Liposomal formulation of aprepitant and methods of manufacturing thereof

Abstract

The present disclosure relates to an injectable pharmaceutical composition comprising a plurality of liposomes each comprising aprepitant, a phospholipid and a surfactant; a tonicity agent; and water, as well as to a method of manufacturing said injectable pharmaceutical composition, and a container comprising said pharmaceutical composition.

Description

[0001] LIPOSOMAL FORMULATION OF APREPITANT AND METHODS OF MANUFACTURING THEREOF

[0002] Field of the invention

[0003] The present invention relates to an injectable pharmaceutical composition comprising a plurality of liposomes each comprising aprepitant, a phospholipid and a surfactant; a tonicity agent; and water, as well as to a method of manufacturing said injectable pharmaceutical composition, and a container comprising said pharmaceutical composition.

[0004] Background

[0005] Aprepitant is a medication used to prevent and treat nausea and vomiting, such as chemotherapy-induced or postoperative nausea and vomiting.

[0006] Aprepitant selectively binds to neurokinin-1 receptors which are present in both the central and peripheral nervous systems. Their primary ligand is substance P, a nociceptive neurotransmitter. Centrally, neurokinin- 1 receptors are found throughout regions of the brainstem that are thought to play a critical role in the vomiting reflex, i.e. the central pattern generator, the nucleus tractus solitarius, and area postrema. By acting as a competitive antagonist in these regions, aprepitant is thought to attenuate the likelihood of the complex vomiting reflex initiation significantly. Peripherally, neurokinin-1 receptors exist throughout the gastrointestinal tract. The binding of aprepitant to said receptors may attenuate vagal afferent signals and contribute to the antiemetic effect.

[0007] Aprepitant is currently available in a capsule formulation for oral administration (EMEND®; Merck Sharp & Dohme). However, oral formulations are not desirable due to the nausea and vomiting experienced by patients. Furthermore, the onset of the therapeutic effect is delayed due to the slow drug absorption after oral administration.

[0008] On the other hand, aprepitant is practically insoluble in water. Therefore, solubilizing aprepitant and preparing injectable formulations of aprepitant is challenging if not impossible when only pharmaceutically and parentally acceptable excipients can be used.

[0009] Presently, aprepitant is available as an opaque and off-white to amber emulsion containing an oil for intravenous injection (APONVIE™ or CINVANTI™, Heron Therapeutics) in the US. However, the opaque appearance makes it difficult to inspect such formulations and to observe the formation of particulate matter in the emulsion. This frequently increases the preparation time of the injections which further delays an effective treatment of a patient suffering from nausea and / or vomiting. Furthermore, opaque emulsions are not desirable from a perspective of patient compliance. Even more strikingly, formulations containing an oil and / or an organic solvent frequently cause side effects at the infusion site, such as pain, hardening, redness and / or itching at the site of infusion. It is understood that commercially available formulations of aprepitant contain large amounts of excipients, such as soy bean oil, that by far exceeds the amount of aprepitant in said formulations. Upon administration, such as intravenous injection, this frequently causes hypersensitivity reactions which are not only unpleasant but may cause serious harm to the patient.

[0010] Therefore, there is still need for injectable pharmaceutical formulations comprising aprepitant which are visually clear and at the same time only contain pharmaceutically acceptable excipients. Furthermore, it is still necessary to develop an injectable formulation of aprepitant that has an improved safety profile, in that the potential for irritations at the injection site and the risk for hypersensitivity are reduced.

[0011] The inventors of the present disclosure have surprisingly found that injectable pharmaceutical compositions can be prepared by using liposomes comprising a phospholipid and a surfactant. Said injectable pharmaceutical compositions are not only visually clear but also show excellent storage stability. Furthermore, said injectable pharmaceutical compositions can be prepared without the use of organic solvents and oils, but with standard procedures and excipients. The resulting highly concentrated aprepitant aqueous formulation allow for smaller volume to be injected and, therefore, have reduced preparation and administration time. Based on the small volume of injection and the clear formulation, the patient compliance is increased. Also, since organic solvents and oils are avoided in the formulation of the present disclosure, side effects at the site of injection are reduced or avoided at all.

[0012] According to a first aspect, the present disclosure relates to an injectable pharmaceutical composition comprising a plurality of liposomes each comprising aprepitant, a phospholipid and a surfactant; a tonicity agent; and water, wherein the liposomes have a mean particle size D50 of less than 100 nm.

[0013] According to a second aspect, the present disclosure relates to a method for manufacturing the injectable pharmaceutical composition according to the first aspect of the present disclosure comprising the steps of mixing a phospholipid, a surfactant, a tonicity agent, and water to yield a first mixture; subjecting said first mixture to a high pressure homogenization to yield a liposome dispersion; mixing said liposome dispersion with a dispersion of aprepitant in water to provide a second mixture; heating said second mixture to yield a liposome composition; and sterilizing the liposome composition to yield the injectable pharmaceutical composition.

[0014] According to a third aspect, the present disclosure relates to an injectable pharmaceutical composition according to the first aspect of the present disclosure prepared by the method according to the second aspect of the present disclosure.

[0015] According to a fourth aspect, the present disclosure relates to a sealed container comprising the injectable pharmaceutical composition according to the first aspect of the present disclosure or the injectable pharmaceutical composition according to the third aspect of the present disclosure.

[0016] According to a fifth aspect, the present disclosure relates to an injectable pharmaceutical composition according to the first aspect of the present disclosure or the third aspect of the present disclosure for use in the treatment or prevention of nausea and / or vomiting.

[0017] Detailed

[0018] The invention of the present disclosure is described in the following in more detail, exemplified by preferred embodiments and embodiment examples. However, it is understood that the scope of the present disclosure is not limited thereto, but only by the appendant claims.

[0019] The present disclosure, in very general terms, relates to five aspects, namely a first aspect being directed to an injectable pharmaceutical composition, a second aspect being directed to a method for manufacturing said injectable pharmaceutical composition, a third aspect being directed to an injectable pharmaceutical composition that is prepared by the method of the second aspect, a fourth aspect being directed to a container comprising said injectable pharmaceutical composition, and a fifth aspect being directed to said injectable pharmaceutical composition for use in the treatment or prevention of nausea and / or vomiting.

[0020] The ini

[0021] According to a first aspect, the present disclosure relates to an injectable pharmaceutical composition comprising: a) a plurality of liposomes each comprising aprepitant, a phospholipid and a surfactant; b) a tonicity agent; and c) water, wherein the liposomes a mean particle size D50 of less than 100 nm.

[0022] The injectable pharmaceutical composition can thus conceptually be divided into a liposome fraction and an aqueous fraction. The liposome fraction consists of the plurality of liposomes. The aqueous fraction consists of water and all components that are dissolved therein, including at least a tonicity agent.

[0023] Practically, a separation of the liposome fraction and the aqueous fraction of the injectable pharmaceutical composition can be achieved by known techniques, such as ultracentrifugation or nanofiltration.

[0024] Ultracentrifugation is a powerful technique that can separate liposomes from the aqueous fraction based on their density. By subjecting the injectable pharmaceutical composition according to the present disclosure to high-speed centrifugation, the liposomes can be pelleted at the bottom of a centrifuge tube, and the aqueous fraction can be decanted.

[0025] Also, filtration through membranes with specific pore sizes can be used to separate liposomes from the aqueous fraction. The size of the filter pores is chosen to retain the liposomes while allowing the aqueous fraction to pass through.

[0026] The plurality of liposomes

[0027] A core element of the injectable pharmaceutical composition according to the present disclosure is the use of a plurality of specific liposomes to stabilize aprepitant in the composition.

