means triglycerides comprising fatty acids having more than 12 carbon atoms. Either term encompasses mixtures, derivatives, and any pharmaceutically acceptable source thereof, including synthetic or natural oils. In one embodiment, the medium chain triglyceride or long chain triglyceride is an oil. Examples of medium chain triglyceride or long chain triglycerides include, but are not limited to, coconut oil, sesame oil, castor oil, com oil, cottonseed oil, olive oil, peanut oil, peppermint oil, soybean oil, hydrogenated soybean oil, and hydrogenated vegetable oils.

[0043] The term “long chain triglyceride” refers to any triglyceride containing fatty acids with an aliphatic tail of greater than 12 carbon atoms, including mixtures and derivatives thereof.

[0044] “Soybean oil” encompasses any oil derived from soybeans and suitable for pharmaceutical use, including but not limited to unrefined, refined, partially or fully hydrogenated forms, and includes pharmaceutically acceptable fractions, blends, or chemically modified soybean oils.

[0045] “Emulsifier” refers to any agent or combination of agents that promotes or stabilizes the dispersion of two or more immiscible phases, including but not limited to natural or synthetic phospholipids, lecithins, saponins, surfactants, or combinations thereof.

[0046] “Lecithin” refers to any naturally or synthetically derived lecithin suitable for pharmaceutical use from any source, including purified, unpurified, fractionated, or chemically modified forms.

[0047] “Solvent” refers to any pharmaceutically acceptable liquid or mixture that can solubilize or disperse drug substance or excipients, including but not limited to organic solvents, water, polyols, glycols, esters, or mixtures thereof.

[0048] The term “tonicity adjusting agent” refers to any pharmaceutically acceptable compound used to alter or maintain the tonicity or osmolality of a composition, including organic or inorganic compounds, sugars, sugar alcohols, salts, or combinations thereof.

[0049] The term “pH adjusting agent” refers to any substance or mixture capable of modifying, buffering, or maintaining the pH within a pharmaceutically acceptable range, including acids, bases, buffers, salts, or mixtures thereof.

[0050] The term “water (q.s. to 1 mL)” refers to water suitable for pharmaceutical use in a quantity sufficient to achieve a final specified composition volume.

[0051] The term “co-surfactant / co-emulsifier” refers to any amphiphilic or surface -active agent, other than a primary emulsifier, that enhances, supports, or modifies the formation or stability of dispersed phases in a composition.

[0052] The term “substantially free of’ refers to the specified substance is absent or, if present, is at a level that does not materially affect the composition's properties, performance, or use as intended, except for trace or unavoidable impurities. For purposes of the present invention, “substantially free of impurities” shall be understood to include aprepitant containing injectable compositions in which the amount of total impurities is less than about 5% of the sum of peak areas of all degradants, as calculated on a normalized peak area response (“PAR) basis as determined by high performance liquid chromatograph (“HPLC) after a period of about 18 months as per ICH guidelines. The amount of impurities is further calculated as being based upon the original amount of aprepitant (or salt thereof) being present in the composition. Preferably, the said injectable compositions of aprepitant prevent degradation of aprepitant such that not more than 2 %, not more than 1%, not more than 0.4%, not more than 0.2% of aprepitant impurity or impurities are formed over the storage period. In yet another preferred embodiment the value of assay of aprepitant remains within the specified limit of 90-110% by weight of the label claim. In one embodiment, the injectable composition of the present invention contains total impurities less than 0.5%.

[0053] The term “ready-to-use” refers to a composition formulated and packaged for direct administration without the need for further preparation, dilution, reconstitution, or adjustment.

[0054] The term “globule size distribution” refers to the measurement of dispersed phase particle sizes in an emulsion, including any statistical parameter describing particle diameters such as D90.

[0055] The term “osmolality” refers to the concentration of osmotically active particles per kilogram of solvent in the composition, measured in milliosmoles per kilogram (mOsm / kg).

[0056] The term “viscosity” refers to the resistance of a composition to flow, measured by any accepted method, and expressed typically in centipoise (cps).

[0057] The term “stable / stability” refers to the ability of the composition to maintain its physical, chemical, and microbiological properties over a defined period under specified storage conditions. Specifically, the term “stable” refers to an injection composition of present invention which is physically as well as chemically stable as demonstrated by compliance to acceptable specification when the composition is stored at convenient temperature, such as between about 0°C and about 40°C, for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years. The term “stable” also refers to an injectable composition as per the present invention which exhibits physical stability for a sufficiently long time to allow for infusion of the product Suitably, the injectable composition of aprepitant of present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18-24 months when stored as per ICH guidelines. Suitably, the injectable composition of aprepitant remains chemically stable when stored as per ICH guidelines, wherein various parameters such as the drug content (assay of aprepitant) and content of related substances, i.e. known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for prolonged period of time such as for at least 12 months, preferably for 18 months, more preferably 24 months or longer.

[0058] “Stable” or “stability” refers to the ability of a composition to retain its physical, chemical, microbiological, and, where relevant, biological characteristics within predefined specifications throughout its shelf life under specified conditions. “Physically stable” refers to maintaining appearance, absence of phase separation, and intended particle size; “chemically stable” refers to retaining the integrity and potency of its ingredients; “microbiologically stable” refers to remaining sterile or within intended bioburden limits.

[0059] The term “sterile” refers to the composition contains no viable microorganisms, as demonstrated by validated compendial methods suitable for injectable products.

