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WO2025128498A1 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2025128498A1
WO2025128498A1 PCT/US2024/059277 US2024059277W WO2025128498A1 WO 2025128498 A1 WO2025128498 A1 WO 2025128498A1 US 2024059277 W US2024059277 W US 2024059277W WO 2025128498 A1 WO2025128498 A1 WO 2025128498A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
composition according
human
administered
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Pending
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PCT/US2024/059277
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English (en)
Inventor
Simone ALIDORI
Chandan BHUGRA
Karina Figueroa
Rennan Pan
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ViiV Healthcare Co
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ViiV Healthcare Co
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Publication of WO2025128498A1 publication Critical patent/WO2025128498A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the invention relates to treatment or prevention of Human Immunodeficiency Virus (HIV) infection.
  • HIV Human Immunodeficiency Virus
  • the invention relates to long-acting treatment or prevention of HIV infection.
  • BACKGROUND TO THE INVENTION Patients with HIV infection commonly undergo complex treatment regimens which involve taking multiple pills at regular intervals each day. Patient non-compliance is a known problem accompanying these complex HIV treatment regimens and can lead to the emergence of multiple drug resistant strains of HIV.
  • the application of long-acting parenteral pharmaceuticals has been established in clinical practice for decades, notably in the areas of contraception, anti-psychotics, and opiate addiction.
  • WO 2017/223280 and WO 2020/086555 disclose integrase inhibitor prodrugs, specifically prodrugs of cabotegravir. These prodrugs may have an extended drug half-life and therefore allow for less frequent dosing compared to the parent compound which could help alleviate issues with patient non-compliance.
  • an anti-HIV drug may be used for prevention of HIV infection (e.g., pre-exposure prophylaxis, or PrEP)
  • achieving an injectable suspension with an anti-HIV drug that provides a longer-acting effect could increase adherence due to less frequent dosing.
  • Suspensions may suffer from difficulty in resuspension and particle size growth.
  • suspensions with larger particle sizes are more difficult to stabilize in ready-to-use suspensions.
  • L yophilized formulations for micro-suspensions offer several advantages over ready-to-use suspensions – namely, avoiding reconstitution/resuspension difficulties or failures, maintaining product physicochemical stability, and overcoming scale-up issues. It is expected that drug substance polymorphism could impact pharmacokinetics (PK) and or bioavailability of suspensions, due to potential solubility difference of different solid-state forms. Identification of a stable, crystalline form of a compound with suitable properties for long-acting administration and a pharmaceutical composition that arrests form conversion would be highly desirable for the treatment and prevention of HIV infection.
  • a ccording to a first aspect there is provided a pharmaceutical composition comprising Compound A, (Compound A), and a A ccording to a second aspect, there is provided a method of treating human immunodeficiency virus (HIV) infection in a human in need thereof comprising administering to said human a therapeutically effective amount of the pharmaceutical composition as described herein.
  • HAV human immunodeficiency virus
  • a ccording to a third aspect there is provided a method of preventing human immunodeficiency virus (HIV) infection in a human in need thereof comprising administering to said human an effective amount of the pharmaceutical composition as described herein.
  • a ccording to a further aspect there is provided a pharmaceutical composition as described herein, for use in therapy.
  • a pharmaceutical composition as described herein for use in treatment or prevention of human immunodeficiency virus (HIV) infection.
  • kits comprising a container comprising the pharmaceutical composition as described herein as a lyophilised powder.
  • the pharmaceutical compositions of the present invention may be advantageous in a number of respects.
  • the pharmaceutical compositions of the invention favourably reduce C max and extend half-life compared to existing formulations, thus permitting ultra long-acting therapy, allowing for longer time intervals between dosing compared to existing therapies. This may improve patient compliance, reducing likelihood of drug-resistant HIV strains.
  • C ompositions of the invention have also been shown to show particle size stability over time, even at a range of different temperature conditions allowing for favourable product storage.
  • compositions of the present invention also favourably prevent form conversion over time, specifically, Form 1 (the most thermodynamically stable single component form of Compound A) has been shown to remain stable in the pharmaceutical composition during storage, i.e. does not convert to another form over time, as well as remaining stable when exposed to conditions of varying temperature and humidity. It is expected that drug substance polymorphism could impact pharmacokinetics/bioavailability of drug product, due to potential solubility difference of different solid-state forms.
  • compositions of the invention limit polymorphic form conversion of Form 1 of Compound A in the composition and offer enhanced control over solid state form, with form conversion less than 10%.
  • BRIEF DESCRIPTION OF THE DRAWINGS Fig.1 shows an X-ray powder diffraction pattern of Form 1 of Compound A measured at room temperature with Cu Ka 1 radiation at 1.54 Angstroms. Fig.
  • FIG. 2 shows a differential scanning calorimetry thermogram of Form 1 of Compound A. Collected at room temperature up to 160 deg C at a heating rate of 10 deg C/min using a sealed hermetic aluminium pan with a pinhole.
  • Fig. 3 shows a thermogravimetric analysis trace of Form 1 of Compound A. Collected at room temperature up to 400 deg C at a heating rate of 15 deg C/min in an open aluminium pan.
  • Fig. 4 shows a Raman spectrum of Form 1 of Compound A. Raman spectra was collected using a Kaiser Optical Systems Raman RXN2-785 controlled by iCRaman software v4.4.21. Resampling Intervals were: 1 cm-1; Channel 2.
  • FIG.5 shows an X-ray powder diffraction pattern of form, Group B of Compound A.
  • Fig. 6 shows X-ray powder diffraction pattern of multicomponent form, Group E of Compound A.
  • Fig. 7 shows a comparison of X-ray powder diffraction patterns for a micronized and lyophilized composition of Compound A.
  • FIG. 8 shows an XRPD of Form 1 made from a method without using a seeding step according to Example 1.
  • Fig.9 shows a DSC of Form 1 made from a method without using a seeding step according to Example 1.
  • Fig.10 shows an XRPD of Form 1 made from the method of Example 2b.
  • Fig. 11 shows a 19F solid-state Nuclear Magnetic Resonance (NMR) spectrum of Form 1 of Compound A.
