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WO2025219743A1 - Formulation liposomale d'aprépitant et ses procédés de fabrication - Google Patents

Formulation liposomale d'aprépitant et ses procédés de fabrication

Info

Publication number
WO2025219743A1
WO2025219743A1 PCT/IB2024/053684 IB2024053684W WO2025219743A1 WO 2025219743 A1 WO2025219743 A1 WO 2025219743A1 IB 2024053684 W IB2024053684 W IB 2024053684W WO 2025219743 A1 WO2025219743 A1 WO 2025219743A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
injectable pharmaceutical
present disclosure
less
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/053684
Other languages
English (en)
Inventor
Herve SCHWEBEL
Claude REVILLIOD
Vincent ADAMO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
B Braun Melsungen AG
Original Assignee
B Braun Melsungen AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by B Braun Melsungen AG filed Critical B Braun Melsungen AG
Priority to PCT/IB2024/053684 priority Critical patent/WO2025219743A1/fr
Publication of WO2025219743A1 publication Critical patent/WO2025219743A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • the present invention relates to an injectable pharmaceutical composition
  • 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.
  • Aprepitant is a medication used to prevent and treat nausea and vomiting, such as chemotherapy-induced or postoperative nausea and vomiting.
  • 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.
  • 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.
  • 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.
  • Aprepitant is currently available in a capsule formulation for oral administration (EMEND®; Merck Sharp & Dohme).
  • EMEND® Merck Sharp & Dohme
  • oral formulations are not desirable due to the nausea and vomiting experienced by patients.
  • the onset of the therapeutic effect is delayed due to the slow drug absorption after oral administration.
  • 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.
  • aprepitant is available as an opaque and off-white to amber emulsion containing an oil for intravenous injection (APONVIETM or CINVANTITM, Heron Therapeutics) in the US.
  • APIONVIETM or CINVANTITM an oil for intravenous injection
  • 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.
  • 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.
  • aprepitant contains large amounts of excipients, such as soy bean oil, that by far exceeds the amount of aprepitant in said formulations.
  • excipients such as soy bean oil
  • 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.
  • 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.
  • the present disclosure relates to an injectable pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure relates to an injectable pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • Ultracentrifugation is a powerful technique that can separate liposomes from the aqueous fraction based on their density.
  • the liposomes can be pelleted at the bottom of a centrifuge tube, and the aqueous fraction can be decanted.
  • 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.
  • the plurality of liposomes are the plurality of liposomes
  • 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.
  • 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.
  • 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.
  • 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.
  • the aqueous fraction is substantially free of phospholipid and surfactant, other than in liposomal form.
  • 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.
  • the injectable pharmaceutical composition according to the present disclosure does not contain particles or particulate matter except for liposomes.
  • 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.
  • liposomes that have a mean particle size D50 of 100 nm or more exhibit turbidity in water.
  • the mean particle size D50 of the liposomes is 100 nm or more, the injectable pharmaceutical composition is not visually clear.
  • 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.
  • 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.
  • 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
  • the mean particle size of the liposomes Df“ -40 and/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.
  • 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.
  • 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 preferred embodiment of the present disclosure, the ratio D — is in the range of from 0.98 to 1 .05. According to another 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
  • the ratio D — is in the range of from 0.99
  • 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
  • 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.
  • the ratio — is in D5O the range of from 1.00 to 1.10.
  • the injectable pharmaceutical composition is no longer visually clear after storage for 6 months.
  • 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.
  • the injectable pharmaceutical compositions according to the present disclosure do not develop a turbidity during storage but remain visually clear.
  • 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.
  • 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.
  • 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 %.
  • One essential component of the liposomes according to the present disclosure is a phospholipid.
  • 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.
  • phosphatidylcholine The content of phosphatidylcholine is important in liposome formation and drug delivery for several reasons:
  • 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.
  • phosphatidylcholine contributes to the structural stability of liposomes and the permeability of the liposome membrane.
  • the content of phosphatidylcholine is important for the uptake and release of aprepitant from the lipid bilayer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the surfactant is the surfactant
  • a surfactant is comprised in the liposome.
  • 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.