[0060] The term “homogenizing” refers to any process by which a composition is subj ected to mechanical, physical, or other treatment to achieve uniform mixing or particle size distribution.

[0061] The term “aseptic filtration / process” refers to any means of sterilization or manufacture that prevents microbial contamination throughout production and packaging.

[0062] The term “in-line filter” refers to any filtration device used during injection or infusion to remove particulates or contaminants from the composition.

[0063] The term “kit” refers to any pre-packaged assembly including the injectable composition and any suitable container, accessory, or labelling materials for storage, distribution, or administration.

[0064] The term “total volume” refers to the final packaged volume of the composition, as measured after manufacturing and filling into a container.

[0065] The term “pharmaceutically acceptable excipient” refers to any carrier, diluent, adjuvant, stabilizer, solubilizer, pH modifying agent, or any other substance, other than the active compound, approved or recognized for safe use in pharmaceutical dosage forms.

[0066] The term “treatment”, “emesis”, and “chemotherapy-induced nausea and vomiting (CINV)” refer respectively to the application of medical therapy to ameliorate disease or symptoms, episodes of nausea or vomiting from any cause, and episodes of nausea or vomiting associated with administration of chemotherapy.

[0067] The term “prodrug” refers to any chemical derivative of aprepitant or other active ingredient that is biologically inactive until converted to the active form after administration.

[0068] The term “free from particulates / particulate matter” refers to a state in which the composition contains no visually or analytically detectable solid particles other than those integral to its intended formulation.

[0069] The term “assay of aprepitant” refers to any quantitative method for determining the concentration of aprepitant in the composition.

[0070] The term “impurity / total impurities” refers to the sum of non-active substances present in the composition, regardless of source, measured according to accepted pharmaceutical standards.

[0071] The term “ready-to-administer” refers to a composition prepackaged or prepared for direct use in patient administration without further modification.

[0072] The term “patient comfort / safety / inj ection site reaction” includes any subjective or objective observation, assessment, or reporting of pain, irritation, inflammation, adverse effect, or other response attributable to the administration procedure, measured by any accepted scale or method.

[0073] The term “grade 2 injection site pain” refers to pain perceived at the site of injection classified according to any medically accepted grading scheme, such as Common Terminology Criteria for Adverse Events (CTCAE), but does not require reference to a specific grading scale.

[0074] The term “5-HT3 antagonist” refers to any agent that binds to and blocks serotonin type 3 (5-HT3) receptors, thereby preventing serotonin from activating these receptors. These agents are typically used for the prevention and treatment of nausea and vomiting, including chemotherapy-induced nausea and vomiting, as well as other conditions involving 5-HT3 receptor-mediated pathways.

[0075] The term “dexamethasone” refers to a synthetic glucocorticoid corticosteroid that mimics naturally occurring adrenal cortex hormones, widely used as an antiinflammatory and immunosuppressant agent to treat various conditions including inflammatory diseases, allergies, asthma, certain cancers, and to prevent chemotherapy-induced nausea and vomiting.

[0076] The term “co-surfactant” refers to an amphiphilic molecule used alongside a primary surfactant in a pharmaceutical composition that accumulates at the interface between immiscible phases, helping to reduce interfacial tension and improve the stability and formation of emulsions or microemulsions. Unlike primary surfactants, co-surfactants may not form self-assembled micelles alone but assist in modulating the overall surface properties of the system.

[0077] The term “co-emulsifier” refers to a substance that works together with a primary emulsifier in a pharmaceutical formulation to enhance or stabilize the emulsification of two immiscible liquids, thereby improving the homogeneity and stability of an emulsion. It may act by modifying interfacial film properties or by supporting the primary emulsifier but is typically present at a lower concentration.

[0078] The term “bolus” refers to the administration of a single, concentrated dose of a pharmaceutical composition, typically delivered rapidly by injection intravenously, intramuscularly, or subcutaneously, intended to achieve immediate therapeutic levels of the active ingredient in the bloodstream.

[0079] The present invention provides an advanced injectable pharmaceutical composition comprising aprepitant in combination with at least one pharmaceutically acceptable excipient. The excipients may include medium chain triglycerides, long chain triglycerides, emulsifiers such as lecithin, solvents, tonicity adjusting agents, and optional pH adjusting agents. This carefully optimized formulation achieves a finely controlled particle or globule size, resulting in an emulsion that balances manufacturability, stability, and clinical utility for parenteral administration. The invention not only addresses and overcomes the solubility and stability issues associated with prior art but also achieves optimal viscosity and osmolality for improved patient tolerability and safety.

[0080] A distinguishing aspect of this invention is the delivery of aprepitant in a ready-to- use, stable emulsion suitable for administration through various parenteral routes, including intravenous, intramuscular, and subcutaneous injection. The inventive compositions maintain osmolality in the range of 240-360 mOsm / kg and viscosity between 2-3.5 cps, both substantially improved over previously marketed products. These formulations demonstrate minimal injection site discomfort and significantly reduce the risk of vein irritation and tissue damage, which are common adverse effects with higher viscosity or osmolality injectable products. The globule size remains well within the pharmaceutically preferred range, allowing for ease of sterile filtration and safe intravenous delivery.

