WO2025068743A1 - Composition pharmaceutique de cabotégravir - Google Patents

Composition pharmaceutique de cabotégravir Download PDF

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Publication number
WO2025068743A1
WO2025068743A1 PCT/IB2023/059640 IB2023059640W WO2025068743A1 WO 2025068743 A1 WO2025068743 A1 WO 2025068743A1 IB 2023059640 W IB2023059640 W IB 2023059640W WO 2025068743 A1 WO2025068743 A1 WO 2025068743A1
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Prior art keywords
pharmaceutical composition
cabotegravir
composition according
equal
once
Prior art date
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PCT/IB2023/059640
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English (en)
Inventor
Kevin Sam Chu
Clinton Frank Jones
Deepak Balkrishna Mundhra
Rennan Pan
Austin Philip
Simone ALIDORI
Manish Kumar Gupta
Pratik SAHA
Pranjal Sameer Taskar
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Viiv Healthcare Uk No3 Ltd
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Viiv Healthcare Uk No3 Ltd
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Priority to AU2023466962A priority Critical patent/AU2023466962A1/en
Priority to PCT/IB2023/059640 priority patent/WO2025068743A1/fr
Priority to US18/895,498 priority patent/US20250099464A1/en
Priority to PCT/IB2024/059356 priority patent/WO2025068912A1/fr
Priority to AU2024353051A priority patent/AU2024353051A1/en
Priority to TW113136400A priority patent/TW202529766A/zh
Priority to ARP240102571A priority patent/AR133924A1/es
Priority to IL327150A priority patent/IL327150A/en
Priority to CN202480061613.8A priority patent/CN121909019A/zh
Publication of WO2025068743A1 publication Critical patent/WO2025068743A1/fr
Priority to US19/339,458 priority patent/US20260021091A1/en
Anticipated expiration legal-status Critical
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
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the invention relates to Human Immunodeficiency Virus (HIV) treatment or prevention.
  • HIV Human Immunodeficiency Virus
  • the invention relates to long-acting treatment or prevention of HIV.
  • long-acting parenteral pharmaceuticals have been established in clinical practice for decades, notably in the areas of contraception, anti-psychotics, and opiate addiction. More recently, long-acting parenteral pharmaceuticals have been proposed as a way of overcoming the non-compliance problem with HIV treatment regimens.
  • Long-acting injectable formulations some of which are approved and marketed, such as CABENUVA®, have demonstrated prolonged exposures (> 30 days) following injection, enabling dosing at once-monthly and bimonthly intervals.
  • an anti-HIV drug may be used for prevention of HIV (e.g., pre-exposure prophylaxis, or PrEP)
  • achieving an injectable suspension with a high concentration of anti-HIV drug that provides a longer-acting effect could increase adherence due to less frequent dosing.
  • high concentration suspensions typically suffer from difficulty in resuspension and particle size growth.
  • Lyophilized formulations offer several advantages over ready-to-use suspensions - namely, avoiding resuspension difficulties or failures, maintaining product stability, and overcoming scale-up issues.
  • a pharmaceutical composition comprising: cabotegravir; a wetting agent; a stabilizer; and a tonicity adjuster; wherein cabotegravir is present in the form of particles having a mass median diameter (X50) of between (and including) 2.5 pm and 10 pm.
  • a) treating HIV in a human in need thereof comprising administering to said human a therapeutically effective amount of the pharmaceutical composition as defined herein; and (b) preventing HIV in a human comprising administering to said human an effective amount of the pharmaceutical composition as defined herein.
  • a pharmaceutical composition as defined herein for use in the treatment or prevention of HIV.
  • kits comprising cabotegravir, wherein cabotegravir is present in the form of particles having a mass median diameter (X50) between (and including) 2.5 pm and 10 pm; a wetting agent; a stabilizer; and a tonicity adjuster.
  • X50 mass median diameter
  • compositions of the invention may be advantageous in a number of respects.
  • the pharmaceutical compositions of the invention allow a high concentration of larger-sized cabotegravir particles to be present in the composition.
  • the larger-size particles of the invention in turn, favorably modify absorption kinetics, thus permitting ultra long-acting therapy, which allows for longer time intervals between dosing compared to existing therapies. This may improve patient compliance, reducing likelihood of drug-resistant HIV strains.
  • Compositions of the invention may also lower injection site reactions therefore improving patient experience.
  • lyophilized compositions of the invention minimize resuspension failures and maintain product stability and syringeability. DESCRIPTION OF DRAWINGS/FIGURES
  • FIGs. 1 and 2 are flowcharts for exemplary processes for manufacturing a lyophilized composition as described herein.
  • 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 tertbutyl), pentyl, and hexyl.