[0028] A liposome is an artificial vesicle having one or more phospholipid bilayers. Phospholipids have a hydrophilic head and two hydrophobic tails that are derived from fatty acids which makes them suitable for forming lipid bilayers. When phospholipids are dispersed in an aqueous solution, they spontaneously arrange themselves into bilayers with the hydrophilic heads oriented towards the water and the hydrophobic tails oriented away from the water and towards each other.

[0029] Thus, liposomes have a hydrophilic outer layer and a hydrophobic inner layer in which aprepitant can be stored. Therefore, the plurality of liposomes is an essential component of the injectable pharmaceutical composition according to the first aspect of the present disclosure. Aprepitant is stored in the lipid bilayer.

[0030] It is understood that the phospholipid and the surfactant form liposomes. Therefore, the injectable pharmaceutical composition according to the present disclosure is substantially free of phospholipid not bound in liposomes and substantially free of surfactant not bound in liposomes. In other words, neither the phospholipid nor the surfactant is present in dissolved or “free” form but only in the liposomes.

[0031] In other words, the aqueous fraction is substantially free of phospholipid and surfactant, other than in liposomal form.

[0032] It is understood that the mean particle size D50 of the particles comprised in the injectable pharmaceutical composition is the mean particle size D50 of the plurality of liposomes. In other words, the injectable pharmaceutical composition according to the present disclosure does not contain particles or particulate matter except for liposomes.

[0033] According to the first aspect of the present disclosure, the liposomes have a mean particle size D50 of less than 100 nm. According to a preferred embodiment of the present disclosure, the liposomes have a mean particle size D50 of 80 nm or less. According to another preferred embodiment of the present disclosure, the liposomes have a mean particle size D50 of 60 nm or less. According to a further preferred embodiment of the present disclosure, the liposomes have a mean particle size D50 of 50 nm or less. According to a yet further preferred embodiment of the present disclosure, the liposomes have a mean particle size D50 of 40 nm or less.

[0034] It is understood that liposomes that have a mean particle size D50 of 100 nm or more exhibit turbidity in water. In other words, if the mean particle size D50 of the liposomes is 100 nm or more, the injectable pharmaceutical composition is not visually clear.

[0035] Furthermore, it is understood that the surface of the liposomes and the particle size of the liposomes is inversely proportional. In other words, if the particle size of the liposomes decreases, the surface are increases. It is understood that a large surface area of the liposomes results in a fast release of aprepitant after administration to a patient. Therefore, the onset of a therapeutic effect is faster when the particle size of the liposomes is less than 100 nm. On the other hand, the same phenomenon may also result in an increased precipitation of aprepitant from the liposomes during storage. However, the inventors of the present disclosure have surprisingly found that the injectable pharmaceutical compositions according to the present disclosure are highly stable, even under stress conditions, and no precipitation of aprepitant is observed as shown in example 2 of the present disclosure. Even after storing the injectable pharmaceutical composition at 40 °C for six months, no precipitates can be observed.

[0036] The excellent storage stability is further evident when comparing the mean particle size D50 directly after preparation of the injectable pharmaceutical composition and the mean particle size D50 after storing said composition for six months at a certain temperature:

[0037] It is particularly interesting to compare the mean particle size of the liposomes D°o, that is the mean particle size D50 of the liposomes directly after the preparation of the injectable pharmaceutical composition with the mean particle size of the liposomes Df“-40and / or Df“_RT, that is the mean particle size D50 of the liposomes after storing the injectable pharmaceutical composition for six months at 40 °C or at room temperature, respectively.

[0038] By calculating the ratios n6M- 40n6M-RT and / or

[0039] D50 D50 the stability of the injectable pharmaceutical composition according to the present disclosure can be quantified. A value close to 1 indicates that the mean particle size D50 of the liposomes does not change upon storage. A value of more than 1 indicates that the liposomes aggregate upon storage.

[0040] According to a preferred embodiment of the present disclosure, the ratio D° — is in D5O the range of from 0.98 to 1.10. According to another preferred embodiment of the present disclosure, the ratio D — is in the range of from 0.98 to 1 .05. According to another

[0041] D°5O preferred embodiment of the present disclosure, the ratio D — is in the range of from 0.99

[0042] D°5O to 1.03. According to a further preferred embodiment of the present disclosure, the ration6M-RTu50

[0043] D° is in the range of from 1 .00 to 1 .02. u50 p6M- 40 According to a preferred embodiment of the present disclosure, the ratio D° — is in

[0044] D5O the range of from 0.98 to 1.20. According to another preferred embodiment of the present p6M- 40 disclosure, the ratio — is in the range of from 0.98 to 1 .15. According to a preferred embodiment of the present disclosure, the ratio — is in the range of from 0.99 to 1.12.

[0045] D5O p6M- 40 According to a further preferred embodiment of the present disclosure, the ratio — is in D5O the range of from 1.00 to 1.10.

[0046] If any one of the above ratio is higher than 1.20, the injectable pharmaceutical composition is no longer visually clear after storage for 6 months. However, the inventors found that the liposomes comprised in the injectable pharmaceutical composition according to the present disclosure do not change their size as is evident from example 2. This means that there is no or very little aggregation of liposomes. Furthermore, the injectable pharmaceutical compositions according to the present disclosure do not develop a turbidity during storage but remain visually clear.

[0047] Another parameter that is representative of the clearness and low / no turbidity of the injectable pharmaceutical compositions according to the present disclosure is the transmission of light, e.g., having a wavelength of 660 nm.

[0048] It is understood that the presence of liposomes in a sample can affect the transmission of light through said sample: When light hits liposomes in a sample, it is scattered in various directions, reducing the transmission of light through the sample. The degree of scattering depends on the size of the liposomes, with larger liposomes causing more pronounced scattering.

[0049] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a transmission T of at least 65 %. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a transmission T of at least 70 %. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a transmission T of at least 75 %. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a transmission T of at least 80 %.

[0050] The phospholipid

[0051] One essential component of the liposomes according to the present disclosure is a phospholipid.

[0052] According to a preferred embodiment of the present disclosure, the phospholipid is a soy phospholipid, or an egg phospholipid, or a mixture thereof. According to a further preferred embodiment of the present disclosure, the phospholipid is an egg phospholipid. According to another preferred embodiment of the present disclosure, the phospholipid has a content of phosphatidylcholine of at least 90 wt.-% based on the total weight of the phospholipid. According to another preferred embodiment of the present disclosure, the phospholipid has a content of phosphatidylcholine of at least 92 wt.-% based on the total weight of the phospholipid. According to a further preferred embodiment of the present disclosure, the phospholipid has a content of phosphatidylcholine of at least 94 wt.-% based on the total weight of the phospholipid.

[0053] The content of phosphatidylcholine is important in liposome formation and drug delivery for several reasons:

[0054] Firstly, phosphatidylcholine is a major component of natural cell membranes. Therefore, liposomes that contain a high proportion of phosphatidylcholine are more biocompatible and less likely to cause adverse reactions when introduced into the body, e.g. by intravenous injection. In other words, phospholipids containing a high amount of phosphatidylcholine have minimal toxicity and immunogenicity.

[0055] Furthermore, phosphatidylcholine contributes to the structural stability of liposomes and the permeability of the liposome membrane. In other words, the content of phosphatidylcholine is important for the uptake and release of aprepitant from the lipid bilayer. Thus, a content of phosphatidylcholine in the phospholipid of at least 90 wt.-% based on the total weight of the phospholipid is essential for storing aprepitant in high amounts.