[0081] The inventive injectable aprepitant compositions are physically and chemically stable, with demonstrated shelflife exceeding 24 months under ICH-recommended storage conditions. Unlike lyophilized fosaprepitant prodrug formulations that require reconstitution prior to use, these emulsions are ready to administer, streamlining both clinical logistics and user convenience. The advanced excipient system provides robustness against aggregation, precipitation, or degradation, making the compositions suitable for various packaging formats, including vials, prefilled syringes, and infusion bags. Clinical advantages include consistent control of nausea and vomiting, enhanced patient compliance, rapid onset of effect, and simplified preparation and dispensing in healthcare settings.

[0082] Beyond oncology and chemotherapy, the injectable aprepitant compositions are broadly applicable to other forms of emesis such as postoperative nausea and vomiting or nausea linked to other medical causes. The versatility of this platform, including its ability to co-administer with 5-HT3 antagonists and corticosteroids, further broadens its utility and commercial potential across a spectrum of antiemetic regimens. The invention also encompasses processes for manufacture, as well as kits and packaged dosage forms that combine the injectable composition with necessary administration devices.

[0083] The injectable composition of the present invention comprises aprepitant along with excipients. The particle size is a significant attribute for improving the solubilization of aprepitant. This precise control over globule size is significant for minimizing the risk of phase separation and sedimentation, thereby extending the stability of the composition. A globule size of less than 200 nm facilitates aseptic filtration, as the injectable composition can easily pass through standard filters without clogging, ensuring sterility. A globule size of less than 200 nm also reduces the risk of embolism during intravenous administration, improves stability, minimizes irritation at the injection site, and ensures consistent dosing. These attributes make the formulation well-suited for both aseptic filtration and safe, effective intravenous administration, addressing key challenges in the development of injectable compositions. As such, the particle size of aprepitant as per the present invention may have a D90 about 10 pm to about 200 pm, preferably from about 15 pm to about 100 pm. Likewise, the injectable composition of the present invention may have a globule size distribution with a D90 value of less than 200 nm, and more preferably within the range of 100 to 180 nm.

[0084] The injectable composition of the present invention comprises at least one emulsifier. Suitable example of emulsifier, include, but is not limited to egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids.

[0085] The injectable composition of the present invention comprises at least one solvent. Non-limiting examples of solvent are N-methyl-2-pyrrolidone, isopropanol, n- butanol, t-butyl alcohol, benzyl benzoate, ethylene glycol dimethyl ether, ethylene glycol, propylene glycol, dimethylacetamide, N,N -dimethylformamide, dimethylsulfoxide (DMSO), glycerin / glycerol, polyethylene glycol (PEG), ethanol and combinations thereof. The injectable composition of the present invention may comprise about 10.0 mg / ml to about 70.0 mg / ml of solvent. Preferably the injectable composition of the present invention may contain dimethylacetamide, N- methyl-2 -pyrrolidone, ethanol as solvent.

[0086] The injectable composition of the present invention comprises at least one tonicity adjusting agent. Suitable tonicity adjusting agent include, but is not limited to glycerol, mannitol, dextrose, sorbitol, xylitol, glucose, dextran, maltose, sucrose, raffinose, sodium chloride, lactose, polyethylene glycol, propylene glycol or trehalose. The injectable composition of the present invention comprises about 20 mg / ml to about 40.0 mg / ml tonicity adjusting agent. Preferably, the injectable composition of the present invention comprises sucrose as the tonicity adjusting agent. Specifically, the injectable composition of the present invention can comprise about 27.0 mg / ml sucrose.

[0087] The injectable composition of the present invention comprises at least one pH adjusting agent. Suitable pH adjusting agent include, but is not limited to sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium oleate, magnesium hydroxide, potassium oleate, ammonium oleate, potassium linoleate, sodium linoleate, ammonium oleate and combination thereof. The injectable composition of the present invention comprises about 2.0 mg / ml to about 4.0 mg / ml of a pH adjusting agent. Preferably, the injectable composition of the present invention comprises sodium oleate as the pH modifying agent. Specifically, the injectable composition of the present invention can comprise about 2.4 mg / ml of pH modifying agent.

[0088] The ICH storage stability studies were performed on the injectable composition of the present invention packaged in the proposed commercial primary packaging and closure system. The stability study samples were stored at 2-8°C, 25°C, 30°C, and 40°C. The necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at both stability conditions. In some preferred aspects of the invention, the time for which long term storage are contemplated include periods of at least about 24 months or longer with such that the composition is substantially free of impurities when stored as per ICH guidelines.

[0089] The injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or an infusion bag or a container fit for the sterile storage of a pharmaceuticals. The stable injectable composition of the present invention can be provided in a kit or package that includes a container enclosing the composition. Suitable containers can be glass vials, i.e. Schott treated vials, molded glass vials, CZ resin vials, polypropylene or polyethylene vials or other special purpose containers. Suitable containers can be prefilled syringes such as glass prefilled syringes, plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of aprepitant. The container may be part of a syringe or separate from the syringe. The kit or package also includes a needle that can be suitably mounted to the syringe. The size of the needle, in some embodiments, is equal to or smaller than 18G, 19G, 20G, 21G, 22G, 23G, 24G, or 25G. In one embodiment, the needle has a size that is 20G or smaller. In one embodiment, the needle has a size that is 21G or smaller. In one embodiment, the needle has a size that is 22G or smaller. In one embodiment, the needle has a size that is 23G or smaller. In one embodiment, the injectable composition of the present invention may be administered without the need of an in-line filter during administration, demonstrating the absence of particulate matter throughout its shelf life. In another embodiment, the injectable composition of the present invention may be filtered by using an in-line filter before administration.