  • alkyl When the term “alkyl” is used in combination with other substituent groups, such as "halo(Ci-4)alkyl” and “hydroxy(Ci-4)alkyl” the term “alkyl” is intended to encompass a divalent straight or branched chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.
  • alkylene refers to a divalent radical derived from a straight or branched, saturated hydrocarbon group of, for example, 1 to 3 carbon atoms (C1-3 alkylene).
  • exemplary groups include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, and - CH 2 CH 2 CH 2 -.
  • cycloalkyl refers to a non-aromatic, saturated, monocyclic, hydrocarbon ring containing the specified number of carbon atoms.
  • cycloalkyl may contain 3 to 8 carbon atoms, i.e., C3-8 cycloalkyl.
  • Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • heteroaryl refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen and sulfur.
  • Exemplary groups include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1 ,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benz
  • Examples of 5-membered “heteroaryl” groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl.
  • Examples of 6-membered “heteroaryl” groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl.
  • 6,6-fused “heteroaryl” groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7- naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl.
  • 6,5-fused “heteroaryl” groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.
  • halogen and "halo" represent chloro, fluoro, bromo, or iodo substituents.
  • a group may be unsubstituted or substituted with one or more substituents as defined herein.
  • substituted in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • member atoms refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group attached to a chain or ring are not member atoms in the chain or ring.
  • 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.
  • lyophilization also known as 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.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley-VCH/VHCA, 2011 (see www(dot)wiley(dot)com/WileyCDA/WileyTitle/productCd-3906390519.html).
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • Suitable pharmaceutically acceptable salts of the invention include base addition salts.
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (W-benzylphenethylamine), benzathine (N,N- dibenzylethylenediamine), b/'s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-pchlorobenzyl-2-pyrrolidine-1 ’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (W-methylglucamine), piperazine, piperidine
  • composition means a composition that is suitable for pharmaceutical use.
  • prevention refers to avoidance of the stated disease in a subject who is not suffering from the stated disease.
  • 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.
  • 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.
  • treatment refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression, invasion, or spread of the condition, and reducing or delaying the recurrence of the condition in a previously afflicted subject.
  • diameter refers to a spherical volume equivalent diameter
  • CD4 binding site (CD4bs) binding protein refers to antibodies and other protein constructs, such as domains, that are capable of binding to the CD4 binding site of the HIV envelope glycoprotein, gp120.
  • CD4bs binding protein CD4bs binding domain
  • antigen binding protein is used interchangeably herein. This does not include the natural cognate ligand or receptor.
  • monoclonal antibodies and antigen binding fragments thereof that bind to the CD4 binding site on gp120 and neutralize HIV-1 are provided herein.
  • the CD4bs binding protein includes N6 and N6LS, or an antigen binding fragment thereof.
  • antibody in the broadest sense refers to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulfide linked Fv, single chain Fv, disulfide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136).
  • DAB domain antibody
  • full antibody or immunoglobulin As used interchangeably herein, the terms “full antibody or immunoglobulin,” “whole antibody or immunoglobulin,” and “intact antibody or immunoglobulin” refer to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 Daltons.
  • An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulfide bonds. This H2L2 structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallizable fragment.
  • the Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light).
  • the Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway.
  • the five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, s and 6 respectively, each heavy chain can pair with either a K or A light chain.
  • Fully human antibodies can be obtained using a variety of methods, for example using yeast-based libraries or transgenic animals (e.g., mice) that are capable of producing repertoires of human antibodies.
  • yeast-based libraries or transgenic animals e.g., mice
  • Yeast presenting human antibodies on their surface that bind to an antigen of interest can be selected using FACS (Fluorescence- Activated Cell Sorting) based methods or by capture on beads using labeled antigens.
  • Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterized for desired properties such as affinity, developability and selectivity.
  • Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non-immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an Avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301 ) or an EGF domain.
  • a suitable non-immunoglobulin protein scaffold or skeleton such as an affibody, a SpA scaffold, an LDL receptor class A domain, an Avimer (see, e.g., U.S. Patent Application Publication Nos. 2005/0053973, 2005/0089932, 2005/0164301 ) or an EGF domain.
  • bnAb narrowly neutralizing antibody
  • Env HIV envelope glycoprotein
  • bnAb is defined as an antibody which inhibits viral attachment and cell entry via binding to the HIV envelope glycoprotein (Env) (e.g., gp160, gp120, gp41), as a non-limiting example, by a 50% inhibition of infection in vitro, in more than 50%, 60%, 70%, 80%, 90%, 95%, 99% or greater, of a large panel of (greater than 100) HIV-1 envelope pseudotyped viruses and viral isolates.
  • Env HIV envelope glycoprotein
  • a large panel of (greater than 100) HIV-1 envelope pseudotyped viruses and viral isolates See, e.g., US Published Patent Application No. 20120121597; Burton et al., Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. Annu Rev Immunol. 2016 May 20; 34:635-59.