[0056] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 10 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 15 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 20 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 30 mg / mL or more. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 40 mg / mL or more. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 50 mg / mL or more. If the concentration of the phospholipid is too low, the number of liposomes that can be formed is low as well. This means that only a low amount of aprepitant can be stored in the liposomes, which in turn means that the volume of an injectable pharmaceutical composition, that needs to be administered to a patient to reach a therapeutic level, is increased.

[0057] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 400 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 350 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 300 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 250 mg / mL or less. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of 200 mg / mL or less.

[0058] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 10 mg / mL to 400 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 15 mg / mL to 350 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 20 mg / mL to 350 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 30 mg / mL to 300 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 40 mg / mL to 300 mg / mL. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 40 mg / mL to 250 mg / mL. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the phospholipid in a concentration of from 50 mg / mL to 200 mg / mL.

[0059] As is evident from the examples, injectable pharmaceutical composition comprising the amounts of phospholipid as defined above cannot only be manufactured in a convenient manner without the use of organic solvents and / or oils, but also efficiently store a high amount of aprepitant for a long time, even under stress conditions.

[0060] The surfactant

[0061] Another essential component of the liposomes is a surfactant. It is understood that the surfactant is comprised in the liposome. In other words, the lipophilic part of the surfactant is contained in the bilayer of the liposome, while the negatively charged group is presented on the surface of the liposome. Therefore, the surface of the liposome is charged. The charge on the surface of the liposomes induced by the surfactant positively affects the solubility of the liposomes in the water.

[0062] According to a preferred embodiment of the present disclosure, the surfactant is a phosphatidylglycerol derivative, a fatty acid, or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, a-linoleic acid, arachidonic acid, eicosapentanoic acid, erucic acid, docosaxexaenoic acid, dioleoyl phosphatidylglycerol (DOPG), dilauroyl phosphatidylglycerol (DLPG), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG), 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), dimyristoyl phosphatidylglycerol (DMPG), and pharmaceutically acceptable salts thereof.

[0063] According to a preferred embodiment of the present disclosure, the surfactant is selected from the group consisting of oleic acid, dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidylglycerol (DMPG), dilauroyl phosphatidylglycerol (DLPG), and a pharmaceutically acceptable salt thereof. According to a further preferred embodiment of the present disclosure, the surfactant is oleic acid, dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidylglycerol (DMPG), or a pharmaceutically acceptable salt thereof. According to a yet further preferred embodiment of the present disclosure, the surfactant is sodium oleate or dimyristoyl phosphatidylglycerol (DMPG).

[0064] According to a preferred embodiment of the present disclosure, the surfactant is a phosphatidylglycerol derivative or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is selected from the group consisting of dioleoyl phosphatidylglycerol (DOPG), dilauroyl phosphatidylglycerol (DLPG), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG), 1 -palmitoyl-2-oleoyl phosphatidylglycerol (POPG), dimyristoyl phosphatidylglycerol (DMPG), and pharmaceutically acceptable salts thereof.

[0065] According to another preferred embodiment of the present disclosure, the surfactant is dioleoyl phosphatidylglycerol (DOPG) or a pharmaceutically acceptable salt thereof, preferably sodium DOPG (DOPG-Na). According to another preferred embodiment of the present disclosure, the surfactant is dilauroyl phosphatidylglycerol (DLPG) or a pharmaceutically acceptable salt thereof, preferably sodium DLPG (DLPG-Na). According to another preferred embodiment of the present disclosure, the surfactant is dipalmitoyl phosphatidylglycerol (DPPG) or a pharmaceutically acceptable salt thereof, preferably sodium DPPG (DPPG-Na). According to another preferred embodiment of the present disclosure, the surfactant is distearoyl phosphatidylglycerol (DSPG) or a pharmaceutically acceptable salt thereof, preferably sodium DSPG (DSPG-Na). According to another preferred embodiment of the present disclosure, the surfactant is 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG) or a pharmaceutically acceptable salt thereof, preferably sodium POPG (POPG-Na). According to a further preferred embodiment of the present disclosure, the surfactant is dimyristoyl phosphatidylglycerol (DMPG) or a pharmaceutically acceptable salt thereof, preferably sodium DMPG (PMPG-Na).

[0066] According to another preferred embodiment of the present disclosure, the surfactant is a fatty acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, a-linoleic acid, arachidonic acid, eicosapentanoic acid, erucic acid, docosaxexaenoic acid, and a pharmaceutically acceptable salt thereof.

[0067] According to another preferred embodiment of the present disclosure, the surfactant is caprylic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is capric acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is lauric acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is myristic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is palmitic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is stearic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is arachidic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is behenic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is lignoceric acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is cerotic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is myristoleic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is palmitoleic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is sapienic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is elaidic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is vaccenic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is linoleic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is linoelaidic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is a-linolenic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is arachidonic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is eicosapentaenoic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is erucic acid or a pharmaceutically acceptable salt thereof. According to another preferred embodiment of the present disclosure, the surfactant is docosahexaenoic acid or a pharmaceutically acceptable salt thereof.

[0068] The inventors of the present disclosure have surprisingly found that liposomes comprising a surfactant as disclosed hereinabove can be prepared by standard method and can be loaded with a high amount of aprepitant (see example 1). Even more, the liposomes comprising a surfactant as disclosed hereinabove are stable upon storage as is evident from example 2. In other words, the liposomes do not aggregate or separate, but the integrity and structure of the liposomes are maintained even after long time storage. According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.1 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.3 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.5 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.7 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.9 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 1.0 mg / mL or more.

[0069] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 5.0 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 4.0 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 3.5 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 3.0 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration of 2.8 mg / mL or less.

[0070] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 0.1 mg / mL to 5.0 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 0.3 mg / mL to 4.0 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 0.5 mg / mL to 3.5 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 0.7 mg / mL to 3.0 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 0.9 mg / mL to 3.0 mg / mL. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 1.0 mg / mL to 3.0 mg / mL. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises the surfactant in a concentration in the range of from 1.0 mg / mL to 2.8 mg / mL.

[0071] The inventors of the present invention have found that if the amount of surfactant in the liposomes is too low, the liposomes cannot be effectively stabilized, but tend to aggregate.

[0072] On the other hand, if the amount of surfactant exceeds 5.0 mg / mL, the liposomes are destabilized. Without wishing to be bound by theory, it may be assumed that the surfactant insert itself into the lipid bilayers to such extend that causes structural instability and release of aprepitant from the bilayer.

[0073] A crepitant

[0074] It is understood that the aprepitant is incorporated into the lipid bilayer of the plurality of liposomes. After administration of the injectable pharmaceutical composition of the present disclosure, aprepitant is released from the liposomes and binds to the neurokin- 1 receptor in a patient.

[0075] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 0.5 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 1 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 2 mg / mL or more. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 3 mg / mL or more. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 4 mg / mL or more. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 5 mg / mL or more.

[0076] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 15 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 12 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 10 mg / mL or less. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration of 8 mg / mL or less.

[0077] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 0.5 mg / mL to 15 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 1 mg / mL to 12 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 1 mg / mL to 10 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 2 mg / mL to 8 mg / mL. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 3 mg / mL to 8 mg / mL. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 4 mg / mL to 8 mg / mL. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises aprepitant in a concentration in the range of from 5 mg / mL to 8 mg / mL.

[0078] The inventors of the present disclosure have surprisingly found that a high concentration of aprepitant can be stored in the liposomes (see example 1). Even after long term storage, no precipitation of aprepitant is observed (see example 2).