[0090] The present invention further provides methods of treating a patient suffering from emesis by injection of the composition of the present invention. In one embodiment, the present invention relates to use of an injectable composition for the treatment of chemotherapy induced nausea and vomiting.

[0091] Specific Ranges, Values, and Embodiments

[0092] The specific embodiments describing the ranges and values provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims.

[0093] In specific embodiments, the injectable composition comprises about 2mg / ml to about 5 mg / ml aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent and water.

[0094] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml oil, (c) about 15.0 mg / ml to about 105.0 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) about 2.0 mg / ml to about 4.0 mg / ml pH adjusting agent and (g) water.

[0095] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml oil, (c) about 15.0 mg / ml to about 105.0 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) optionally pH adjusting agent and (g) water.

[0096] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml ethanol, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate and (g) water.

[0097] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml dimethylacetamide, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate and (g) water.

[0098] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml N-methyl-2-pyrrolidone, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate and (g) water.

[0099] In specific embodiments, the injectable composition consisting essentially of (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml ethanol, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate and (g) water.

[0100] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0101] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 100 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0102] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 102 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0103] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 55.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0104] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 75.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0105] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0106] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72.0 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0107] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72 mg / ml lecithin, (d) about 41.5 mg / ml N-methyl -2 -pyrrolidone, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0108] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 41.7 mg / ml N-methyl-2 -pyrrolidone, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0109] In specific embodiments, the particle size of aprepitant has a D90 of at least about 10 pm.

[0110] In specific embodiments, the particle size of aprepitant has a D90 of at least about 20 pm.

[0111] In specific embodiments, the particle size of aprepitant has a D90 of at least about 30 pm.

[0112] In specific embodiments, the particle size of aprepitant has a D90 of at least about 40 pm.

[0113] In specific embodiments, the particle size of aprepitant has a D90 of at least about 50 pm.

[0114] In specific embodiments, the particle size of aprepitant has a D90 of at least about 60 pm.

[0115] In specific embodiments, the composition contains at least about 2.0 mg / ml to about 5.0 mg / ml aprepitant.

[0116] In specific embodiments, the composition contains at least about 3.0 mg / ml to about 4.0 mg / ml aprepitant.

[0117] In specific embodiments, the composition contains about 3.6 mg / ml aprepitant.

[0118] In specific embodiments, the injectable composition comprises (a) aprepitant, (b) long chain triglyceride, (c) emulsifier, (d) solvent, (e) tonicity adjusting agent, (f) optionally a pH adjusting agent, and (g) water.

[0119] In specific embodiments, the injectable composition comprises (a) aprepitant, (b) medium chain triglyceride, (c) emulsifier, (d) solvent, (e) tonicity adjusting agent, (f) optionally a pH adjusting agent, and (g) water.

[0120] In specific embodiments, the injectable composition comprises at least one medium chain triglyceride or at least one long chain triglyceride.

[0121] In specific embodiments, the injectable composition comprises about 40.0 mg / ml to about 60.0 mg / ml of a medium chain triglyceride or a long chain triglyceride.

[0122] In specific embodiments, the injectable composition comprises soybean oil.

[0123] In specific embodiments, the injectable composition comprises about 48.2 mg / ml of a medium chain triglyceride or a long chain triglyceride.

[0124] In specific embodiments, the emulsifier is a lecithin.

[0125] In specific embodiments, the injectable composition includes about 15.0 mg / ml to about 105.0 mg / ml of an emulsifier.

[0126] In specific embodiments, the injectable composition comprises egg lecithin as the emulsifier.

[0127] In specific embodiments, the injectable composition comprises about 55.0 mg / ml egg lecithin.

[0128] In specific embodiments, the injectable composition comprises about 72.0 mg / ml egg lecithin.

[0129] In specific embodiments, the injectable composition comprises about 75.0 mg / ml egg lecithin.

[0130] In specific embodiments, the injectable composition comprises about 97.5 mg / ml of egg lecithin.

[0131] In specific embodiments, the injectable composition comprises about 100.0 mg / ml of egg lecithin.

[0132] In specific embodiments, the injectable composition comprises about 102.0 mg / ml of egg lecithin.

[0133] In specific embodiments, the injectable composition comprises about 144.0 mg / ml of egg lecithin.

[0134] In specific embodiments, the injectable composition comprises about 192.0 mg / ml of egg lecithin.

[0135] In specific embodiments, the injectable composition comprises about 204.0 mg / ml of egg lecithin.

[0136] In specific embodiments, the injectable composition comprises about 14.3 mg / ml of ethanol.

[0137] In specific embodiments, the injectable composition comprises about 55.5 mg / ml of dimethylacetamide.

[0138] In specific embodiments, the injectable composition comprises about 41.5 mg / ml of N-methyl pyrrolidone.

[0139] In specific embodiments, the injectable composition comprises about 41.7 mg / ml of N-methyl pyrrolidone.

[0140] In specific embodiments, the injectable composition comprises about 2.0 mg / ml to about 5.0 mg / ml aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent and water.

[0141] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0.0 mg / ml oil, (c) about 15.0 mg / ml to about 105.0 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) about 2.0 mg / ml to about 4.0 mg / ml pH adjusting agent, and (g) water.