  • NMR Nuclear Magnetic Resonance
  • FIG. 12 shows a log plot of the Cabotegravir plasma concentrations time course after subcutaneous administration in Cynomolgus monkeys
  • A Sodium Carboxymethylcellulose formulation at 40 mg/Kg ( ⁇ ) and 75 mg/Kg ( ⁇ ) of compound A
  • B of Polyvinylpyrrolidone K12 formulation at 40 mg/Kg ( ⁇ ) and 75 mg/Kg (x) of compound A.
  • Fig. 13 shows a high resolution X-ray powder diffraction pattern (XRPD) of Form 1 of Compound A measured at room temperature with Cu Ka 1 radiation at 1.54 Angstroms.
  • Fig. 14 shows a DSC of Group B (made using impurities from the drug substance process and Form 1).
  • Fig.15 shows an overlay of XRPDs of several mixtures of Group B and Form 1 (Top to bottom (50:50, 70:30, 90:10, 95:5 Form 1: Grp B)), second from the bottom pure Group B, bottom pure Form 1.
  • Fig. 16 shows an overlay of XRPDs of several mixtures of Group B and Form 1 (Top to bottom (50:50, 70:30, 90:10, 95:5 Form 1: Grp B)), second from the bottom pure Group B, bottom pure Form 1 in the range of 4.5 to 9.5 °2 ⁇ .
  • alkyl refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms.
  • C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), pentyl, and hexyl.
  • aqueous solution refers to any solution comprising water or in which the solvent is water. Additionally, “aqueous solution” is used to describe solutions displaying commonalities to water or watery solutions, not limited to characteristics such as appearance, smell, color, taste, viscosity, pH, absorbance, or physical state under particular temperatures.
  • treatment refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject.
  • prevention refers to avoidance of the stated disease in a subject who is not suffering from the stated disease.
  • therapeutically effective amount refers to the quantity of a compound of formula (I) [and insert any others], or a pharmaceutically acceptable salt thereof, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity and the age and weight of the subject to be treated.
  • lyophilization also known as freeze-drying or cryodesiccation
  • freeze-drying or cryodesiccation is a dehydration process which involves freezing the product without destroying the physical structure of the matter.
  • lyophilized and “freeze-dried” can be used interchangeably herein and refer to a condition and/or state of a sample, formulation, or product obtained by means of lyophilization.
  • lyophilized pharmaceutical composition and “lyophilized composition” refer to a pharmaceutical composition in lyophilized form, as taught herein.
  • pharmaceutical composition means a composition that is suitable for pharmaceutical use.
  • substitution refers to the process of restoring a dried, lyophilized, dehydrated, or concentrated matter to its original or liquid state by adding a solvent to the lyophilized matter, allowing the lyophilized matter to rehydrate, followed by agitating the mixture of the solvent and lyophilized matter.
  • the reconstituted matter may be part of a product, formulation, sample, raw material, or any biological material but is certainly not limited to matter falling under the common definition of these terms. Reconstitution can be assessed visually with the naked eye.
  • the lyophilized matter is deemed reconstituted when a homogeneous suspension is observed. In particular, a suspension with a cloudy appearance is considered suitably reconstituted.
  • the term “self-administered” means administration by someone other than a healthcare professional, for example, a patient may administer the pharmaceutical composition to their self or someone else, other than a healthcare professional administering the pharmaceutical composition to the patient.
  • the term “subject” or “patient” refers to a human.
  • size refers to a spherical volume equivalent size.
  • X50 (or “the X50 value”) is the particle size, in microns, at which 50% by volume of the particles have a smaller size and 50% by volume have a larger size, also known as the mass median size (MMS) or the median of the particle size distribution by volume.
  • X90 (or “the X90 value”) is the particle size, in microns, at which 90% by volume of the particles have a smaller size and 10% by volume have a larger size.
  • X10 (or “the X10 value”) is the particle size, in microns, at which 10% by volume of the particles have a smaller size and 90% by volume have a larger size.
  • a pharmaceutical composition comprising Compound A A) Compound A (3R,6S)-12- ⁇ [(2,4-difluorophenyl)methyl]carbamoyl ⁇ -6-methyl-8,11-dioxo-4- oxa-1,7-diazatricyclo[7.4.0.03,7]trideca-9,12-dien-10-yl octadecenoate is a stearoyl ester prodrug of cabotegravir. O ther ester prodrugs of cabotegravir are disclosed in WO 2017/223280 and WO 2020/086555 and are incorporated by reference herein.
  • the ester prodrug of cabotegravir may be a compound of Formula I: (Formula I) R C 3 -C 30
  • R is an alkyl chain of length 3 to 30 carbons.
  • R is C 10 -C 20 alkyl.
  • R is C 15 -C 20 alkyl.
  • R is C 15 -C 18 alkyl.
  • the alkyl chain may be a linear alkyl chain i.e. R is the residue of a fatty acid.
  • R is a linear 17 carbon alkyl i.e. the ester prodrug of cabotegravir is Compound A.
  • Cabotegravir (3S,11AR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7- dioxo-2,3,5,7,11,11a-hexahydrooxazolo [3,2-a] pyrido[1,2-d]pyrazine-8-carboxamide is described in US 8,129,385 in example Z-1, which example is incorporated herein by reference.
  • Cabotegravir is an integrase strand transfer inhibitor (INSTI) that exhibits subnanomolar potency and antiviral activity against a broad range of HIV-1 strains.
  • INSTI integrase strand transfer inhibitor
  • cabotegravir has exhibited acceptable safety and tolerability profiles, a long half-life, and few drug-drug interactions.
  • Cabotegravir has been demonstrated to be efficacious in treatment and prevention of HIV infection both in oral and parenteral dosage forms, see for instance, Margolis DA, Brinson CC, Eron JJ, et al.744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21 st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA, Margolis DA, Podzamczer D, Stellbrink H-J, et al.
  • Cabotegravir has been approved by the FDA for long-acting prevention of HIV infection dosed every two months; and in combination with Rilpivirine for long-acting treatment of HIV infection dosed once a month or once every two months.
  • Cabotegravir is represented by Compound B: (Compound B).