[0079] If the concentration of aprepitant in the injectable pharmaceutical composition is below 0.5 mg / mL, the volume of composition that needs to be administered into a patient to achieve the desired therapeutic effect is too high. Therefore, therapeutic effectivity is reduced. If the concentration of aprepitant in the injectable pharmaceutical composition is higher than 15 mg / mL, the aprepitant cannot be sufficiently stabilized and precipitation occurs.

[0080] As is evident from example 3 of the present disclosure, also the amount of aprepitant in the injectable pharmaceutical compositions according to the first aspect of the present disclosure is also chemically stable. In other words, aprepitant is not susceptible to degradation.

[0081] The inventors of the present application have surprisingly found that an injectable pharmaceutical composition is particularly stable if the ratio between the concentration of the phospholipid and the concentration of aprepitant is controlled.

[0082] It is understood that calculating the ratio between the concentration of the phospholipid and the concentration of aprepitant requires that both concentrations have the same unit: Therefore, it might be necessary to transform the unit of one concentration into the unit of the other concentration. For example, calculating the ratio between the concentration of the phospholipid and the concentration of aprepitant requires transforming both concentrations to the unit of mg / mL.

[0083] According to a preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 10. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 12. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 15. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 17. According to a further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 19. According to a yet further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 20.

[0084] According to a preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 50 or less. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 45 or less. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 40 or less. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 35 or less. According to a further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 32 or less. According to a yet further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is 30 or less.

[0085] According to a preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 10 to 50. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 12 to 45. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 15 to 35. According to another preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 17 to 32. According to a further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 19 to 32. According to a yet further preferred embodiment of the present disclosure, the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 20 to 30.

[0086] The inventors of the present disclosure have found that if the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 10, aprepitant can be efficiently stored in the liposomes (see examples 1 and 2). If on the other hand, the ratio between the concentration of phospholipid and the concentration of aprepitant is 50 or more, the volume that needs to be injected into a patient for delivering a therapeutically effective amount of aprepitant is considerably increased.

[0087] It might be possible that during the preparation of the liposomes, not all of the liposomes are actually loaded with aprepitant and / or incorporate the surfactant into the lipid bilayer. Therefore, the injectable pharmaceutical composition according to the first aspect of the present disclosure might comprise liposomes comprising phospholipid, or liposomes comprising phospholipid and surfactant, or liposomes comprising phospholipid and aprepitant.

[0088] The aqueous fraction

[0089] It is understood that the phospholipid and the surfactant form liposomes, in which the aprepitant is stored. Therefore, the injectable pharmaceutical composition according to the present disclosure is substantially free of dissolved phospholipid and substantially free of dissolved surfactant. In other words, neither the phospholipid nor the surfactant is present in dissolved form but only in the liposomes.

[0090] In other words, the aqueous fraction is substantially free of phospholipid and surfactant, except for in the liposomes.

[0091] The aqueous fraction of the injectable pharmaceutical composition comprises water and a tonicity agent.

[0092] According to a preferred embodiment, the water is water for injection.

[0093] According to the first aspect of the present disclosure, the injectable pharmaceutical composition comprises a tonicity agent. It is understood that the tonicity agent is dissolved in the aqueous fraction of the injectable pharmaceutical composition to adjust the tonicity of the solution. According to a preferred embodiment of the present disclosure, the tonicity agent is a sugar alcohol or a sugar.

[0094] According to another preferred embodiment of the present disclosure, the tonicity agent is selected from the group consisting of glycerol, sucrose, glucose, trehalose, lactose, mannitol, and mixtures thereof.

[0095] According to another preferred embodiment of the present disclosure, the tonicity agent is a sugar alcohol. According to another preferred embodiment of the present disclosure, the tonicity agent is ethylene glycol. According to another preferred embodiment of the present disclosure, the tonicity agent is erythritol. According to another preferred embodiment of the present disclosure, the tonicity agent is threitol. According to another preferred embodiment of the present disclosure, the tonicity agent is arabitol. According to another preferred embodiment of the present disclosure, the tonicity agent is xylitol. According to another preferred embodiment of the present disclosure, the tonicity agent is ribitol. According to another preferred embodiment of the present disclosure, the tonicity agent is mannitol. According to another preferred embodiment of the present disclosure, the tonicity agent is sorbitol. According to a further preferred embodiment of the present disclosure, the tonicity agent is glycerol.

[0096] According to another preferred embodiment of the present disclosure, the tonicity agent is a sugar. According to another preferred embodiment of the present disclosure, the tonicity agent is glucose. According to another preferred embodiment of the present disclosure, the tonicity agent is trehalose. According to another preferred embodiment of the present disclosure, the tonicity agent is sucrose. According to another preferred embodiment of the present disclosure, the tonicity agent is lactose. According to another preferred embodiment of the present disclosure, the tonicity agent is fructose. According to another preferred embodiment of the present disclosure, the tonicity agent is galactose. According to another preferred embodiment of the present disclosure, the tonicity agent is maltose.

[0097] It is preferable to use a non-ionic tonicity agent. Usually, ions destabilize liposomes which results in accelerated decomposition of an injectable pharmaceutical composition and precipitation of aprepitant.

[0098] According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a pH in the range of from 6.0 to 9.0. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a pH in the range of from 6.2 to 8.5. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition has a pH in the range of from 6.5 to 8.5.

[0099] It is understood that the pH may result from the method of manufacturing and it is not necessary to adjust the pH. For the case that pH adjustment is required or needed, the pH can be adjusted using HCI or NaOH as needed. In other words, the pH of the injectable pharmaceutical composition is adjusted with HCI and / or NaOH.

[0100] Excluded components

[0101] It is understood that the aprepitant can be stored in the liposomes of the injectable pharmaceutical compositions according to the first aspect of the present disclosure for a long time without any precipitation of aprepitant.

[0102] Furthermore, the injectable pharmaceutical composition according to the first aspect of the present disclosure can be prepared without the use of an organic solvent and / or an oil as shown in example 1 of the present disclosure.

[0103] Therefore, the injectable pharmaceutical compositions according to the first aspect of the present disclosure are substantially free or free of organic solvents and oils.

[0104] It is understood that the presence of an oil and / or an organic in an injectable pharmaceutical composition is associated with countless disadvantages:

[0105] Oil- or solvent-containing injections can cause pain, discomfort, and irritation at the injection site including hardening, redness and / or itching at the site of infusion. This can be particularly problematic for patients who require frequent injections or have a low tolerance for pain. Specifically, injections containing an oil can lead to injection site reactions, such as granulomas or abscesses, where the body's immune response creates localized lumps or inflammation. Furthermore, some patients may be allergic to specific oils or solvents used in the formulation, leading to allergic reactions or hypersensitivity.

[0106] Also, oil- or solvent-containing formulations are frequently incompatible with other injectable drug formulations. This is particularly relevant for patients who receive chemotherapy which is often associated with the administration of multiple drugs.

[0107] Furthermore, the presence of an oil and / or organic solvents in a formulation poses higher requirements to the production, e.g. as regards safety. Additionally, sterilizing oil- or solvent-containing formulations can be more challenging than sterilizing aqueous solutions, as some methods of sterilization may not be suitable for these types of formulations.

[0108] Therefore, one advantage of the injectable pharmaceutical composition according to the first aspect of the present disclosure is the absence of organic solvents and oils.

[0109] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an organic solvent in a concentration of 0.1 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an organic solvent in a concentration of 0.05 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an organic solvent in a concentration 0.02 mg / mL or less. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition does not comprise an organic solvent.