[0142] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml oil, (c) about 15.0 mg / ml to about 105 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) optionally pH adjusting agent, and (g) water.

[0143] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml ethanol, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate, and (g) water.

[0144] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml dimethylacetamide, (e) about 20.0 mg / ml to about 40.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate, and (g) water.

[0145] In specific embodiments, the injectable composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml soybean oil, (c) about 15.0 mg / ml to about 105.0 mg / ml lecithin, (d) about 10.0 mg / ml to about 70.0 mg / ml N-methyl-2-pyrrolidone, (e) about 20.0 mg / ml to about 40.0.0 mg / ml sucrose, (f) about 2.0 mg / ml to about 4.0 mg / ml sodium oleate, and (g) water.

[0146] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0147] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 100.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0148] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 102.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0149] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 55.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0150] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 75.0 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0151] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0152] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72.0 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0153] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72 mg / ml lecithin, (d) about 41.5 mg / ml N-methyl -2 -pyrrolidone, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0154] In specific embodiments, the injectable composition comprises (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 41.7 mg / ml N-methyl-2 -pyrrolidone, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0155] In specific embodiments, the injectable composition comprises (a) about 5.0 mg / ml to about 10.0 mg / ml aprepitant, (b) about 50.0 mg / ml to about 150.0 mg / ml oil, (c) about 100.0 mg / ml to about 250.0 mg / ml emulsifier, (d) about 50.0 mg / ml to about 250.0 mg / ml solvent, (e) about 50.0 mg / ml to about 60.0 mg / ml tonicity adjusting agent, (f) about 1.0 mg / ml to about 10.0 mg / ml pH adjusting agent and (g) water.

[0156] In specific embodiments, the injectable composition comprises (a) about 5.0 mg / ml to about 10.0 mg / ml aprepitant, (b) about 50.0 mg / ml to about 150.0 mg / ml oil, (c) about 100.0 mg / ml to about 250.0 mg / ml emulsifier, (d) about 50.0 mg / ml to about 250.0 mg / ml solvent, (e) about 50.0 mg / ml to about 60.0 mg / ml tonicity adjusting agent, (f) optionally a pH adjusting agent and (g) water

[0157] In specific embodiments, the injectable composition is free of co-surfactant and / or co-emulsifier.

[0158] In specific embodiments, the injectable composition has an osmolality of about 240 mosm / kg to about 360 mosm / kg.

[0159] In specific embodiments, the injectable composition has a viscosity from about 2 cps to about 3.5 cps.

[0160] In specific embodiments, the injectable composition has a total volume of about 1 ml to about 50 ml.

[0161] In specific embodiments, the injectable composition has a total volume of about 10 ml to about 40 ml.

[0162] In specific embodiments, the injectable composition has a total volume of about 36 ml.

[0163] In specific embodiments, the injectable composition has a total volume of about 18 ml.

[0164] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 1 below.

[0165] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 1 below, in the amount shown.

[0166] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 1 below, in the amount (value) shown below.

[0167] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 1 below, in the amount (range) shown below.

[0168]

[0169]

[0170]

[0171] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 2 below.

[0172] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 2 below, in the amount shown.

[0173] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 2 below, in the amount (value) shown below.

[0174] In specific embodiments, the injectable composition includes any one or more of the ingredients in Table 2 below, in the amount (range) shown below.

[0175] Table 2

[0176]

[0177]

[0178] Enumerated Embodiments

[0179] Specific enumerated embodiments <1> to <42> provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims. These enumerated embodiments encompass all combinations, sub-combinations, and multiply referenced (e.g., multiply dependent) combinations described therein.

[0180] <Embodiment 1> An injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water.

[0181] <Embodiment 2> The injectable composition of <Embodiment 1>, comprising aprepitant, one of a medium chain triglyceride and a long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water.

[0182] <Embodiment 3> The injectable composition of any one of the preceding Embodiments, wherein the aprepitant is present in about 2 mg / ml to about 10 mg / ml.

[0183] <Embodiment 4> The injectable composition of any one of the preceding Embodiments, wherein the aprepitant is present in about 2 mg / ml to about 5 mg / ml.

[0184] <Embodiment 5> The injectable composition of any one of the preceding Embodiments, wherein the aprepitant is present in about 5 mg / ml to about 10 mg / ml.

[0185] <Embodiment 6> The injectable composition of any one of the preceding Embodiments, wherein the medium chain triglyceride or long chain triglyceride is at least one of coconut oil, sesame oil, castor oil, com oil, cottonseed oil, olive oil, peanut oil, peppermint oil, soybean oil, hydrogenated soybean oil, and hydrogenated vegetable oils.

[0186] <Embodiment 7> The injectable composition of any one of the preceding Embodiments, wherein the medium chain triglyceride or long chain triglyceride is soybean oil.

[0187] <Embodiment 8> The injectable composition of any one of the preceding Embodiments, wherein the emulsifier is egg lecithin or soy lecithin.

[0188] <Embodiment 9> The injectable composition of any one of the preceding Embodiments, wherein the solvent is at least one of ethanol and dimethylacetamide .

[0189] <Embodiment 10> The injectable composition of any one of the preceding Embodiments, wherein the tonicity adjusting agent is sucrose.