  • CDRs are defined as the complementarity determining region amino acid sequences of an antigen binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, “CDRs” as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.
  • variable domain sequences and variable domain regions within full-length antigen binding sequences are numbered according to the Kabat numbering convention.
  • the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used in the Examples follow the Kabat numbering convention.
  • Kabat et al. Sequences of Proteins of Immunological Interest, 4th Ed., U.S. Department of Health and Human Services, National Institutes of Health (1987).
  • Table 1 represents one definition using each numbering convention for each CDR or binding unit.
  • the Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequence. It should be noted that some of the CDR definitions may vary depending on the individual publication used.
  • antibody half-life refers to the time required for the serum concentration of an antigen binding protein to reach half of its original value.
  • the serum half-life of proteins can be measured by pharmacokinetic studies according to the method described by Kim et al., 1994, Eur. J. of Immuno. 24: 542-548. According to this method, radio-labelled protein is injected intravenously into mice and its plasma concentration is periodically measured as a function of time, for example, at about 3 minutes to about 72 hours after the injection. Other methods for pharmacokinetic analysis and determination of the serum half-life of a molecule will be familiar to those skilled in the art.
  • Antigen binding proteins of the present invention may have amino acid modifications that increase the affinity of the constant domain or fragment thereof for FcRn. Increasing the serum half-life of therapeutic and diagnostic IgG antibodies and other bioactive molecules has many benefits including reducing the amount and/or frequency of dosing of these molecules.
  • an antigen binding protein of the invention comprises all or a portion (an FcRn binding portion) of an IgG constant domain having one or more of the following amino acid modifications.
  • M252Y/S254T/T256E (commonly referred to as “YTE” mutations) and M428L/N434S (commonly referred to as “LS” mutations) increase FcRn binding at pH 6.0 (Wang et al. 2018).
  • Serum half-life can also be enhanced by T250Q/M428L, V259I/V308F/M428L, N434A, and T307A/E380A/N434A mutations (with reference to lgG1 and Kabat numbering) (Monnet et al.).
  • H433K and N434F mutations commonly referred to as “HN” or “NHance” mutations
  • HN H433K and N434F mutations
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: cabotegravir; a wetting agent; a stabilizer; and a tonicity adjuster; wherein cabotegravir is present in the form of particles having a mass median diameter (X50) of between (and including) 2.5 pm and 10 pm.
  • an embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising cabotegravir having a mass median diameter (X50) of between (and including) 2.5 pm and 10 pm; polysorbate 80; sodium CMC; and mannitol.
  • the pharmaceutical compositions described herein may be administered by any appropriate route.
  • the compositions are administered parenterally (including subcutaneously, intramuscularly, intravenously, or intradermally).
  • the composition is administered intramuscularly.
  • the composition is administered subcutaneously.
  • Cabotegravir W-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo- 2, 3, 5,1 ,11 ,11a hexahydro(1 ,3)oxazolo(3,2-a)pyrido(1 ,2-d)pyrazine-8-carboxamide
  • 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 both in oral and parenteral dosage forms, see for instance, Margolis DA, Brinson CC, Eron J J, 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 + Rilpivirine as Long-Acting Maintenance Therapy LATTE-2 Week 48 Results, 21 st International AIDS Conference; July 18-22, 2016; Durban, South Africa, Abstract THAB0206LB.
  • Levin Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2016, and Markowitz M, Frank I, Grant R, et al.
  • ECLAIR Phase 2A Safety and PK Study of Cabotegravir LA in HIV- Uninfected Men. Abstract presented at 23 rd CROI; February 22-25, 2016; Boston, MA.
  • Cabotegravir is represented by formula (I):
  • cabotegravir is present in the pharmaceutical composition as the free acid.
  • the pharmaceutical composition of the present invention comprises particles of crystalline cabotegravir.
  • cabotegravir particles of the pharmaceutical composition have an X50 value greater than or equal to 2.5 pm and less than or equal to 10 pm (i.e., 2.5 pm ⁇ X50 ⁇ 10 pm).
  • Particle size distribution may be measured by any suitable method, for example, by laser diffraction as described in the Examples section herein.
  • the larger drug particle size favorably modifies absorption kinetics, thus permitting ultra long-acting therapy.
  • the larger drug particle size favorably reduces injection site reactions, therefore improving patient experience.
  • an injectable microsuspension formulation may provide an additional sustained therapeutic effect over commercial nanosuspension formulations due to a reduced drug substance specific surface area resulting in a slower drug depot dissolution.
  • the prolonged dissolution may enable further enhancement to patient compliance and treatment effectiveness when compared to commercial nanosuspension formulations.