[0110] Organic solvents are methanol, ethanol, i-propanol, t-butanol, dichloromethane, chloroform, THF, and the like.

[0111] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an oil in a concentration of 0.1 mg / mL or less. According to another preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an oil in a concentration of 0.05 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises an oil in a concentration 0.02 mg / mL or less. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition does not comprise an oil. Oils are soybean oil, coconut oil, olive oil, safflower oil, sunflower oil, fish oil, algae oil, and the like.

[0112] According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises tocopherol in a concentration of 1.5 mg / mL or less. According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises tocopherol in a concentration of 1 mg / mL or less. According to a preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises tocopherol in a concentration of 0.75 mg / mL or less. According to a further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises tocopherol in a concentration 0.50 mg / mL or less. According to a yet further preferred embodiment of the present disclosure, the injectable pharmaceutical composition comprises tocopherol in a concentration 0.25 mg / mL or less.

[0113] The inventors of the present application have surprisingly found that the injectable pharmaceutical compositions according to the first aspect of the present disclosure can be prepared without the use of oils, organic solvents or other bilayer stabilizers as is evident from example 1 of the present disclosure. Furthermore, the injectable pharmaceutical compositions according to the first aspect of the present disclosure are highly stable as is evident from example 2 of the present disclosure. No precipitation of aprepitant or aggregation of liposomes was observed.

[0114] The method of manufacturing

[0115] According to a second aspect, the present disclosure relates to a method for manufacturing the injectable pharmaceutical composition according to the first aspect of the present disclosure comprising the steps of mixing a phospholipid, a surfactant, a tonicity agent, and water to yield a first mixture; subjecting said first mixture to a high pressure homogenization to yield a liposome dispersion; mixing said liposome dispersion with a dispersion of aprepitant in water to provide a second mixture; heating said second mixture to yield a liposome composition; and sterilizing the liposome composition to yield the injectable pharmaceutical composition.

[0116] Preparation of a liposome dispersion

[0117] In a first step of the method according to the second aspect of the present disclosure, a liposome dispersion is prepared. For that, a phospholipid, a surfactant, a tonicity agent, and water are mixed to provide a first mixture (For example by applying a high shear mixing process at ambient temperature).

[0118] In a second step, said first mixture is subjected to a homogenization, preferably high- pressure homogenization, to yield a liposome dispersion. According to a preferred embodiment of the present disclosure, high-pressure homogenization is performed at a pressure in the range of from about 1100 bar to about 1300 bar. According to another preferred embodiment of the present disclosure, high-pressure homogenization is performed at a temperature in the range of from about 50 °C to about 60 °C. According to a further preferred embodiment of the present disclosure, high-pressure homogenization is performed until the liposomal dispersion has a transmittance at 660 nm of at least 90 %. In other words, a homogenization treatment is carried out until the transmittance of the mixture is at least 90 % at 660 nm. Suitable high pressure homogenizers are known in the art. For example, the Avestin Emulsiflex-C5 (Avestin, Canada) can be used.

[0119] According to a preferred embodiment of the present disclosure, the first mixture is subjected to a high pressure homogenization at a pressure in the range of from about 1100 bar to about 1300 bar. According to a preferred embodiment of the present disclosure, the first mixture is subjected to a high pressure homogenization at a temperature in the range of from about 50 °C to about 65 °C. It is understood that such conditions are advantageous for achieving a liposome dispersion quickly.

[0120] It is understood that it is essential to add the surfactant before the high pressure homogenization step to ensure that the surfactant is incorporated into the lipid bilayer of the liposomes. Only then, the storage stability of the liposomes is achieved.

[0121] The conditions of high pressure homogenization are chosen to yield liposomes of the desired size.

[0122] After homogenization, preferably high pressure homogenization, a liposome dispersion is obtained.

[0123] Loading the liposomes with aprepitant

[0124] In a third step of the method according to the second aspect of the present disclosure, the liposomes are loaded with aprepitant. For that, aprepitant is mixed with the liposome dispersion obtained from the homogenization or high-pressure homogenization step to provide a second third mixture. According to a preferred embodiment of the present disclosure, micronized aprepitant is mixed with the liposome dispersion. According to a further preferred embodiment of the present disclosure, the micronized aprepitant has a Dgo particle size of 10 pm or less. According to a further preferred embodiment of the present disclosure, the micronized aprepitant has a Dgo particle size of less than 10 pm.

[0125] It is understood that a small particle size of aprepitant is advantageous for incorporating the aprepitant into the liposomes. A high shear mixing process is applied for several minutes in order to break aprepitant agglomerates (if any) and improve the wettability of the solid surface.

[0126] The second mixture is then heated to yield a liposome composition (step d)). This step is also referred to as heat solubilization.

[0127] According to a preferred embodiment of the present disclosure, the second mixture is heated to a temperature of at least 50 °C. According to another preferred embodiment of the present disclosure, the second mixture is heated to a temperature of at least 60 °C. According to a further preferred embodiment of the present disclosure, the second mixture is heated to a temperature of at least 70 °C. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated to a temperature of at least 75 °C.

[0128] According to a preferred embodiment of the present disclosure, the second mixture is heated to a temperature of 100 °C or less. According to a further preferred embodiment of the present disclosure, the second mixture is heated to a temperature of 90 °C or less. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated to a temperature of 85 °C or less.

[0129] According to a preferred embodiment of the present disclosure, the second mixture is heated to a temperature in the range of from 50 °C to 100 °C. According to another preferred embodiment of the present disclosure, the second mixture is heated to a temperature in the range of from 60 °C to 90 °C. According to a further preferred embodiment of the present disclosure, the second mixture is heated to a temperature in the range of from 70 °C to 90 °C. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated to a temperature in the range of from 75 °C to 85 °C. According to a preferred embodiment of the present disclosure, the second mixture is heated for at least 1 min. According to a preferred embodiment of the present disclosure, the second mixture is heated for at least 3 min. According to a further preferred embodiment of the present disclosure, the second mixture is heated for at least 5 min. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated for at least 7 min.

[0130] According to a preferred embodiment of the present disclosure, the second mixture is heated for up to 30 min. According to a preferred embodiment of the present disclosure, the second mixture is heated for up to 20 min. According to a further preferred embodiment of the present disclosure, the second mixture is heated for up to 15 min. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated for up to 10 min.

[0131] According to a preferred embodiment of the present disclosure, the second mixture is heated for a period in the range of from 1 min to 30 min. According to a preferred embodiment of the present disclosure, the second mixture is heated for a period in the range of from 3 min to 20 min. According to a further preferred embodiment of the present disclosure, the second mixture is heated for a period in the range of from 5 min to 15 min. According to a yet further preferred embodiment of the present disclosure, the second mixture is heated for a period in the range of from 7 min up to 10 min.

[0132] The inventors of the present application have surprisingly found that a heat solubilization under relatively mild conditions in terms of temperature and time is sufficient to load the liposomes with a high amount of aprepitant as is evident from example 1.

[0133] Sterilizing and packing

[0134] After the heat solubilization the resulting liposome composition is sterilized to yield the injectable pharmaceutical composition.

[0135] According to a preferred embodiment of the present disclosure, sterilizing comprises filtering the liposome composition through a filter having a pore size of 0.2 pm.

[0136] Suitable filters for sterile filtration having a pore size of 0.2 pm are available from commercial suppliers.