[0190] <Embodiment 11> The injectable composition of any one of the preceding Embodiments, wherein the pH adjusting agent is sodium oleate.

[0191] <Embodiment 12> The injectable composition of any one of the preceding Embodiments, wherein the composition comprises about 3.6 mg / ml aprepitant.

[0192] <Embodiment 13> The injectable composition of any one of the preceding Embodiments, wherein the composition comprises about 7.2 mg / ml aprepitant.

[0193] <Embodiment 14> The injectable composition according to <Embodiment 1>, comprising (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0194] <Embodiment 15> The injectable composition according to <Embodiment 1>, comprising (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72.0 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

[0195] <Embodiment 16> The injectable composition according to <Embodiment 1>, comprising (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml to about 204 mg / ml lecithin, (d) about 14.3 mg / ml to about 111 mg / ml solvent selected from ethanol, dimethylacetamide, N-methyl-2 -pyrrolidone, propylene glycol, or dimethylsulfoxide, (e) about 27.0 mg / ml to about 55 mg / ml sucrose, (f) about 2.4 mg / ml to about 6 mg / ml sodium oleate, and (g) water.

[0196] <Embodiment 17> The injectable composition of any one of the preceding Embodiments, wherein the osmolality of the composition is about 240 mosm / kg to about 360 mosm / kg.

[0197] <Embodiment 18> The injectable composition of any one of the preceding Embodiments, wherein the viscosity of the composition is about 2 cps to about 3.5 cps.

[0198] <Embodiment 19> The injectable composition of any one of the preceding Embodiments, wherein the total volume of about 1 ml to about 50 ml.

[0199] <Embodiment 20> The injectable composition of any one of the preceding Embodiments, wherein the total volume of said composition is about 36 ml.

[0200] <Embodiment 21> The injectable composition of any one of the preceding Embodiments, wherein the total volume of said composition is about 18 ml.

[0201] <Embodiment 22> The injectable composition according to <Embodiment 1>, wherein the said composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml oil, (c) about 15.0 mg / ml to about 105.0 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) optionally about 2.0 mg / ml to about 4.0 mg / ml pH adjusting agent, and (g) water.

[0202] <Embodiment 23> The injectable composition according to <Embodiment 1>, wherein the said composition comprises (a) about 5.0 mg / ml to about 10.0 mg / ml aprepitant, (b) about 50.0 mg / ml to about 150.0 mg / ml oil, (c) about 100.0 mg / ml to about 250.0 mg / ml emulsifier, (d) about 50.0 mg / ml to about 250.0 mg / ml solvent, (e) about 50.0 mg / ml to about 60.0 mg / ml tonicity adjusting agent, (f) optionally about 1 mg / ml to about 10 mg / ml pH adjusting agent, and (g) water.

[0203] <Embodiment 24> The injectable composition of any one of the preceding

[0204] Embodiments, having a globule size distribution D90 value of less than 200 nm.

[0205] <Embodiment 25> The injectable composition of any one of the preceding Embodiments, which remains physically and chemically stable for at least 24 months when stored at 2-8 °C, 25 °C, or 30 °C, as measured by retention of aprepitant assay above 90% and total impurities less than 0.5%.

[0206] <Embodiment 26> The injectable composition of any one of the preceding Embodiments, wherein the composition is ready-to-use and does not require reconstitution prior to administration.

[0207] <Embodiment 27> The injectable composition of any one of the preceding Embodiments, wherein the composition does not require in-line filtration prior to intravenous administration.

[0208] <Embodiment 28> The injectable composition of any one of the preceding Embodiments, further characterized by causing less than grade 2 injection site pain or vein irritation when administered as a bolus.

[0209] <Embodiment 29> The injectable composition of any one of the preceding Embodiments, wherein the composition is substantially free of co-surfactants or co-emulsifiers other than lecithin.

[0210] <Embodiment 30> The injectable composition of any one of the preceding Embodiments, wherein the only emulsifier present is lecithin.

[0211] <Embodiment 31> The injectable composition of any one of the preceding Embodiments, wherein the composition does not contain a co-surfactant selected from the group consisting of poloxamers, polysorbates, polyoxyl castor oils, sodium lauryl sulfate, and sorbitan esters.

[0212] <Embodiment 32> The injectable composition of any one of the preceding Embodiments, wherein the composition is free from co-surfactants or co- emulsifiers.

[0213] <Embodiment 33> A method of treating a patient suffering from emesis (vomiting), the method comprising administering by injection the injectable composition of any one of <Embodiment 1> to <Embodiment 31>.

[0214] <Embodiment 34> The method of <Embodiment 33>, wherein the patent is suffering from chemotherapy-induced nausea and vomiting.

[0215] <Embodiment 35> The method of <Embodiment 23>, wherein the subject is immune-compromised, pediatric, or elderly.

[0216] <Embodiment 36> A method of treating chemotherapy-induced nausea and vomiting by co-administering the injectable composition of any one of <Embodiment 1> to <Embodiment 31> with a 5-HT3 antagonist and dexamethasone.

[0217] <Embodiment 37> A process for preparing the injectable composition of any one of <Embodiment 1> to <Embodiment 31>, comprising dispersing aprepitant and lecithin in an oil phase, forming an emulsion with an aqueous phase comprising atonicity adjusting agent and pH adjusting agent, homogenizing at 10,000 to 30,000 psi, and sterile filtering or aseptic processing.