  • Highly potent hydrophobic compounds like cabotegravir may benefit from an increased specific surface area via size reduction to increase drug dissolution in vivo.
  • optimization of particle size of these compounds may influence resultant pharmacokinetic performance — smaller crystal sizes of active substances may dissolve more rapidly than larger crystal sizes due to the increased relative surface area.
  • suspensions of larger average particle sizes may exhibit an extended and more controlled release profile from the injected depot when compared to suspensions of smaller average particle sizes.
  • the pharmaceutical composition contains about 100 to about 800 mg/mL of cabotegravir. In a further embodiment, the pharmaceutical composition contains about 200 mg/mL to about 700 mg/mL, from about 300 mg/mL to about 650 mg/mL, from about 400 mg/mL to about 600 mg/mL, about 400, about 500, or about 533 mg/mL of cabotegravir. In an embodiment the pharmaceutical composition contains about 400 mg/mL of cabotegravir. In a further embodiment, the pharmaceutical composition contains about 533 mg/mL of cabotegravir.
  • the pharmaceutical composition contains cabotegravir in an amount between about 300 mg and about 4800 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount between about 350 mg and about 4000 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount between about 375 mg and about 3200 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount between about 400 mg and about 2000 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about
  • the pharmaceutical composition contains cabotegravir in an amount of about 800 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 1600 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 2665 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 3200 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 4000 mg. In an embodiment, the pharmaceutical composition contains cabotegravir in an amount of about 4800 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. In addition, 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.
  • surfactants include, but are not limited to, polysorbate 20 (Tween-20), polysorbate 80 (Tween-80), sorbitan monolaurate (Span-20), sorbitan monooleate (Span-80), poloxamer 188 (Kolliphor P188), poloxamer 338 (Kolliphor P338), and poloxamer 407 (Kolliphor P407).
  • the pharmaceutical composition of the invention comprises polysorbate 80 (PS80) as the wetting agent.
  • PS80 (IUPAC name: polyoxyethylene (20) sorbitan monooleate; CAS No. 9005- 65-6) is a nonionic surfactant and emulsifier derived from polyethoxylated sorbitan and oleic acid.
  • the hydrophilic groups in PS80 are polyethers also known as polyoxyethylene groups, which are polymers of ethylene oxide.
  • polysorbate e.g., “polysorbate 80” refers to the lipophilic group, in this case, the oleic acid.
  • the structure of PS80 is provided by formula (II):
  • the inventors have surprisingly found that the use of PS80 in a lyophilized microsuspension resulted in superior in vivo performance, tolerability, and increased flexibility in manufacturability.
  • the pharmaceutical composition contains from about 0.1 mg/mL to about 150 mg/mL of the wetting agent. In a further embodiment, the pharmaceutical composition contains from about 1 mg/mL to about 80 mg/mL, from about 2 mg/mL to about 40 mg/mL, or from about 2.5 mg/mL to about 5 mg/mL of the wetting agent.
  • the pharmaceutical composition contains about, in mg/mL, 2.0,
  • the pharmaceutical composition contains about 3.0 mg/mL of the wetting agent. In another embodiment, the pharmaceutical composition contains about 4.0 mg/mL of the wetting agent.
  • the pharmaceutical composition contains about 0.1 mg to about 900 mg of the wetting agent. In another embodiment, the pharmaceutical composition contains about 0.5 mg to about 200 mg of the wetting agent. In another embodiment, the pharmaceutical composition comprises about 1 .0 mg to about 100 mg of the wetting agent. In another embodiment, the pharmaceutical composition contains about 2.0 mg to about 50 mg of the wetting agent. In another embodiment, the pharmaceutical composition contains about, in mg, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 ,
  • the pharmaceutical composition comprises about 5.9 mg of the wetting agent. In an embodiment, the pharmaceutical composition comprises about 8.0 mg of the wetting agent.
  • a weight ratio of the wetting agent to cabotegravir is in a range of from 1 :10 to 1 :400. In another embodiment, the weight ratio of the wetting agent to cabotegravir is in a range of from 1 :50 to 1 :200. In another embodiment, the weight ratio of the wetting agent to cabotegravir is in a range of from 1 :100 to 1 :150.
  • the weight ratio of the wetting agent to cabotegravir is about 1 :100, about 1 :101 , about 1 :102, about 1 :103, about 1 :104, about 1 :105, about 1 :106, about 1 :107, about 1 :108, about 1 :109, about 1 :110, about 1 :111 , about 1 :112, about 1 :113, about 1 :114, about 1 :115, about 1 :116, about 1 :117, about 1 :118, about 1 :119, about 1 :120, about 1 :121 , about 1 :122, about 1 :123, about 1 :124, about 1 :125, about 1 :126, about 1 :127, about 1 :128, about 1 :129, about 1 :130, about 1 :131 , about 1 :132, about 1 :133, about 1 :134, about 1 :135, about 1 :136, about 1 :137, about 1 :
  • 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, povidone K12, and povidone K17.