[0137] The resulting injectable pharmaceutical composition can then be packed into a sterile container. Preferably, packing is carried out under sterile conditions. According to another preferred embodiment of the present disclosure, sterilizing comprises filtering the liposome composition through a filter having a pore size of 0.2 pm, whereas the filtrate is collected in a sterile container.

[0138] The injectable pharmaceutical composition prepared by a method of the present disclosure

[0139] According to a third aspect, the present disclosure relates to an injectable pharmaceutical composition according to the first aspect of the present disclosure prepared by the method according to the second aspect of the present disclosure.

[0140] The sealed container

[0141] According to a fourth aspect, the present disclosure relates to a sealed container comprising the injectable pharmaceutical composition according to the first aspect of the present disclosure or the injectable pharmaceutical composition according to the third aspect of the present disclosure.

[0142] According to a preferred embodiment of the present disclosure, the sealed container is a glass vial.

[0143] According to another preferred embodiment of the present disclosure, the sealed container is a plastic vial. According to another preferred embodiment of the present disclosure, the sealed container is a plastic vial comprises cyclo-olefin polymers (COP). According to another preferred embodiment of the present disclosure, the sealed container is a plastic vial comprises cyclo-olefin copolymers (COC).

[0144] According to a preferred embodiment of the present disclosure, the sealed container is a syringe.

[0145] According to a preferred embodiment of the present disclosure, the sealed container is an IV bag.

[0146] Medical use

[0147] According to a fifth aspect, the present disclosure relates to an injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of nausea and / or vomiting. According to a preferred embodiment, the present disclosure relates to the injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of chemotherapy-induced nausea. According to another preferred embodiment, the present disclosure relates to the injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of chemotherapy-induced vomiting. According to another preferred embodiment, the present disclosure relates to the injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of postoperative nausea. According to another preferred embodiment, the present disclosure relates to the injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of postoperative vomiting.

[0148] According to a preferred embodiment, the present disclosure relates to the injectable pharmaceutical composition according to the first aspect of the present disclosure for use in the treatment or prevention of chemotherapy-induced nausea, wherein the injectable pharmaceutical composition is administered via intravenous administration.

[0149] Intravenous administration has the advantage that the patient suffering from nausea and / or vomiting does not need to swallow a medicine and that the onset of the therapeutic effect is not delayed.

[0150] In the sense of the present disclosure, it is understood that the medical use of the injectable pharmaceutical composition is equivalent to the use of the injectable pharmaceutical composition according to the first or third aspect of the present disclosure in the manufacture of a medicament for the treatment or prevention of nausea and / or vomiting, preferably in the manufacture of a medicament for the treatment or prevention of chemotherapy-induced nausea, or chemotherapy-induced vomiting, or postoperative nausea, or postoperative vomiting.

[0151] Furthermore, it is understood that the medical use of the injectable pharmaceutical composition is equivalent to a method of treating or preventing nausea / and or vomiting comprising administering to a subject an effective amount of the injectable pharmaceutical composition according to the first or third aspect of the present disclosure.

[0152] Definitions and general embodiments

[0153] As used herein, the term “room temperature” refers to a temperature of about 25 °C. The term “about" in conjunction with a numerical value refers to normal deviations of said numerical value. It is to be understood that the term “about” can mean a deviation of ± 10 %, preferably ± 5 %, more preferably ± 2.5 % of said numeric value as indicated.

[0154] Where the term “comprising” is used in the present disclosure and claims, it does not exclude other elements. For the purposes of the present invention, the term “consisting of’ is considered to be a preferred embodiment of the term “comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group, which preferably consists only of these embodiments. Furthermore, if a composition is defined using the term “comprising”, it may additionally comprise other elements not explicitly listed, but no further amounts of an element listed. If, for example, an injectable pharmaceutical composition comprises aprepitant in a concentration of 7.5 mg / mL, said injectable pharmaceutical composition may comprise components other than aprepitant, however, not additional amounts of aprepitant, thereby exceeding the amount of 7.5 mg / mL.

[0155] As used herein, “aprepitant” refers to a compound of the name 5-{[(2F?,3S)-2-{(1F?)-1- [3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)morpholinyl]methyl}-1 ,2-dihydro-3 / 7- 1 ,2,4-triazol-3-one. In other words, the term “aprepitant” as used herein refers to a compound of the structure

[0156] It is understood that the term “aprepitant” also refers to all possible triazole tautomers. Aprepitant has the CAS-number 170729-80-3.

[0157] As used herein, the term “phospholipid” refers to a phospholipid that is obtained from a natural source. In other words, the phospholipid is prepared by purification of a natural material: “Egg phospholipid” as used herein is a mixture of naturally occurring phospholipids which are isolated from hen egg yolk. Since the composition of egg phospholipid is closely related to that of human cells, egg phospholipid is highly suitable for parenteral applications. Phosphatidylcholine from egg has the CAS number 97281-44-2.

[0158] The terms “soy phospholipid” and “soy bean phospholipid” are used interchangeably.

[0159] Soy phospholipid” as used herein is a mixture of naturally occurring phospholipids which are isolated from soy beans. Phosphatidylcholine from soy bean has the CAS number 97281-48-6.

[0160] As used herein, the term “phosphatidylcholine” refers to a class of phospholipids that incorporate a choline as the hydrophilic head.

[0161] As used herein, the term “surfactant” refers to a class of compounds having a group with at least one negative charge at neutral pH, that is balanced by a pharmaceutically acceptable cation of corresponding positive charge, and a lipophilic group. Non-limiting examples of surfactants are fatty acids or pharmaceutically acceptable salts thereof, such as sodium oleate or sodium stearate, or phosphatidylglycerol derivatives or pharmaceutically acceptable salts thereof, such as the sodium salts of dimyristoyl phosphatidylglycerol (DMPG-Na), dioleoyl phosphatidylglycerol (DOPG-Na), or dilauroyl phosphatidylglycerol (DLPG-Na).

[0162] As used herein, the term “pharmaceutically acceptable salt of a phosphatidylglycerol derivative” refers to a compound of the general structure wherein Y+is a pharmaceutically acceptable cation, and wherein R1and R2are each esters of a fatty acid, wherein the fatty acid is preferably selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, a-linoleic acid, arachidonic acid, eicosapentanoic acid, erucic acid, and docosaxexaenoic acid.

[0163] As used herein, the term “pharmaceutically acceptable cation" refers to a cation that is not toxic to mammals. Preferred pharmaceutically acceptable cations are lithium, sodium, potassium, aluminium, and zinc, cations made from organic bases such as choline, diethanolamine, morpholine, ammonium salts, quaternary salts such as tetramethylammonium salts.

[0164] As used herein, the term “pharmaceutically acceptable salt" refers to a salt of a compound that is not toxic to mammals.

[0165] As used herein, “dimyristoyl phosphatidylglycerol” (abbreviated as “DMPG”) refers to 1 ,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 185463-23-4) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1,2-dimyristoyl-sn- glycero-3-phospho-rac-(1-glycerol) (CAS number 200880-40-6; abbreviated as “DMPG-Na”).

[0166] As used herein, “dioleoyl phosphatidylglycerol” (abbreviated as “DOPG”) refers to 1 ,2- dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 62700-69-0) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1,2-dioleoyl-sn-glycero- 3-phospho-rac-(1-glycerol) (CAS number 67254-28-8; abbreviated as “DOPG-Na”).

[0167] As used herein, “dilauroyl phosphatidylglycerol” (abbreviated as “DLPG”) refers to

[0168] 1.2-dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1,2-dilauroyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 322647-27-8; abbreviated as “DLPG-Na”).