  • a also referred to herein as the steric acid ester prodrug of cabotegravir
  • the pharmaceutical compositions of the present invention comprise particles of crystalline Compound A.
  • Compound A particles of the pharmaceutical composition have a mass median size (X50) value greater than or equal to 1 ⁇ m and less than or equal to 15 ⁇ m (i.e., 1 ⁇ m ⁇ X50 ⁇ 15 ⁇ m). Particle size distribution may be measured by any suitable method, for example, by laser diffraction as described in the Examples section herein.
  • Compound A is present in the composition as Form 1 i.e. the most thermodynamically stable single component form of Compound A. Form 1 is as described herein.
  • Compound A is present at a concentration of 100 to 600 mg/mL.
  • the pharmaceutical composition contains about 200 mg/mL to about 400 mg/mL of Compound A.
  • the composition contains, about 200 mg/mL, about 300 mg/mL, or about 400 mg/mL of Compound A.
  • the pharmaceutical composition contains Compound A in an amount between about 600 mg to about 1800 mg.
  • Wetting agents or surfactants are compounds that, when dissolved in a liquid, can reduce the surface tension of a gas, liquid, or solid surface in that liquid. They are often amphiphilic and may aid in wetting and enhance manufacturability of the drug product.
  • a surfactant may additionally impart long-term product stability by steric or electrostatic repulsion. Non-ionic surfactants are preferred over ionic surfactants as they are generally non-toxic, non-irritating, and inert.
  • P harmaceutical compositions of the invention comprise a poloxamer as a wetting agent.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide) flanked by two hydrophilic chains of polyoxyethylene (polyethylene glycol).
  • the poloxamer is P338. Without wishing to be bound by theory, it is thought that poloxamer may play a role in limiting form conversion in the pharmaceutical composition. Further, the present inventors have found that using a poloxamer in the pharmaceutical composition of the present invention lowers viscosity of the pharmaceutical composition compared to other surfactants or wetting agents.
  • the pharmaceutical composition contains from about 5 mg/mL to about 15 mg/mL of the poloxamer. In a further embodiment, the pharmaceutical composition contains from about 10mg/mL to about 15 mg/mL of the poloxamer. In an embodiment the pharmaceutical composition contains from about 1 to 5 % w/v of the poloxamer.
  • the pharmaceutical composition contains about 1 to 2% w/v of the poloxamer.
  • a weight ratio of the poloxamer to Compound A is in a range of from 1:10 to 1:50.
  • the weight ratio of the poloxamer to Compound A is in a range of from 1:10 to 1:40.
  • the weight ratio of the poloxamer to Compound A is in a range of from 1:25 to 1:35.
  • the weight ratio of the poloxamer to Compound A is about 1:30.
  • the pharmaceutical composition further comprises a stabilizer and a tonicity adjuster. Stabilizers are components added to help preserve critical product attributes throughout shelf life.
  • stabilizers can be used to induce charge effects, add steric stabilization, increase viscosity of the vehicle, etc. These factors can preserve particle size, product resuspendability, and/or improve manufacturability.
  • stabilizers include, but are not limited to, sodium carboxymethylcellulose (CMC), polyethylene glycol 3350, polyethylene glycol 4000, and polyvinylpyrrolidone (PVP) (e.g., povidone K12 (PVP K12) and povidone K17 (PVP K17)).
  • the pharmaceutical composition of the invention comprises sodium CMC (NaCMC) or polyvinylpyrrolidone (PVP) as the stabilizer.
  • the pharmaceutical composition of the invention comprises sodium CMC as the stabilizer.
  • the pharmaceutical composition of the invention comprises polyvinylpyrrolidone (PVP) as the stabiliser.
  • PVP polyvinylpyrrolidone
  • the PVP is PVP K12.
  • PVP and NaCMC in comparison to other stabilisers (for example polyethylene glycol (PEG)), lower viscosity of the composition allowing for effective reconstitution/resuspension.
  • PEG polyethylene glycol
  • the pharmaceutical composition contains about 1 mg/mL to about 30 mg/mL of the stabilizer.
  • the pharmaceutical composition contains about 1 mg/mL to about 25 mg/mL, from about 2 mg/mL to about 15 mg/mL, or from about 5 mg/mL to about 15 mg/mL of the stabilizer. In an embodiment, the pharmaceutical composition contains about 5 mg/mL of the stabilizer. In an embodiment, the pharmaceutical composition contains about 10 mg/mL of the stabilizer. In an embodiment, the pharmaceutical composition contains about 15 mg/mL of the stabilizer. In an embodiment, the pharmaceutical composition contains about 20 mg/mL of the stabilizer. In an embodiment the pharmaceutical composition contains from about 0.1 to 5 % w/v of the stabilizer. In an embodiment, the pharmaceutical composition contains about 0.1 to 2% w/v of the stabilizer.
  • the stabilizer is NaCMC and the pharmaceutical composition comprises about 0.5 % w/v of NaCMC. In another embodiment, the stabilizer is PVP and the pharmaceutical composition comprises about 1.5 % w/v of PVP. In another embodiment, the stabilizer is PVP K12 and the pharmaceutical composition comprises about 1.5 % w/v of PVP K12. In an embodiment, a weight ratio of the stabilizer to Compound A is in a range of from 1:5 to 1:100. In another embodiment, the weight ratio of the stabilizer to Compound A is in a range of from 1:10 to 1:80. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is in a range of 1:5 to 1:40.
  • the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is in a range of 1:10 to 1:30. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is about 1:15 to 1:25. In an embodiment, the stabiliser is PVP and the weight ratio of the stabilizer to Compound A is about 1:20. In an embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is in a range of 1:5 to 1:40. In another embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is in a range of 1:10 to 1:30.
  • the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is in a range of 1:15 to 1:25. In an embodiment, the stabiliser is PVP K12 and the weight ratio of the stabilizer to Compound A is about 1:20. In an embodiment, the stabiliser is NaCMC and the weight ratio of the stabilizer to Compound A is in a range of 1:40 to 1:80. In another embodiment, the stabiliser is NaCMC and the weight ratio of the stabilizer to Compound A is in a range of 1:50 to 1:70. In an embodiment, the stabiliser is NaCMC and the weight ratio of the stabilizer to Compound A is about 1:60.