  • the pharmaceutical composition of the invention comprises sodium CMC as the stabilizer.
  • the pharmaceutical composition contains about 0.1 to about 150 mg/mL of the stabilizer. In a further embodiment, 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 3 mg/mL to about 10 mg/mL of the stabilizer.
  • the pharmaceutical composition contains about, in mg/mL, 3.0,
  • the pharmaceutical composition contains about 3.7 mg/mL of the stabilizer. In another embodiment, the pharmaceutical composition contains about 5.0 mg/mL of the stabilizer. In an embodiment, the pharmaceutical composition contains about 0.1 mg to about 300 mg of the stabilizer. In another embodiment, the pharmaceutical composition contains about 1 .0 mg to about 200 mg of the stabilizer. In another embodiment, the pharmaceutical composition comprises about 2.0 mg to about 100 mg of the stabilizer. In another embodiment, the pharmaceutical composition contains about 4.0 mg to about 50 mg of the stabilizer.
  • the pharmaceutical composition contains about, in mg, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6,
  • the pharmaceutical composition comprises about 7.4 mg of the stabilizer. In an embodiment, the pharmaceutical composition comprises about 10.0 mg of the stabilizer.
  • a weight ratio of the stabilizer to cabotegravir is in a range of from 1 :10 to 1 :400. In another embodiment, the weight ratio of the stabilizer to cabotegravir is in a range of from 1 :40 to 1 :200. In another embodiment, the weight ratio of the stabilizer to cabotegravir is in a range of from 1 :70 to 1 :120.
  • the weight ratio of the stabilizer to cabotegravir is about 1 :70, about 1 :71 , about 1 :72, about 1 :73, about 1 :74, about 1 :75, about 1 :76, about 1 :77, about 1 :78, about 1 :79, about 1 :80, about 1 :81 , about 1 :82, about 1 :83, about 1 :84, about 1 :85, about 1 :86, about 1 :87, about 1 :88, about 1 :89, about 1 :90, about 1 :91 , about 1 :92, about 1 :93, about 1 :94, about 1 :95, about 1 :96, about 1 :97, about 1 :98, about 1 :99, about 1 :100, about 1 :101 , about 1 :102, about 1 :103, about 1 :104, about 1 :105, about 1 :106, about 1 :107, about 1 :108
  • Tonicity adjusters act to provide and maintain a stable tonicity for the pharmaceutical composition disclosed herein.
  • tonicity adjusters also function as a non-aqueous solvent, a solubilizer, and/or a stabilizer.
  • tonicity adjusters may be used at concentrations higher than needed for tonicity if their primary purpose is stabilization or may be used at concentrations higher than needed for stabilization if their primary purpose is tonicity adjustment.
  • the tonicity adjuster is a pharmaceutically acceptable inorganic chloride, e.g., potassium chloride, sodium chloride, magnesium chloride or calcium chloride.
  • 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, polygalacturonic acid, galacturonic acid, polyvinylpyrrolidine (PVP), for example, PEG 300, PEG 400, PEG 3350, PEG 6000, or PEG 8000.
  • 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, and polyvinylpyrrolidone, and 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 to about 250 mg/mL of the tonicity adjuster. In a further embodiment, the pharmaceutical composition contains about 1 mg/mL to about 150 mg/mL, from about 10 mg/mL to about 125 mg/mL, from about 15 mg/mL to about 50 mg/mL, or from about 20 mg/mL to about 40 mg/mL of the tonicity adjuster.
  • the pharmaceutical composition contains about, in mg/mL, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1 , 21.2, 21.3, 21.4, 21.5,
  • the pharmaceutical composition contains about 25.9 mg/mL of the tonicity adjuster. In another embodiment, the pharmaceutical composition contains about 35.0 mg/mL of the tonicity adjuster.
  • the pharmaceutical composition contains about 0.1 mg to about 400 mg of the tonicity adjuster. In another embodiment, the pharmaceutical composition contains about 1 .0 mg to about 300 mg of the tonicity adjuster. In another embodiment, the pharmaceutical composition comprises about 10 mg to about 100 mg of the tonicity adjuster. In another embodiment, the pharmaceutical composition contains about 35 mg to about 80 mg of the tonicity adjuster. In another embodiment, the pharmaceutical composition contains about, in mg, 35.0, 35.1 , 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8,
  • the pharmaceutical composition comprises about 51 .8 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 70 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 105 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 140 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 175 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 210 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 245 mg of the tonicity adjuster. In an embodiment, the pharmaceutical composition comprises about 280 mg of the tonicity adjuster.