  • the surfactant is a phosphatidylglycerol derivative, a fatty acid, or a pharmaceutically acceptable salt thereof.
  • 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
  • DOPG dioleoyl phosphatidylgly
  • 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.
  • the surfactant is oleic acid, dioleoyl phosphatidylglycerol (DOPG), dimyristoyl phosphatidylglycerol (DMPG), or a pharmaceutically acceptable salt thereof.
  • the surfactant is sodium oleate or dimyristoyl phosphatidylglycerol (DMPG).
  • the surfactant is a phosphatidylglycerol derivative or a pharmaceutically acceptable salt thereof.
  • 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.
  • DOPG dioleoyl phosphatidylglycerol
  • DLPG dilauroyl phosphatidylglycerol
  • DPPG dipalmitoyl phosphatidylglycerol
  • DSPG distearoyl phosphatidyl
  • the surfactant is dioleoyl phosphatidylglycerol (DOPG) or a pharmaceutically acceptable salt thereof, preferably sodium DOPG (DOPG-Na).
  • DOPG-Na dioleoyl phosphatidylglycerol
  • the surfactant is dilauroyl phosphatidylglycerol (DLPG) or a pharmaceutically acceptable salt thereof, preferably sodium DLPG (DLPG-Na).
  • the surfactant is dipalmitoyl phosphatidylglycerol (DPPG) or a pharmaceutically acceptable salt thereof, preferably sodium DPPG (DPPG-Na).
  • the surfactant is distearoyl phosphatidylglycerol (DSPG) or a pharmaceutically acceptable salt thereof, preferably sodium DSPG (DSPG-Na).
  • the surfactant is 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG) or a pharmaceutically acceptable salt thereof, preferably sodium POPG (POPG-Na).
  • POPG 1-palmitoyl-2-oleoyl phosphatidylglycerol
  • POPG-Na a pharmaceutically acceptable salt thereof, preferably sodium POPG (POPG-Na).
  • the surfactant is dimyristoyl phosphatidylglycerol (DMPG) or a pharmaceutically acceptable salt thereof, preferably sodium DMPG (PMPG-Na).
  • the surfactant is a fatty acid or a pharmaceutically acceptable salt thereof.
  • 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.
  • the surfactant is caprylic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is capric acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is lauric acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is myristic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is palmitic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is stearic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is arachidic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is behenic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is lignoceric acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is cerotic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is myristoleic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is palmitoleic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is sapienic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is elaidic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is vaccenic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is linoleic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is linoelaidic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is a-linolenic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is arachidonic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is eicosapentaenoic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is erucic acid or a pharmaceutically acceptable salt thereof.
  • the surfactant is docosahexaenoic acid or a pharmaceutically acceptable salt thereof.
  • the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.1 mg/mL or more.
  • the injectable pharmaceutical composition comprises the surfactant in a concentration of 0.3 mg/mL or more.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 0.5 mg/mL or more.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 1 mg/mL or more.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 2 mg/mL or more.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 3 mg/mL or more.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 4 mg/mL or more.
  • the injectable pharmaceutical composition comprises aprepitant in a concentration of 5 mg/mL or more.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • an injectable pharmaceutical composition is particularly stable if the ratio between the concentration of the phospholipid and the concentration of aprepitant is controlled.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the aqueous fraction is substantially free of phospholipid and surfactant, except for in the liposomes.
  • the aqueous fraction of the injectable pharmaceutical composition comprises water and a tonicity agent.
  • the water is water for injection.
  • 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.
  • the tonicity agent is a sugar alcohol or a sugar.
  • the tonicity agent is selected from the group consisting of glycerol, sucrose, glucose, trehalose, lactose, mannitol, and mixtures thereof.
  • 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.
  • the tonicity agent is a sugar.
  • the tonicity agent is glucose.
  • the tonicity agent is trehalose.
  • the tonicity agent is sucrose.
  • the tonicity agent is lactose.
  • the tonicity agent is fructose.
  • the tonicity agent is galactose.
  • the tonicity agent is maltose.
  • ions destabilize liposomes which results in accelerated decomposition of an injectable pharmaceutical composition and precipitation of aprepitant.
  • 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.
  • the pH may result from the method of manufacturing and it is not necessary to adjust the pH.
  • the pH can be adjusted using HCI or NaOH as needed.
  • the pH of the injectable pharmaceutical composition is adjusted with HCI and/or NaOH.
  • 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.
  • 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.
  • the injectable pharmaceutical compositions according to the first aspect of the present disclosure are substantially free or free of organic solvents and oils.
  • 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.
  • 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.