  • the tonicity adjuster is a saccharide such as mannitol, sorbitol, lactose, trehalose, raffinose, dextrose, maltose, galactose, sucrose, or polysucrose.
  • the tonicity adjuster is mannitol.
  • the tonicity adjuster is a non-aqueous polar aprotic or protic materials such as polyethylene glycol, N,N-dimethylacetamide, N-methyl pyrrolidone, glycerol, propylene glycol, ethanol, t- butyl alcohol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, or glycerol.
  • the tonicity adjuster is a polymer such as polyethylene glycol (PEG) (for example, PEG 300, PEG 400, PEG 3350, PEG 6000, or PEG 8000), polygalacturonic acid, galacturonic acid, or polyvinylpyrrolidine (PVP).
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidine
  • the tonicity adjuster is an amino acid such as lysine, arginine, glycine, methionine, or other amino acids.
  • the tonicity adjuster is a cyclodextrin such as dextran, Ficoll, or polyvinylpyrrolidone, or other similar excipients and combinations of these agents.
  • the pharmaceutical composition of the invention comprises mannitol as the tonicity adjuster.
  • the pharmaceutical composition contains about 0.1 mg/mL to about 250 mg/mL of the tonicity adjuster.
  • a weight ratio of the tonicity adjuster to cabotegravir is in a range of from 1:5 to 1:50. In another embodiment, the weight ratio of the tonicity adjuster to Compound A is in a range of from 1:5 to 1:35. In another embodiment, the weight ratio of the tonicity adjuster to cabotegravir is in a range of from 1:5 to 1:25. In another embodiment, the weight ratio of the tonicity adjuster to cabotegravir is in a range of from 1:5 to 1:10. In another embodiment, the weight ratio of the tonicity adjuster to cabotegravir is in a range of from 1:5 to 1:12.
  • the weight ratio of the tonicity adjuster to cabotegravir is about 1:9. In another embodiment, the weight ratio of the tonicity adjuster to cabotegravir is about 1:8.5.
  • Dissolution properties of the pharmaceutical composition are affected, inter alia, by particle size and particle size distribution of the active pharmaceutical ingredient (i.e., Compound A).
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the Compound A particles have a particle size less than or equal to 10 ⁇ m (i.e. mass median size, or X50, is 10 ⁇ m).
  • the pharmaceutical composition has a mass median size (X50) of about 5 ⁇ m.
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles have a particle size less than or equal to 25 ⁇ m (i.e., X90 is 25 ⁇ m).
  • Compound A particles of the pharmaceutical composition have an X90 value greater than or equal to 5 ⁇ m and less than or equal to 25 ⁇ m (i.e., 5 ⁇ m ⁇ X90 ⁇ 25 ⁇ m), provided that X90 is larger than X50.
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles have a particle size less than or equal to 20 ⁇ m (i.e., X90 is 20 ⁇ m).
  • Compound A particles of the pharmaceutical composition have an X90 value greater than or equal to 8 ⁇ m and less than or equal to 13 ⁇ m (i.e., 8 ⁇ m ⁇ X90 ⁇ 13 ⁇ m).
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles (X90) have a particle size smaller than or equal to 7.0 ⁇ m, 7.1 ⁇ m, 7.2 ⁇ m, 7.3 ⁇ m, 7.4 ⁇ m, 7.5 ⁇ m, 7.6 ⁇ m, 7.7 ⁇ m, 7.8 ⁇ m, 7.9 ⁇ m, 8.0 ⁇ m, 8.1 ⁇ m, 8.2 ⁇ m, 8.3 ⁇ m, 8.4 ⁇ m, 8.5 ⁇ m, 8.6 ⁇ m, 8.7 ⁇ m, 8.8 ⁇ m, 8.9 ⁇ m, 9.0 ⁇ m, 9.1 ⁇ m, 9.2 ⁇ m, 9.3 ⁇ m, 9.4 ⁇ m, 9.5 ⁇ m, 9.6 ⁇ m, 9.7 ⁇ m, 9.8 ⁇ m, 9.9 ⁇ m, 10.0 ⁇ m, 10.1 ⁇ m, 10.2 ⁇ m, 10.3 ⁇ m, 10.4 ⁇ m, 10.5 ⁇ m, 10.
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles (X90) have a particle size smaller than or equal to 9 ⁇ m (i.e., X90 is 9 ⁇ m). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles (X90) have a particle size smaller than or equal to 9.5 ⁇ m (i.e., X90 is 9.5 ⁇ m). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the Compound A particles (X90) have a particle size smaller than or equal to 11 ⁇ m (i.e., X90 is 11 ⁇ m).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles have a particle size smaller than or equal to 4 ⁇ m (i.e., X10 is 4 ⁇ m).
  • Compound A particles of the pharmaceutical composition have an X10 value greater than or equal to 0.5 ⁇ m and less than or equal to 4 ⁇ m (i.e., 0.5 ⁇ m ⁇ X10 ⁇ 4 ⁇ m).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles have a particle size less than or equal to 3.5 ⁇ m.
  • Compound A particles of the pharmaceutical composition have an X10 value greater than or equal to 1 ⁇ m and less than or equal to 3.5 ⁇ m (i.e., 1 ⁇ m ⁇ X10 ⁇ 3.5 ⁇ m).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles have a particle size less than or equal to 3 ⁇ m.
  • Compound A particles of the pharmaceutical composition have an X10 value greater than or equal to 1.5 ⁇ m and less than or equal to 3 ⁇ m (i.e., 1.5 ⁇ m ⁇ X10 ⁇ 3 ⁇ m).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles (X10) have a particle size smaller than or equal to 1.0 ⁇ m, 1.1 ⁇ m, 1.2 ⁇ m, 1.3 ⁇ m, 1.4 ⁇ m, 1.5 ⁇ m, 1.6 ⁇ m, 1.7 ⁇ m, 1.8 ⁇ m, 1.9 ⁇ m, 2.0 ⁇ m, 2.1 ⁇ m, 2.2 ⁇ m, 2.3 ⁇ m, 2.4 ⁇ m, 2.5 ⁇ m, 2.6 ⁇ m, 2.7 ⁇ m, 2.8 ⁇ m, 2.9 ⁇ m, 3.0 ⁇ m, 3.1 ⁇ m, 3.2 ⁇ m, 3.3 ⁇ m, 3.4 ⁇ m, 3.5 ⁇ m, 3.6 ⁇ m, 3.7 ⁇ m, 3.8 ⁇ m, 3.9 ⁇ m, or 4.0 ⁇ m.