  • a weight ratio of the tonicity adjuster to cabotegravir is in a range of from 1 :1 to 1 :100. In another embodiment, the 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 cabotegravir is in a range of from 1 :8 to 1 :25.
  • the weight ratio of the tonicity adjuster to cabotegravir is about 1 :8, about 1 :9, about 1 :10, about 1 :11 , about 1 :12, about 1 :13, about 1 :14, about 1 :15, about 1 :16, about 1 :17, about 1 :18, about 1 :19, about 1 :20, about 1 :21 , about 1 :22, about 1 :23, about 1 :24, or about 1 :25.
  • the weight ratio of the tonicity adjuster to cabotegravir is about 1 :11.
  • the weight ratio of the tonicity adjuster to cabotegravir is about 1 :15.
  • Dissolution properties of the pharmaceutical composition are affected, inter alia, by particle size and particle size distribution of the active pharmaceutical ingredient (i.e., cabotegravir).
  • X50 is the cabotegravir particle diameter, in microns, at which 50% by volume of the particles of cabotegravir have a smaller diameter and 50% by volume have a larger diameter, also known as the mass median diameter (MMD) or the median of the particle size distribution by volume.
  • MMD mass median diameter
  • X90 is the cabotegravir particle diameter, in microns, at which 90% by volume of the cabotegravir particles have a smaller diameter and 10% by volume have a larger diameter.
  • X10 is the cabotegravir particle diameter, in microns, at which 10% by volume of the cabotegravir particles have a smaller diameter and 90% by volume have a larger diameter.
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles have a particle diameter less than or equal to 25 gm (i.e., X90 is 25 gm).
  • cabotegravir particles of the pharmaceutical composition have an X90 value greater than or equal to 5 gm and less than or equal to 25 gm (i.e., 5 gm ⁇ X90 ⁇ 25 gm).
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles have a particle diameter less than or equal to 20 gm (i.e., X90 is 20 gm).
  • cabotegravir particles of the pharmaceutical composition have an X90 value greater than or equal to 6 gm and less than or equal to 20 gm (i.e., 6 gm ⁇ X90 ⁇ 20 gm).
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles have a particle diameter less than or equal to 18 gm (i.e., X90 is 18 gm).
  • cabotegravir particles of the pharmaceutical composition have an X90 value greater than or equal to 7 gm and less than or equal to 18 gm (i.e., 7 gm ⁇ X90 ⁇ 18 gm).
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles (X90) have a particle diameter smaller than or equal to 7.0 gm, 7.1 gm, 7.2 gm, 7.3 gm, 7.4 gm, 7.5 gm, 7.6 gm, 7.7 gm, 7.8 pm, 7.9 pm, 8.0 pm, 8.1 pm, 8.2 pm, 8.3 pm, 8.4 pm, 8.5 pm, 8.6 pm, 8.7 pm, 8.8 pm,
  • the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles (X90) have a particle diameter smaller than or equal to 9 pm (/'.e., X90 is 9 pm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles (X90) have a particle diameter smaller than or equal to 14 pm (/'.e., X90 is 14 pm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 90% of the cabotegravir particles (X90) have a particle diameter smaller than or equal to 17 pm (/'.e., X90 is 17 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles have a particle diameter less than or equal to 10 pm (/'.e., X50 is 10 pm).
  • cabotegravir particles of the pharmaceutical composition have an X50 value greater than or equal to 2.5 pm and less than or equal to 10 pm (/'.e., 2.5 pm ⁇ X50 ⁇ 10 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles have a particle diameter less than or equal to 8.5 pm (/'.e., X50 is 8.5 pm).
  • cabotegravir particles of the pharmaceutical composition have an X50 value greater than or equal to 3 pm and less than or equal to 8.5 pm (/'.e., 3 pm ⁇ X50 ⁇ 8.5 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles have a particle diameter less than or equal to 8 pm (/'.e., X50 is 8 pm).
  • cabotegravir particles of the pharmaceutical composition have an X50 value greater than or equal to 3.5 pm and less than or equal to 8 pm (/'.e., 3.5 pm ⁇ X50 ⁇ 8 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles (X50) have a particle diameter smaller than or equal to 3.0 pm, 3.1 pm, 3.2 pm, 3.3 pm, 3.4 pm, 3.5 pm, 3.6 pm, 3.7 pm, 3.8 pm, 3.9 pm, 4.0 pm, 4.1 pm, 4.2 pm, 4.3 pm, 4.4 pm, 4.5 pm, 4.6 pm, 4.7 pm, 4.8 pm,
  • the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles (X50) have a particle diameter smaller than or equal to 4 pm (/'.e., X50 is 4 pm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 50% of the cabotegravir particles (X50) have a particle diameter smaller than or equal to 6 pm (/'.e., X50 is 6 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles have a particle diameter smaller than or equal to 4 pm (/'.e., X10 is 4 pm).