[0169] As used herein, “dipalmitoyl phosphatidylglycerol” (abbreviated as “DPPG”) refers to

[0170] 1.2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 74313-95-4) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1,2-dipalmitoyl-sn- glycero-3-phospho-rac-(1-glycerol) (CAS number 67232-81-9; abbreviated as “DPPG-Na”).

[0171] As used herein, “distearoyl phosphatidylglycerol” (abbreviated as “DSPG”) refers to

[0172] 1.2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 217939-97-4) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1,2-distearoyl-sn- glycero-3-phospho-rac-(1-glycerol) (CAS number 200880-42-8; abbreviated as “DSPG-Na”).

[0173] As used herein, “1-palmitoyl-2-oleoyl phosphatidylglycerol” (abbreviated as “POPG”) refers to 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 87246-80-8) or a pharmaceutically acceptable salt thereof, such as the sodium salt of 1- palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (CAS number 268550-95-4; abbreviated as “POPG-Na”).

[0174] As used herein, the “transmission” (T) of an injectable pharmaceutical composition is determined in a photometer, using the ratio between the intensity (I) of light having a wavelength of 660 nm which exits a sample having an optical path of 1 cm and the intensity (Io) of light having a wavelength of 660 nm which enters the sample. In other words, the transmission T is calculated as T = l / l0.

[0175] As used herein, the term “D50” refers to the intensity-weighted mean particle size diameter determined by dynamic light scattering (DLS). The intensity-weighted distribution is specific to the dynamic light scattering (DLS) technique. In that, the results are expressed as a measure of the intensity fluctuations of the light scattered by a particle. This is considered to give even greater weighting to the large particles than the volume-weighted distribution, so that native DLS particle size distributions are even more skewed towards large particles than laser diffraction results, in other words, dynamic light scattering techniques give an intensity weighted distribution, where the contribution of each particle in a plurality of particles relates to the intensity of light scattered by said particle.

[0176] As used herein, the term “D°o” refers to the intensity-weighted mean particle size diameter determined by dynamic light scattering (DLS) directly after the preparation of the injectable pharmaceutical composition according to the present invention.

[0177] As used herein, the term refers to the intensity-weighted mean particle size diameter determined by dynamic light scattering (DLS) after storing injectable pharmaceutical composition according to the present invention in a sealed glass vial for 6 months at a temperature of 40 °C and 75 % relative humidity.

[0178] As used herein, the term “D f“-RT” refers to the intensity-weighted mean particle size diameter determined by dynamic light scattering (DLS) after storing injectable pharmaceutical composition according to the present invention in a sealed glass vial for 6 months at room temperature (25 °C) and 60 % relative humidity.

[0179] Assay (I)

[0180] As used herein, the amount of aprepitant in an injectable pharmaceutical composition is determined according to assay (I), that is the following 5-minute reversed-phase UHPLC method: The injectable pharmaceutical composition is diluted in isopropanol to yield a solution containing a theoretical amount included in the calibration range (19 pmol / L to 380 pmol / L). The analysis of 5 pL injected sample is performed on a UHPLC Waters Acquity H- Class system using a Waters Acquity BEH C18 column (150x2.1 mm, 1.7 pm, cat. n°# 186002352) maintained at 40 °C and at a flow rate of 0.60 mL / min. Elution conditions involve a gradient of binary mobile phases. Mobile phases consist of Solvent A (0.1% Formic acid solution in water) and Solvent B (acetonitrile) with the following gradient elution program: 0 to 0.5 min 90 % solvent A and 10 % solvent B; 0.5 to 3.5 min solvent A from 90 to 10 %, solvent B from 10 to 90 %; then holding 1 min before returning to initial conditions.

[0181] Aprepitant is detected by UV detection at 264 nm and the amount reported as % recovery (w / w), is performed by external calibration using as working standard the same Ph. Eur. aprepitant raw material as the injectable pharmaceutical compositions. Examples

[0182] Example 1 : Preparation of formulations

[0183] To investigate the properties and the storage stability of injectable pharmaceutical compositions according to the present disclosure, the formulations as shown in Table 1 were prepared:

[0184] Table 1 Overview on compositions and storage stability.

[0185] For preparing the formulation according to Table 1 , egg phospholipid and sodium oleate or DMPG were mixed in water, and subjected to high pressure homogenization in an EmulsiFlex-C5 (obtained from Avestin: for example at a pressure of about 1100 to about 1300 bar and a temperature from 50 to 65 °C until a transmittance of at least 90 % at 660 nm is reached). The resulting liposome dispersion was mixed with a dispersion of aprepitant in water and heated to 80 °C for 8 min. Then the liposome composition was allowed to cool down to room temperature and filtered through a filter having a pore size of 0.2 pm. The resulting formulation was visually clear and stored in sealed glass vials.

[0186] Example 2: Stability of liposomes

[0187] To investigate the stability of liposomes, the formulations as prepared in example 1 were stored at 2-8 °C, 25 °C and 60 % relative humidity (rH), or 40 °C and 75 % relative humidity (rH), respectively. The samples were visually checked for the formation of aprepitant crystals or any other particle formation. The samples were analysed for the transmission at 660 nm, pH and particle size. The results for formulations 1 and 3 are shown in tables 2 and 3, respectively. Table 2 Results of stability testing of formulation 1 n.d. means not determined.

[0188] Table 3 Results of stability testing of formulation 3 n.d. means not determined. It can be concluded from the results of tables 2 and 3 that the liposomes are highly stable because neither the particle size of the liposomes nor the transmission of the formulation is changed over time. Furthermore, the formulations can be easily checked visually for the appearance of any aprepitant crystals or other particulate matter. However, no precipitation was observed. This shows superior storage stability of the injectable pharmaceutical compositions according to the present disclosure.

[0189] Example 3: Stability of aprepitant

[0190] To investigate the stability of aprepitant in the injectable pharmaceutical compositions prepared according to example 1 , the formulations were stored under the same conditions as in example 2. The content of aprepitant in the formulations was determined by LIHPLC according to Assay (I). The results are shown in table 4: Table 4 Results of stability testing for amount of aprepitant

[0191] It can be concluded from the results of table 4 that the aprepitant that is stored in the liposomes is highly stable and not susceptible to degradation. In conclusion, the injectable pharmaceutical formulations according to the present disclosure can be conveniently stored at room temperature. In other words, there is no need to store the compositions in the refrigerator.

Claims

Claims1 . An injectable pharmaceutical composition comprising a) a plurality of liposomes each comprising aprepitant, a phospholipid and a surfactant; b) a tonicity agent; and c) water; wherein the liposomes have a mean particle size D50 of less than 100 nm.

2. The injectable pharmaceutical composition according to claim 1 , wherein the liposomes have a mean particle size D50 of 80 nm or less, more preferably of 60 nm or less, most preferably of 50 nm or less.

3. The injectable pharmaceutical composition according to any one of claims 1 or 2, wherein the injectable pharmaceutical composition comprises aprepitant a) in a concentration of 0.5 mg / mL or more, preferably of 1 mg / mL or more, more preferably 2 mg / mL or more, more preferably 3 mg / mL or more, further preferably4 mg / mL or more, most preferably 5 mg / mL more; and / or b) in a concentration of 15 mg / mL or less, preferably of 12 mg / mL or less, more preferably of 10 mg / mL or less, most preferably of 8 mg / mL or less; or c) in a concentration in the range of from 0.5 mg / mL to 15 mg / mL, preferably of from 1 mg / mL to 12 mg / mL, more preferably of from 1 mg / mL to 10 mg / mL, more preferably of from 2 mg / mL to 8 mg / mL, further preferably of from 3 mg / mL to8 mg / mL, yet further preferably of from 4 mg / mL to 8 mg / mL, most preferably of from5 mg / mL to 8 mg / mL.