[0218] <Embodiment 38> A kit comprising the injectable composition of any one of <Embodiment 1> to <Embodiment 31>, packaged in a sterile vial, prefilled syringe, or infusion bag.

[0219] <Embodiment 39> Use of an injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water, for the manufacture of a medicament for the prevention or treatment of emesis or chemotherapy-induced nausea and vomiting.

[0220] <Embodiment 40> An injectable composition comprising aprepitant, soybean oil, lecithin, dimethylacetamide, sucrose, sodium oleate, and water, for use in the prevention or treatment of chemotherapy-induced nausea and vomiting.

[0221] <Embodiment 41> An injectable composition as defined in any one the preceding Embodiments, for use in the treatment or prevention of emesis.

[0222] <Embodiment 42> Use of the composition of any preceding Embodiment for the manufacture of a medicament for the treatment of emesis in pediatric, elderly, or immune-compromised subjects.

[0223] <Embodiment 43> Use of an injectable composition consisting essentially of aprepitant, lecithin, soybean oil, sucrose, sodium oleate, water, and optionally solvent, for the manufacture of a medicament for the treatment or prevention of emesis, wherein the composition does not contain a co-surfactant or co-emulsifier.

[0224] Examples

[0225] The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.

[0226] Example 1A

[0227]

[0228] Example IB

[0229] Example 1C

[0230] Example ID

[0231] Example IE

[0232] Manufacturing process:

[0233] 1. Aprepitant, egg lecithin and soybean oil were dispersed in ethanol. The mixture was heated to a temperature range of 55-70°C until a clear, yellow to dark brown solution was obtained.

[0234] 2. In a separate vessel, sucrose and sodium oleate was dissolved in water. The solution was heated to 55-70°C until clear solution was obtained.

[0235] 3. The primary emulsion was then formed by mixing the solution of step (1) with the solution of step (2) using a high shear homogenizer at 55-70°C.

[0236] 4. The primary emulsion of step (3) was passed through a Microfluidizer or high- pressure homogenizer at pressures ranging from 10,000 to 30,000 psi, with repeated passes until the target globule size and distribution were attained.

[0237] 5. The particle size, zeta potential and pH of the liquid were recorded. The shelflife stability of emulsion was checked at various environmental conditions.

[0238] The below table demonstrates the stability data of Example 1AA.

[0239] Example 2

[0240] Manufacturing process:

[0241] 1. Aprepitant, egg lecithin and soybean oil were dispersed in dimethyl acetamide. The mixture was heated to a temperature range of 55-70°C until a clear, yellow to dark brown solution is obtained.

[0242] 2. In a separate vessel, sucrose and sodium oleate was dissolved in water. The solution was heated to 55-70°C until clear solution was obtained.

[0243] 3. The primary emulsion was then formed by mixing the solution of step (1) with the solution of step (2) using a high shear homogenizer at 55-70°C.

[0244] 4. The primary emulsion of step (3) was passed through a Microfluidizer or high- pressure homogenizer at pressures ranging from 10,000 to 30,000 psi, with repeated passes until the target globule size and distribution were attained.

[0245] 5. The particle size, zeta potential and pH of the liquid were recorded. The shelflife stability of emulsion was checked at various environmental conditions.

[0246] The below table demonstrates the stability data of Example 2A.

[0247] Example 3

[0248] Manufacturing process:

[0249] 1. Aprepitant, egg lecithin and soybean oil were dispersed in N-methyl-2- pyrrolidone. The mixture was heated to a temperature range of 55-70°C until a clear, yellow to dark brown solution is obtained.

[0250] 2. In a separate vessel, sucrose and sodium oleate was dissolved in water. The solution was heated to 55-70°C until clear solution was obtained.

[0251] 3. The primary emulsion was then formed by mixing the solution of step (1) with the solution of step (2) using a high shear homogenizer at 55-70°C.

[0252] 4. The primary emulsion of step (3) was passed through a Microfluidizer or high- pressure homogenizer at pressures ranging from 10,000 to 30,000 psi, with repeated passes until the target globule size and distribution were attained.

[0253] 5. The particle size, zeta potential and pH of the liquid were recorded. The shelflife stability of emulsion was checked at various environmental conditions.

[0254] Although the invention herein has been described with reference to embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

Claims

We Claims,1. An injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water.

2. The injectable composition of claim 1, comprising aprepitant, one of a medium chain triglyceride and a long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water.

3. The injectable composition of any one of the preceding claims, wherein the aprepitant is present in about 2 mg / ml to about 10 mg / ml.

4. The injectable composition of any one of the preceding claims, wherein the aprepitant is present in about 2 mg / ml to about 5 mg / ml.

5. The injectable composition of any one of the preceding claims, wherein the aprepitant is present in about 5 mg / ml to about 10 mg / ml.

6. The injectable composition of any one of the preceding claims, wherein the medium chain triglyceride or long chain triglyceride is at least one of coconut oil, sesame oil, castor oil, com oil, cottonseed oil, olive oil, peanut oil, peppermint oil, soybean oil, hydrogenated soybean oil, and hydrogenated vegetable oils.

7. The injectable composition of any one of the preceding claims, wherein the medium chain triglyceride or long chain triglyceride is soybean oil.

8. The injectable composition of any one of the preceding claims, wherein the emulsifier is egg lecithin or soy lecithin.

9. The injectable composition of any one of the preceding claims, wherein the solvent is at least one of ethanol and dimethylacetamide.