  • cabotegravir particles of the pharmaceutical composition have an X10 value greater than or equal to 0.5 pm and less than or equal to 4 pm (/'.e., 0.5 pm ⁇ X10 ⁇ 4 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles have a particle diameter less than or equal to 3.5 pm.
  • cabotegravir particles of the pharmaceutical composition have an X10 value greater than or equal to 1 pm and less than or equal to 3.5 pm (/'.e., 1 pm ⁇ X10 ⁇ 3.5 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles have a particle diameter less than or equal to 3 pm.
  • cabotegravir particles of the pharmaceutical composition have an X10 value greater than or equal to 1 .5 pm and less than or equal to 3 pm (/'.e., 1 .5 pm ⁇ X10 ⁇ 3 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles (X10) have a particle diameter smaller than or equal to 1 .0 pm, 1.1 pm, 1 .2 pm, 1 .3 pm, 1 .4 pm, 1 .5 pm, 1.6 pm, 1 .7 pm,
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles (X10) have a particle diameter smaller than or equal to 1 .7 pm (/'.e., X10 is 1 .7 pm). In another embodiment, the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles (X10) have a particle diameter smaller than or equal to 2.2 pm (/'.e., X10 is 2.2 pm).
  • the pharmaceutical composition has a particle size distribution by volume such that 10% of the cabotegravir particles (X10) have a particle diameter smaller than or equal to 2.6 pm (/'.e., X10 is 2.6 pm).
  • the value X90 refers to the 90% value of the volume distribution measured using a laser diffractometer.
  • the X90 value denotes the particle size below which 90% of the quantity of particles is found based on the volume distribution.
  • the value X50 refers to the 50% value (median) of the volume distribution measured using a laser diffractometer.
  • the X50 value denotes the particle size below which 50% of the quantity of particles is found based on the volume distribution.
  • the value X10 refers to the 10% value of the volume distribution measured using a laser diffractometer.
  • the X10 value denotes the particle size below which 10% of the quantity of particles is found based on the volume distribution.
  • all X90, X50, and X10 values described herein are by volume and determined by laser diffraction method.
  • the laser diffraction method is sensitive to the volume of a particle and provides a volume-average particle size, which is equivalent to the weight-average particle size if the density is constant. It will be apparent to those skilled in the art that the results of the particle size distribution determination by one technique can be correlated with that from another technique, for example on an empirical basis by routine experimentation. Alternatively, particle size distribution can be determined by microscopy, in particular electron microscopy or scanning electron microscopy.
  • aqueous pharmaceutical suspensions For aqueous pharmaceutical suspensions, one pathway of long-term failure is irreversible product settling that creates an inability for these systems to be easily resuspended over the expected product shelf-life. In these cases of physical instability, drug content may not be uniform in the vial at time of administration, which may lead to inconsistent product dosing into patients.
  • the physical stability of suspensions can be greatly influenced by the size of the particle being suspended. Particles size-reduced to under a few hundred nanometers may be stabilized by a variety of factors such as Brownian motion, steric stabilization by excipients, electric stabilization, flocculation, etc., which can all minimize effects of Van der Waals forces between particles that may result in irreversible product settling.
  • 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. Advantages of lyophilization may include, but are not limited to, enhanced stability of a dry powder, the removal of water without excessive heating of the product, and enhanced product stability in a dry state.
  • APIs Active pharmaceutical product ingredients
  • micronized cabotegravir free acid is packaged in antistatic linear low-density polyethylene bags.
  • the packaged cabotegravir is enclosed in a corrugated plastic box and gamma irradiated as a bioburden reduction step and referred to as gamma irradiated cabotegravir.
  • Gamma irradiated cabotegravir is dispersed in a filtered aqueous vehicle comprising a stabilizer (e.g., sodium CMC), a tonicity agent (e.g., mannitol), and a wetting agent (e.g., PS80).
  • the resulting suspension is filled into washed, sterilized/depyrogenated 10 mL Type I clear glass vials.
  • Container materials are then processed: vials are depyrogenated by dry heat, and stoppers and overseals are sterilized by steam.
  • Product vials are lyophilized, backflushed with nitrogen, sealed with halobutyl rubber stoppers and secured by an aluminum overseal.
  • the sealed vials are terminally sterilized by gamma irradiation. See FIGs. 1 & 2.
  • lyophilized pharmaceutical compositions As evidenced in the examples, which illustrate certain representative embodiments of the invention, the inventors have developed lyophilized pharmaceutical compositions and methods to obtain said compositions that allow for larger-size particles of cabotegravir. Data provided herein indicate that such lyophilized pharmaceutical compositions reduce injection site reactions and contribute to improved pharmacokinetic properties, thus addressing one or more above-mentioned problems in the art.