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles (X10) have a particle size smaller than or equal to 1.7 ⁇ m (i.e., X10 is 1.7 ⁇ m). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 10% of the Compound A particles (X10) have a particle size smaller than or equal to 2.2 ⁇ m (i.e., X10 is 2.2 ⁇ m).
  • the value X90 refers to the 90% value of the volume distribution measured using a laser diffractometer. For purposes of the present disclosure, the X90 value denotes the particle size below which 90% of the quantity of particles is found based on the volume distribution.
  • Lyophilized compositions of the invention have been shown to have lower Cmax and longer half-life as shown, for example, in Example 5 herein. Further, the inventors have found that lyophilized compositions, compared to, for example, compositions that have been wet bead milled, limit form conversion from Form 1 of Compound A. Lyophilization comprises at least a freezing step and a sublimation step. Lyophilization may be used in the manufacturing of pharmaceutical products and intermediates thereof. During freezing, the material is cooled to a temperature wherein the solid, liquid, and gas phases of the material may exist. Active pharmaceutical product ingredients (APIs) may be lyophilized to achieve chemical and physical stability allowing room temperature storage. This is different from a conventional method that evaporates water using heat.
  • APIs Active pharmaceutical product ingredients
  • Gamma irradiated Compound A is dispersed in a filtered aqueous vehicle comprising a stabilizer (e.g., PVP or sodium CMC), a tonicity agent (e.g., mannitol), and a wetting agent (e.g., Poloxamer e.g. Poloxamer 338).
  • a stabilizer e.g., PVP or sodium CMC
  • a tonicity agent e.g., mannitol
  • a wetting agent e.g., Poloxamer e.g. Poloxamer 338
  • the lyophilized pharmaceutical composition advantageously suspends when reconstituted in an aqueous or non-aqueous solution, that is, all or substantially all, such as at least 90 percent, at least 95 percent, at least 96 percent, at least 97 percent, at least 98 percent, at least 99 percent, at least 99.5 percent or 100 percent of the lyophilized pharmaceutical composition is suspended when reconstituted. Reconstitution can be assessed visually with the naked eye. The lyophilized matter is deemed reconstituted when a homogeneous suspension is observed. In particular, a suspension with a cloudy appearance is considered suitably reconstituted. It will be apparent to those skilled in the art that pharmaceutical compositions of the invention may be reconstituted in an aqueous or non-aqueous solution to a desired concentration.
  • the pharmaceutical composition described below in Example 3 may be reconstituted in 1.1 mL water for injection (WFI) to achieve a Compound A concentration of 400 mg/mL.
  • the same pharmaceutical composition described below in Example 2 may be reconstituted in 1.7 mL WFI to achieve a Compound A concentration of 300 mg/mL.
  • the present disclosure provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particles having a mass median size (X50) of between (and including) 1.5 ⁇ m and 15 ⁇ m; a poloxamer; a stabilizer; and a tonicity adjuster; wherein the formulation, when reconstituted in an aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less.
  • X50 mass median size
  • the present disclosure provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particles having a mass median size (X50) of between (and including) 1.5 ⁇ m and 15 ⁇ m; poloxamer; sodium CMC; and mannitol; wherein the formulation, when reconstituted in an aqueous or non-aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less.
  • X50 mass median size
  • the present disclosure provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising Compound A, wherein Compound A is present in the form of particles having a mass median size (X50) of between (and including) 1.5 ⁇ m and 15 ⁇ m; poloxamer; PVP; and mannitol; wherein the formulation, when reconstituted in an aqueous or non-aqueous solution, has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less.
  • Compound A is present in the pharmaceutical composition as crystalline Form 1 of Compound A.
  • Pharmaceutical compositions of the present invention surprisingly prevent form conversion of Form 1 to other forms.
  • Form landscape studies for Compound A identified Form 1 as the most thermodynamically stable single component polymorphic form in the solid state.
  • the drug substance has been shown to convert to Group B (shown in Fig. 5), and multicomponent Group E (shown in Fig. 6) of Compound A which can form through multiple avenues including in the presence of formulation excipients (for example, if polysorbates are used instead of poloxamers) as well as aliphatic impurities.
  • D evelopment work conducted using wet bead milling process resulted in in-situ form conversion of drug substance from stable single component Form 1 to a Group B, with estimated form conversion of approximately 90% conversion if uncontrolled.
  • compositions disclosed herein limit polymorphic form conversion of the drug substance in the formulation and therefore offer enhanced control over solid state form in the drug product, with form conversion estimated to be less than 10%.
  • Polymorphic form In an embodiment, Compound A is present in the pharmaceutical composition as Form 1 of Compound A.
  • Form 1 is a crystalline form of Compound A.
  • Form 1 is the most thermodynamic single component form of Compound A.
  • crystalline Form 1 of Compound A is characterised by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 1.
  • XRPD X-ray powder diffraction
  • An XRPD pattern will be understood to comprise a diffraction angle (expressed in degrees 2 ) of “about” a value specified herein when the XRPD pattern comprises a diffraction angle within 0.3 degrees 2 of the specified value.
  • XRPD X-ray powder diffraction
  • An XRPD pattern that is “substantially in accordance” with that of Figure 1 provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of Figure 1. That is, the XRPD pattern may be identical to that of Figure 1 or more likely it may be somewhat different. Such an XRPD pattern may not necessarily show each of the lines of the diffraction pattern presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data.
  • a person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, the form disclosed herein by comparison of their XRPD patterns. For example, one skilled in the art can overlay an XRPD pattern of a sample of a different form or group of Compound A, with Figure 1 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern of Form 1 of Compound A. If the XRPD pattern is substantially in accordance with Figure 1, the sample form can be readily and accurately identified as being Form 1 of Compound A.