10. The injectable composition of any one of the preceding claims, wherein the tonicity adjusting agent is sucrose.

11. The injectable composition of any one of the preceding claims, wherein the pH adjusting agent is sodium oleate.

12. The injectable composition of any one of the preceding claims, wherein the composition comprises about 3.6 mg / ml aprepitant.

13. The injectable composition of any one of the preceding claims, wherein the composition comprises about 7.2 mg / ml aprepitant.

14. The injectable composition according to claim 1, comprising (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 97.5 mg / ml lecithin, (d) about 14.3 mg / ml ethanol, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

15. The injectable composition according to claim 1, comprising (a) about 3.6 mg / ml aprepitant, (b) about 48.2 mg / ml soybean oil, (c) about 72.0 mg / ml lecithin, (d) about 55.5 mg / ml dimethylacetamide, (e) about 27.0 mg / ml sucrose, (f) about 2.4 mg / ml sodium oleate, and (g) water.

16. The injectable composition of any one of the preceding claims, wherein the osmolality of the composition is about 240 mosm / kg to about 360 mosm / kg.

17. The injectable composition of any one of the preceding claims, wherein the viscosity of the composition is about 2 cps to about 3.5 cps.

18. The injectable composition of any one of the preceding claims, wherein the total volume of about 1 ml to about 50 ml.

19. The injectable composition of any one of the preceding claims, wherein the total volume of said composition is about 36 ml.

20. The injectable composition of any one of the preceding claims, wherein the total volume of said composition is about 18 ml.

21. The injectable composition according to claim 1, wherein the said composition comprises (a) about 2.0 mg / ml to about 5.0 mg / ml aprepitant, (b) about 40.0 mg / ml to about 60.0 mg / ml oil, (c) about 15.0 mg / ml to about 105.0 mg / ml emulsifier, (d) about 10.0 mg / ml to about 70.0 mg / ml solvent, (e) about 20.0 mg / ml to about 40.0 mg / ml tonicity adjusting agent, (f) optionally about 2.0 mg / ml to about 4.0 mg / ml pH adjusting agent, and (g) water.

22. The injectable composition according to claim 1, wherein the said composition comprises (a) about 5.0 mg / ml to about 10.0 mg / ml aprepitant, (b) about 50.0 mg / ml to about 150.0 mg / ml oil, (c) about 100.0 mg / ml to about 250.0 mg / ml emulsifier, (d) about 50.0 mg / ml to about 250.0 mg / ml solvent, (e) about 50.0 mg / ml to about 60.0 mg / ml tonicity adjusting agent, (f) optionally about 1 mg / ml to about 10 mg / ml pH adjusting agent, and (g) water.

23. The injectable composition of any one of the preceding claims, having a globule size distribution D90 value of less than 200 nm.

24. The injectable composition of any one of the preceding claims, which remains physically and chemically stable for at least 24 months when stored at 2-8 °C, 25 °C, or 30 °C, as measured by retention of aprepitant assay above 90% and total impurities less than 0.5%.

25. The injectable composition of any one of the preceding claims, wherein the composition is ready-to-use and does not require reconstitution prior to administration.

26. The injectable composition of any one of the preceding claims, wherein the composition does not require in-line filtration prior to intravenous administration.

27. The injectable composition of any one of the preceding claims, further characterized by causing less than grade 2 injection site pain or vein irritation when administered as a bolus.

28. A method of treating a patient suffering from emesis (vomiting), the method comprising administering by injection the injectable composition of any one of claims 1-27.

29. The method of claim 23, wherein the patent is suffering from chemotherapy- induced nausea and vomiting.

30. The method of claim 29, wherein the subject is immune-compromised, pediatric, or elderly.

31. A method of treating chemotherapy-induced nausea and vomiting by coadministering the injectable composition of any one of claims 1-27 with a 5- HT3 antagonist and dexamethasone.

32. A process for preparing the injectable composition of any one of claims 1-27, comprising dispersing aprepitant and lecithin in an oil phase, forming an emulsion with an aqueous phase comprising a tonicity adjusting agent and pH adjusting agent, homogenizing at 10,000 to 30,000 psi, and sterile filtering or aseptic processing.

33. A kit comprising the injectable composition of any one of claims 1-27, packaged in a sterile vial, prefilled syringe, or infusion bag.

34. Use of an injectable composition comprising aprepitant and at least one excipient selected from medium chain triglyceride, long chain triglyceride, emulsifier, solvent, tonicity adjusting agent, optionally a pH adjusting agent, and water, for the manufacture of a medicament for the prevention or treatment of emesis or chemotherapy-induced nausea and vomiting.

35. An injectable composition comprising aprepitant, soybean oil, lecithin, dimethylacetamide, sucrose, sodium oleate, and water, for use in the prevention or treatment of chemotherapy-induced nausea and vomiting.

36. An injectable composition as defined in any one the preceding claims, for use in the treatment or prevention of emesis.

37. Use of the composition of any preceding claim for the manufacture of a medicament for the treatment of emesis in pediatric, elderly, or immune- compromised subjects.

38. Use of an injectable composition consisting essentially of aprepitant, lecithin, soybean oil, sucrose, sodium oleate, water, and optionally solvent, for the manufacture of a medicament for the treatment or prevention of emesis, wherein the composition does not contain a co-surfactant or co-emulsifier.

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