4. The injectable pharmaceutical composition according to any one of claims 1 to 3, wherein the injectable pharmaceutical composition has a pH in the range of from 6.0 to 9.0, preferably of from 6.2 to 8.5, more preferably from 6.5 to 8.5.

5. The injectable pharmaceutical composition according to any one of claims 1 to 4, wherein the phospholipid is a soy phospholipid, or an egg phospholipid, or a mixture thereof, preferably an egg phospholipid.

6. The injectable pharmaceutical composition according to any one of claims 1 to 5, wherein the injectable pharmaceutical composition comprises the phospholipid a) in a concentration of 10 mg / mL or more, preferably of 15 mg / mL or more, more preferably of 20 mg / mL or more, more preferably of 30 mg / mL or more, further preferably of 40 mg / mL or more, most preferably of 50 mg / mL or more; and / orb) in a concentration of 400 mg / mL or less, preferably of 350 mg / mL or less, more preferably of 300 mg / mL or less, more preferably of 250 mg / mL or less, most preferably of 200 mg / mL or less; or c) in a concentration in the range of from 10 mg / mL to 400 mg / mL, preferably of from 15 mg / mL to 350 mg / mL, more preferably of from 20 mg / mL to 350 mg / mL, more preferably of from 30 mg / mL to 300 mg / mL, further preferably of from 40 mg / mL to 300 mg / mL, yet further preferably of from 40 mg / mL to 250 mg / mL, most preferably of from 50 mg / mL to 200 mg / mL.

7. The injectable pharmaceutical composition according to any one of claims 1 to 6, wherein a) the ratio between the concentration of phospholipid and the concentration of aprepitant is at least 10, preferably at least 12, more preferably at least 15, more preferably at least 17, further preferably at least 19, most preferably at least 20; and / or, b) the ratio between the concentration of phospholipid and the concentration of aprepitant is 50 or less, preferably 45 or less, more preferably 40 or less, more preferably 35 or less, further preferably 32 or less, most preferably 30 or less; or c) the ratio between the concentration of phospholipid and the concentration of aprepitant is in the range of from 10 to 50, preferably of from 12 to 45, more preferably of from 15 to 35, more preferably of from 17 to 32, further preferably of from 19 to 32, most preferably of from 20 to 30.

8. The injectable pharmaceutical composition according to any one of claims 1 to 7 the tonicity agent is a sugar or sugar alcohol, preferably wherein the tonicity agent is selected from the group consisting of glycerol, sucrose, glucose, trehalose, lactose, mannitol, and mixtures thereof.

9. The injectable pharmaceutical composition according to any one of claims 1 to 8, wherein the surfactant is selected from the group consisting of oleic acid, dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidylglycerol (DM PG), dilauroyl phosphatidylglycerol (DLPG), and a pharmaceutically acceptable salt thereof, more preferably wherein the surfactant is sodium oleate or dimyristoyl phosphatidylglycerol (DMPG).

10. The injectable pharmaceutical composition according to claim 9, wherein the injectable pharmaceutical composition comprises the surfactanta) in a concentration of 0.1 mg / mL or more, preferably of 0.3 mg / mL or more, more preferably 0.5 mg / mL or more, more preferably 0.7 mg / mL or more, further preferably 0.9 mg / mL or more, most preferably 1.0 mg / mL more; and / or b) in a concentration of 5.0 mg / mL or less, preferably of 4.0 mg / mL or less, more preferably of 3.5 mg / mL or less, more preferably of 3.0 mg / mL or less, most preferably of 2.8 mg / mL or less; or c) in a concentration in the range of from 0.1 mg / mL to 5.0 mg / mL, preferably of from 0.3 mg / mL to 4.0 mg / mL, more preferably of from 0.5 mg / mL to 3.5 mg / mL, more preferably of from 0.7 mg / mL to 3.0 mg / mL, further preferably of from 0.9 mg / mL to 3.0 mg / mL, yet further preferably of from 1 .0 mg / mL to 3.0 mg / mL, most preferably of from 1.0 mg / mL to 2.8 mg / mL.

11. The injectable pharmaceutical composition according to any one of claims 1 to 10, wherein the ratiois in the range of from 0.98 to 1.20, preferably of from 0.98 to 1.15, more preferably of from 0.99 to 1.12, most preferably of from 1.00 to 1.10, whereinDf“-40is the mean particle size of the liposomes after storing the injectable pharmaceutical composition for 6 months at 40 °C, andD°ois the mean particle size of the liposomes directly after preparation of the injectable pharmaceutical composition.

12. The injectable pharmaceutical composition according to any one of claims 1 to 11 , wherein the ratio n6M-RT U50DU°50 is in the range of from 0.98 to 1.10, preferably of from 0.98 to 1 .05, more preferably of from 0.99 to 1.03, most preferably of from 1.00 to 1.02, whereinDf“_RTis the mean particle size of the liposomes after storing the injectable pharmaceutical composition for 6 months at room temperature, andD°ois the mean particle size of the liposomes directly after preparation of the injectable pharmaceutical composition.

13. The injectable pharmaceutical composition according to any one of claims 1 to 12, wherein the injectable pharmaceutical composition comprises an organic solvent in aconcentration of 0.1 mg / mL or less, preferably of 0.05 mg / mL or less, more preferably 0.02 mg / mL or less, most preferably wherein the injectable pharmaceutical does not comprise an organic solvent.

14. The injectable pharmaceutical composition according to any one of claims 1 to 13, wherein the injectable pharmaceutical composition comprises an oil in a concentration of 0.1 mg / mL or less, preferably of 0.05 mg / mL or less, more preferably 0.02 mg / mL or less, most preferably wherein the injectable pharmaceutical does not comprise an organic solvent.

15. A method of manufacturing an injectable pharmaceutical composition according to any one of claims 1 to 15, comprising the steps of a) mixing a phospholipid, a surfactant, a tonicity agent, and water to yield a first mixture; b) subjecting said first mixture to a high pressure homogenization to yield a liposome dispersion; c) mixing said liposome dispersion with aprepitant in water to provide a second mixture; d) heating said second mixture to yield a liposome composition; and e) sterilizing the liposome composition to yield the injectable pharmaceutical composition.

16. An injectable pharmaceutical composition prepared by the method according to claim 15.

17. A sealed container comprising the injectable pharmaceutical composition according to any one of claims 1-15 or 17, preferably wherein the sealed container is a glass vial, or a plastic vial, or a syringe, or an IV-bag.

18. An injectable pharmaceutical composition according to any one of claims 1-15 or 17 for use in the treatment or prevention of nausea and / or vomiting, preferably for use in the treatment or prevention of chemotherapy-induced nausea, or chemotherapy-induced vomiting, or postoperative nausea, or postoperative vomiting.

19. The injectable pharmaceutical composition for use according to claim 19, wherein the injectable pharmaceutical composition is administered via intravenous administration.

20. Use of an injectable pharmaceutical composition according to any one of claims 1-15 or 17 in the manufacture of a medicament for the treatment or prevention of nausea and / orvomiting, preferably in the manufacture of a medicament for the treatment or prevention of chemotherapy-induced nausea, or chemotherapy-induced vomiting, or postoperative nausea, or postoperative vomiting.

21. Method of treating or preventing nausea / and or vomiting comprising administering to a subject an effective amount of the injectable pharmaceutical composition according to any one of claims 1-15 or 17.

Images