  • Form 1 is characterised by an XRPD pattern exhibiting at least X-ray peaks (2-theta values) in a powder diffractogram when measured using Cu K ⁇ 1 radiation at 1.54 Angstroms.
  • Form 1 is characterised by an XRPD pattern exhibiting reflections at 2 ⁇ angles when measured using Cu K ⁇ radiation at 1.54 Angstroms. As discussed above, a XRPD pattern of Form 1 is shown in Fig.1. The corresponding reflections and heights are provided in Table 1 below. Table 1 Pos.
  • Form 1 is characterised by an XRPD pattern exhibiting reflections at 2 ⁇ angles when measured using Cu K ⁇ radiation at 1.54 Angstroms. An XRPD pattern of Form 1 is shown in Fig.13.
  • Form 1 of Compound A is characterized by a DSC trace substantially in accordance with Figure 2 and/or a thermogravimetric analysis trace substantially in accordance with Figure 3.
  • the DSC thermogram of Form 1 of Compound A exhibits a single endotherm, with an onset temperature of about 121 °C.
  • the DSC thermogram of Form 1 of Compound A exhibits a single endotherm, with an onset temperature of 121 °C.
  • the DSC thermogram of Form 1 of Compound A does not exhibit a broad peak at about 40 to about 80 °C.
  • the DSC thermogram of Form 1 of Compound A does not exhibit a broad peak at 40 to 80 °C.
  • Form 1 is characterized by a Raman spectrum substantially in accordance with Fig 4.
  • Raman spectra was collected using a Kaiser Optical Systems Raman RXN2-785 controlled by iCRaman software v4.4.21. Resampling Intervals were: 1 cm-1; Channel 2.
  • the pharmaceutical composition comprises Form 1 in at least 90% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 90% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 95% polymorphic purity. In an embodiment, Form 1 of Compound A is in at least 99% polymorphic purity .
  • the pharmaceutical composition comprises Compound A, poloxamer P338 and NaCMC. In another embodiment, the pharmaceutical composition comprises Compound A, poloxamer P338 and PVP.
  • the pharmaceutical composition of the invention has a pH of between 4 and 5.
  • the pharmaceutical composition of the invention comprises a buffer.
  • buffer means a buffered solution that resists changes in pH by the action of its acid- base conjugate components.
  • the buffer may be any suitable buffer.
  • the buffer is an acetate buffer.
  • the acetate buffer is an acetate buffer solution comprising sodium acetate trihydrate and acetic acid or glacial acetic acid.
  • the buffer is a citrate buffer.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every 8 to 14 months. In another embodiment, the pharmaceutical composition is administered or self-administered intramuscularly via injection once every 12 months. In an embodiment, the pharmaceutical composition is intramuscularly administered in one injection during a visit with a healthcare professional. In an embodiment the pharmaceutical compositions of the present invention are administered in combination with other pharmaceutical compositions as a component of a multi drug treatment regimen. In an embodiment, the other pharmaceutical compositions are drugs which treat or prevent HIV infection. Marketed medicines are currently available to treat HIV infection. Medical Use In a third aspect, the present invention provides a pharmaceutical composition defined herein for use in the treatment or prevention of HIV infection. In one embodiment the use comprises administering the pharmaceutical composition parenterally.
  • the pharmaceutical composition is suitable for use as an injectable composition.
  • the use comprises administering the pharmaceutical composition intramuscularly.
  • the use comprises administering the pharmaceutical composition subcutaneously.
  • the use comprises administering the pharmaceutical composition parenterally.
  • the pharmaceutical composition is administered intramuscularly.
  • the pharmaceutical composition is administered subcutaneously.
  • the use comprises administering around 2 mL to around 10 mL of the pharmaceutical composition to a patient.
  • the use comprises administering about 300 mg to about 3000 mg of Compound A to the human.
  • the pharmaceutical composition is administered to a patient once every 4 to 18 months.
  • the pharmaceutical composition is administered to the human once every 6 months to once every 12 months.
  • the pharmaceutical composition is administered once every 6 months. In an embodiment, the pharmaceutical composition is administered once every 7 months. In an embodiment, the pharmaceutical composition is administered once every 8 months. In an embodiment, the pharmaceutical composition is administered once every 9 months. In an embodiment, the pharmaceutical composition is administered once every 10 months. In an embodiment, the pharmaceutical composition is administered once every 11 months. In an embodiment, the pharmaceutical composition is administered once every 12 months. In an embodiment, the pharmaceutical composition may be administered by any suitable means. In one embodiment, the pharmaceutical composition may be administered subcutaneously. In this embodiment, the pharmaceutical composition may be administered subcutaneously by another (e.g., by a healthcare professional) or may be self-administered by a patient. In this embodiment, the pharmaceutical composition may be administered subcutaneously via injection.
  • the pharmaceutical composition is administered subcutaneously via injection. In an embodiment, the pharmaceutical composition is administered or self-administered once monthly by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self- administered once every two months by subcutaneous injection. In another embodiment the pharmaceutical composition is administered intramuscularly via injection. In this embodiment, the pharmaceutical composition may be administered intramuscularly by another (e.g., by a healthcare professional) or may be self- administered by a patient. In an embodiment of the invention, the pharmaceutical composition is administered intramuscularly via injection once every 6 to 18 months. In another embodiment, the pharmaceutical composition is administered or self-administered intramuscularly via injection once every 8 to 14 months.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every 12 months.
  • the pharmaceutical composition is intramuscularly administered in one injection during a visit with a healthcare professional.
  • the pharmaceutical compositions of the present invention are administered in combination with other pharmaceutical compositions as a component of a multi drug treatment regimen.
  • the other pharmaceutical compositions are drugs which treat or prevent HIV infection. Marketed medicines are currently available to treat HIV infection.
  • Manufacture of a Medicament provides a pharmaceutical composition as described herein, in the manufacture of a medicament for treatment or prevention of HIV infection.
  • the medicament for treatment or prevention of HIV infection can be as described herein above.
  • the pharmaceutical composition according to embodiment 11, wherein the tonicity adjuster is mannitol.