  • some patients may be allergic to specific oils or solvents used in the formulation, leading to allergic reactions or hypersensitivity.
  • 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.
  • 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.
  • one advantage of the injectable pharmaceutical composition according to the first aspect of the present disclosure is the absence of organic solvents and oils.
  • 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.
  • Organic solvents are methanol, ethanol, i-propanol, t-butanol, dichloromethane, chloroform, THF, and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • a liposome dispersion is prepared.
  • 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).
  • a homogenization preferably high- pressure homogenization, to yield a liposome dispersion.
  • high-pressure homogenization is performed at a pressure in the range of from about 1100 bar to about 1300 bar.
  • high-pressure homogenization is performed at a temperature in the range of from about 50 °C to about 60 °C.
  • high-pressure homogenization is performed until the liposomal dispersion has a transmittance at 660 nm of at least 90 %.
  • 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.
  • the Avestin Emulsiflex-C5 (Avestin, Canada) can be used.
  • 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.
  • 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.
  • the conditions of high pressure homogenization are chosen to yield liposomes of the desired size.
  • a liposome dispersion is obtained.
  • the liposomes are loaded with aprepitant.
  • aprepitant is mixed with the liposome dispersion obtained from the homogenization or high-pressure homogenization step to provide a second third mixture.
  • micronized aprepitant is mixed with the liposome dispersion.
  • the micronized aprepitant has a Dgo particle size of 10 pm or less.
  • the micronized aprepitant has a Dgo particle size of less than 10 pm.
  • 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.
  • the second mixture is then heated to yield a liposome composition (step d)). This step is also referred to as heat solubilization.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the resulting liposome composition is sterilized to yield the injectable pharmaceutical composition.
  • sterilizing comprises filtering the liposome composition through a filter having a pore size of 0.2 pm.
  • Suitable filters for sterile filtration having a pore size of 0.2 pm are available from commercial suppliers.
  • the resulting injectable pharmaceutical composition can then be packed into a sterile container.
  • packing is carried out under sterile conditions.
  • 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.
  • the injectable pharmaceutical composition prepared by a method of the present disclosure
  • 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.
  • 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.
  • the sealed container is a glass vial.
  • the sealed container is a plastic vial.
  • the sealed container is a plastic vial comprises cyclo-olefin polymers (COP).
  • the sealed container is a plastic vial comprises cyclo-olefin copolymers (COC).
  • the sealed container is a syringe.
  • the sealed container is an IV bag.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the term “aprepitant” as used herein refers to a compound of the structure
  • aprepitant also refers to all possible triazole tautomers. Aprepitant has the CAS-number 170729-80-3.
  • phospholipid refers to a phospholipid that is obtained from a natural source.
  • 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.
  • 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.
  • phosphatidylcholine refers to a class of phospholipids that incorporate a choline as the hydrophilic head.
  • 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).
  • DMPG-Na dimyristoyl phosphatidylglycerol
  • DOPG-Na dioleoyl phosphatidylglycerol
  • DLPG-Na dilauroyl phosphatidylglycerol
  • 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 R 1 and R 2 are 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.
  • 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.
  • pharmaceutically acceptable salt refers to a salt of a compound that is not toxic to mammals.
  • DMPG diristoyl phosphatidylglycerol
  • dioleoyl phosphatidylglycerol 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”).
  • DOPG dioleoyl phosphatidylglycerol
  • DLPG dibenzyl phosphatidylglycerol
  • DPPG dipalmitoyl phosphatidylglycerol
  • 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”).
  • DSPG disearoyl phosphatidylglycerol
  • 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”).
  • 1-palmitoyl-2-oleoyl phosphatidylglycerol 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”).
  • 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.
  • 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.
  • 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.
  • 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.
  • DLS dynamic light scattering
  • 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.
  • 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.
  • 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
  • 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).
  • 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.
  • 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.
  • 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.

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Abstract

La présente divulgation concerne une composition pharmaceutique injectable comprenant une pluralité de liposomes comprenant chacun de l'aprépitant, un phospholipide et un tensioactif; un agent de tonicité; et de l'eau, ainsi qu'un procédé de fabrication de ladite composition pharmaceutique injectable, et un récipient contenant ladite composition pharmaceutique.
PCT/IB2024/053684 2024-04-15 2024-04-15 Formulation liposomale d'aprépitant et ses procédés de fabrication Pending WO2025219743A1 (fr)

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