  • the stabilizer is selected from the group consisting of sodium carboxymethylcellulose (NaCMC), polyvinylpyrrolidone (PVP), polyethylene glycol 3350 and polyethylene glycol 4000.
  • the stabilizer is sodium carboxymethylcellulose (NaCMC).
  • the weight ratio of NaCMC to Compound A is about 1:60.
  • composition according to embodiment 22 wherein mannitol is present at a weight ratio of mannitol to Compound A of about 1:8.5; poloxamer is present at a weight ratio of poloxamer to Compound A of about 1:30; and PVP is present at a weight ratio of PVP to Compound A of about 1:20.
  • Compound A is present in the form of particles having a mass median size (X50) of between (and including) 1 ⁇ m and 15 ⁇ m.
  • E26 The pharmaceutical composition according to embodiment 25, wherein the particles have a mass median size (X50) of between (and including) 1 ⁇ m and 15 ⁇ m.
  • Hunig's base (0.517 mL, 2.96 mmol) was then added, over approximately 15 seconds at room temperature over stirring. Upon adding the base (at 22.5 C), an exotherm was observed where the temperature increased to 30.5 C, within 3 minutes, then stabilized and decreased back to room temperature (22.5 C) within 5 minutes, all during which time the reaction mixture thickened up but remained a stirrable slurry. The suspension was then heated to 55 °C where all almost all solids dissolved, at 60°C a solution (light orange in color) formed. After cooling to room temperature (+21°C), 5 vol% of water (0.5 mL) was slowly added, at room temperature stirring was continued to induce crystallisation (for 15 minutes). This material was stirred for an additional hour.
  • Fig.9 s hows an XRPD of the material produced from the above method (top line), an XRPD of Group B of Compound A (middle line) and an XRPD of Form 1 of Compound A (bottom line), showing that the XRPD of the material produced from the above method is characteristic of Form 1.
  • Example 2 (3R,6S)-12- ⁇ [(2,4-difluorophenyl)methyl]carbamoyl ⁇ -6-methyl-8,11-dioxo-4- oxa-1,7-diazatricyclo[7.4.0.03,7]trideca-9,12-dien-10- octadecenoate
  • stearic acid 1.6 equiv
  • dicholoromethane 3.8 vol
  • Oxalyl chloride (1.76 equiv) was added slowly over no less than 3 h at 22-28 °C.
  • the reaction mixture was cooled to 17-23 °C at 0.1 °C/min, and then held at 17-23 °C for no less than 2 h.
  • the slurry was then filtered in a filter dryer, washed with the crystallization composition solvents (2.04 vol N-Methylpyrrolidone, 2.04 vol methanol, 0.51 vol toluene, and 0.41 vol water) and then filtered.
  • the wet cake was reslurried in methanol (12 vol) for at least 1 h and then filtered.
  • the wet cake was reslurried in 14 vol cyclohexane twice at 17-23 °C for at least 1 h each time and then filtered.
  • the slurry was sampled and nuclear magnetic resonance (NMR) analysis was used to confirm the stearic anhydride is ⁇ 6.0 wt%.
  • the wet cake was then washed with 7 vol cyclohexane and then filtered. Nitrogen was passed through the wet cake for not less than 1 h.
  • the product was then dried at 45-50 °C under vacuum.
  • the product (intermediate grade Compound A) was offloaded from a filter dryer once the loss on drying of a sample showed ⁇ 3.0% weight change after 10 minutes at 110 °C. Material that was synthesised was predominantly form 1 once dried. Yielding 19.9 kg of Compound A.
  • the slurry was held at 12-18 °C for no less than 4 h.
  • the slurry was then transferred to a filter dryer at 12-18 °C.
  • Cyclopentyl methyl ether (4 vol, filtered) was used to rinse the cold crystallizer, and the rinse was transferred to the filter dryer to wash the wet cake.
  • the cake wash was filtered.
  • Cyclohexane (10 vol, filtered) was charged to the filter dryer and then agitated to suspend. Cyclopentyl methyl ether (4 vol, filtered) was transferred to the filter dryer to wash the wet cake once more.
  • a sample of the wet cake in the filter dryer was taken and dried in a lab vacuum oven. XRPD, NMR, and DSC analysis were performed on the dried sample.
  • the DSC thermogram of Form 1 of Compound A was recorded on a TA Instruments Q100 Differential Scanning Calorimeter equipped with an autosampler is shown in Fig.2. The experiments were conducted using a heating rate of 10 °C/min in a crimped aluminum pan. The DSC thermogram of Form 1 of Compound A exhibits a single endotherm with an onset temperature of about 120 °C.
  • the thermogravimetric analysis (TGA) thermogram of Form 1 of Compound A was recorded on a TA Instruments Q500 Thermogravimetric Analyzer and is shown in Fig.3.
  • the XRPD of Form 1 of Compound A obtained after Example 2b is shown in Fig.10.
  • N ano size formulation dosed in group 3 was prepared dissolving 11.4 g of P338 in 204.0 g of WFI. Once the P338 was fully dispersed, 9.7 g of PS20, 8.9 g of PEG 3350, and 9.7 g of Mannitol was added to the solution and stirred until fully dissolved. The bulk vehicle was then filtered through a 0.22 ⁇ m filter. 75.0 g Compound A was then added to 187.5 g of filtered vehicle. The suspension was stirred for approximately three days before milling. The suspension was then milled for 45 minutes, reaching 200 nm at x50.
  • Table 8 API Particle size Group API Concentration distribution Formulation composition (mg/mL) ( ⁇ m) x10 x50 x90 2% Polysorbate 20, 2% 1 Cabotegravir 200.6 0.10 0.23 0.60 Polyethylene Glycol 3350, 3.5% Mannitol 1% Poloxamer 338, 0.5% 2 Compound A 300 2.0 4.1 9.5 Carboxymethycellulose sodium; 3.5% Mannitol 3.0 % Polysorbate-20, 3.5% 3 Compound A 300 0.17 0.46 3.9 Poloxamer 338, 2.73% Polyethylene Glycol 3350; 3% Mannitol Table 9 shows Cabotegravir plasma pharmacokinetics for the preclinical study and statistical analysis through t-test for several pharmacoKinetics (PK) parameters.
  • PK pharmacoKinetics
  • Lyophilized Group 2 is > 95% Form 1 of Compound A.
  • Table 10 Particle Viscosity API size (cP) Group API Concentration distribution Formulation composition (mg/mL) ( ⁇ m) X10X50X90 1% Poloxamer 338, 0.5% 28.0 1 Compound A 300 2.0 4.1 9.5 Carboxymethycellulose sodium; 3.5% Mannitol Comp 1% Poloxamer 338, 1.5% 7.5 2 ound A 300 2.1 4.511.8 Polyvinylpyrrolidone; 3.5% Mannitol Table 11 shows Cabotegravir plasma concentrations at different time points post- administration, and statistical analysis through t-test for plasma concentrations at each time point.
  • Example 7 Comparison of intramuscular (IM) and subcutaneous (SC) administration This example examines outcomes from selected groups to understand impact of route of administration (Intramuscular and Subcutaneous) on PK performance of Compound A Lyophile formulation.
  • Lyophile formulation of Compound A was dosed subcutaneously (SC) and intramuscularly (IM) in Sprague Dawley male rats at 75mg/Kg of Compound A with a single bolus injection in the thigh (hindlimb) and into the right interscapular region, respectively.
  • the lyophilized product was reconstituted with water for injection at 300mg/mL Compound A and administered IM or SC through a single injection at target dose of 45mg/kg of Cabotegravir equivalents (corresponding to 75mg/Kg effective Compound A dose), in each rat. Details of the formulation are described in Table 12.
  • Table 12 Particle size API distribution Formulation composition Group API Concentration ( ⁇ m) and route of (mg/mL) x10 x50 x90 administration 1% Poloxamer 338, 0.5% 1 Compound A 300 2.0 4.1 9.5 Carboxymethycellulose s odium; 3.5% Mannitol – IM 1% Poloxamer 338, 0.5% 2 Compound A 300 2.0 4.1 9.5 Carboxymethycellulose sodium; 3.5% Mannitol – SC Table 13 shows Cabotegravir plasma concentrations at different time points post- administration and statistical analysis through t-test for plasma concentrations at each time point.
  • Example 8 Compound A Pharmacokinetics in Non-Human Primates (NHP)
  • NHP Non-Human Primates
  • Both lyophilized products were reconstituted with water for injection at 300mg/mL Compound A and were administered SC through a single injection at target dose of 24mg/Kg or 45mg/Kg of Cabotegravir equivalents (corresponding to 40mg/Kg or 75mg/Kg effective Compound A dose), in each rat.
  • target dose 24mg/Kg or 45mg/Kg of Cabotegravir equivalents (corresponding to 40mg/Kg or 75mg/Kg effective Compound A dose)
  • Table 14 Details of the formulation compositions, Compound A particle size, and in vivo study groups and doses are described in Table 14.
  • Table 14 Compound A Particle size Dose Group Concentration distribution ( ⁇ m) Formulation composition (mg/Kg) (mg/mL) x10 x50 x90 1.0% Poloxamer-338, 0.5% Sodium 1 300 2.0 4.1 9.5 Carboxymethylcellulose; 3.5% 40 Mannitol 1.0% Poloxamer-338, 0.5% Sodium 2 300 2.0 4.1 9.5 Carboxymethylcellulose; 3.5% 75 Mannitol 1.0% Poloxamer-338, 1.5% 3 300 2.1 4.5 11.8 Polyvinylpyrrolidone K12; 3.5% 40 Mannitol 1.0% Poloxamer-338, 1.5% 4 300 2.1 4.5 11.8 Polyvinylpyrrolidone K12; 3.5% 75 Mannitol Figure 12 shows the pharmacokinetics time course for Cabotegravir plasma concentrations post-administration.
  • Figure 4A and 4B highlight the dose-response for the Sodium Carboxymethylcellulose and for the Polyvinylpyrrolidone K12 formulations, respectively.
  • the PK profiles reported in figure 4 indicate a steady release of compound A and sustained plasma concentrations for 6 months post-injections for both formulations and both doses, indicating potential for a twice-yearly dosing regimen.
  • Example 9 Pharmaceutical Compositions Table 15 I ngredient Concentration measured pre-lyophilization and pre- reconstitution (mg/mL) C ompound A, micronized 300.0 PVP K12 15.0 Poloxamer 338 10.0 Mannitol 35.0 Citric acid monohydrate 0.75 Sodium citrate dihydrate 1.75
  • Table 15 shows an exemplary pharmaceutical composition of the invention which was made using the following method: A formulation vehicle was prepared by dissolving 33.3 g Poloxamer 338 (BASF, Kolliphor P338) in about 2323 g water for injection (WFI).
  • the suspension was homogenized for up to 11 minutes at 15 Hz rpm and up to 109 minutes at 40 Hz.
  • the suspension was filtered, deaerated (if needed) and filled into vials.
  • the product was lyophilized by freezing at -45°C for 185 minutes, annealing at - 18°C for 207 minutes, refreezing at -45°C for 207 minutes (each transition at a ramp rate of +/- 1°C/min), primary drying at -10°C (ramp rate: 0.175°C/min) for approximately 28 hours at approximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.145°C/min) for approximately 34 hours at approximately 150 mTorr.
  • the lyophilized vials were backflushed with nitrogen to about 650 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25kGy.
  • the formulation was reconstituted with WFI and briefly shaken to resuspend prior to administration.
  • Table 16 I ngredient Concentration post reconstitution (mg/mL) C ompound A, micronized 300 Povidone 15 Poloxamer 338 10 Mannitol 35 Citric acid monohydrate 0.75 Sodium citrate dihydrate 1.75
  • Table 16 shows a lyophilized suspension reconstituted at drug concentration of 300 mg/mL.

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Abstract

La présente invention concerne la prévention et le traitement du virus de l'immunodéficience humaine (VIH). En particulier, l'invention concerne une composition pharmaceutique comprenant un promédicament de cabotégravir et un poloxamère.
PCT/US2024/059277 2023-12-12 2024-12-10 Compositions pharmaceutiques Pending WO2025128498A1 (fr)

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