  • the lyophilized pharmaceutical composition is a suspension.
  • 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.
  • a solution with a cloudy appearance is considered suitably reconstituted.
  • compositions of the invention may be reconstituted in an aqueous or non-aqueous solution to a desired concentration.
  • the pharmaceutical composition described below in Examples 1-3 may be reconstituted in 1 .7 mL water to achieve a cabotegravir concentration of 400 mg/mL.
  • the same pharmaceutical composition described below in Examples 1-3 may be reconstituted in 1 .1 mL water to achieve a cabotegravir concentration of 533 mg/mL.
  • the present disclosure provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising cabotegravir, wherein cabotegravir is present in the form of particles having a mass median diameter (X50) of between (and including) 2.5 pm and 10 pm; a wetting agent; 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 diameter
  • the present disclosure provides a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising cabotegravir, wherein cabotegravir is present in the form of particles having a mass median diameter (X50) of between (and including) 2.5 pm and 10 pm; PS80; 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 diameter
  • the pharmaceutical composition comprises cabotegravir, mannitol, PS80, and sodium CMC; wherein cabotegravir is present in the form of particles having a mass median diameter (X5) of between (and including) 2.5 pm and 10 pm.
  • the pharmaceutical composition comprises cabotegravir, wherein cabotegravir is present in the form of particles having an X50 value greater than or equal to 3.5 pm and less than or equal to 8 pm; PS80; sodium CMC; and mannitol; wherein a weight ratio of cabotegravir:PS80:sodium CMC:mannitol is about 100:1 :1.25:8.75.
  • the pharmaceutical composition comprises cabotegravir, wherein cabotegravir is present in the form of particles having an X50 value greater than or equal 3.5 pm and less than or equal to 8 pm; PS80; sodium CMC; and mannitol; wherein a weight ratio of cabotegravir:PS80:sodium CMC:mannitol is about 400:3:3.7:25.9.
  • the pharmaceutical composition after lyophilization and reconstitution, is as described in Table 2a: Table 2a
  • the pharmaceutical composition after lyophilization and reconstitution, is as described in Table 2b:
  • the pharmaceutical composition after lyophilization and reconstitution, is as described in Table 2d: Table 2d
  • the pharmaceutical composition after lyophilization and reconstitution, is as described in Table 2e: Table 2e nH
  • the pharmaceutical composition of the invention has a pH of about 4 or greater. A pH of about 4 or more reduces pain to the patient if the composition is administered via injection. In an embodiment, the pharmaceutical composition of the invention has a pH of about 6.5.
  • a pharmaceutical composition described herein is administered in combination with a broadly neutralising antibody.
  • the broadly neutralizing antibody is selected from the group consisting of VRC01 , VRC01 -LS, N6, N6LS, VRC07 and VRC07-523.
  • An example of a disclosure of VRC01 is set forth in U.S Patent No. 8,637,036.
  • An example of a disclosure of VRC01-LS is set forth in WO 2012/106578.
  • Examples of disclosures of N6 and N6LS are set forth in WO 2016/196975.
  • Examples of disclosures of VRC07 and VRC07-523 are set forth in U.S. Patent No. 8,637,036, US Patent Publication No. 2014/0322163 A1 , WO 2016/196975 and WO 2017/79479.
  • the broadly neutralising antibody is an isolated N6 monoclonal antibody or an antigen binding fragment thereof, comprising a heavy chain complementarity determining region (CDRH) having a CDRH1 amino acid sequence of SEQ ID NO: 1 , a CDRH2 amino acid sequence of SEQ ID NO: 2, and a CDRH3 amino acid sequence of SEQ ID NO: 3; and a light chain complementarity determining region (CDRL) having a CDRL1 amino acid of SEQ ID NO: 4, a CDRL2 amino acid sequence of SEQ ID NO: 5, and a CDRH3 amino acid sequence of SEQ ID NO: 6.
  • CDRH heavy chain complementarity determining region
  • CDRL light chain complementarity determining region
  • the broadly neutralising antibody is an isolated N6LS monoclonal antibody or an antigen binding fragment, comprising a heavy chain complementarity determining region (CDRH) having a CDRH1 amino acid sequence of SEQ ID NO: 1 , a CDRH2 amino acid sequence of SEQ ID NO: 2, and a CDRH3 amino acid sequence of SEQ ID NO: 3; a light chain complementarity determining region (CDRL) having a CDRL1 amino acid of SEQ ID NO: 4, a CDRL2 amino acid sequence of SEQ ID NO: 5, and a CDRH3 amino acid sequence of SEQ ID NO: 6; and a recombinant constant domain comprising M428L and N434S mutations.
  • CDRH heavy chain complementarity determining region
  • CDRL light chain complementarity determining region
  • the antigen binding fragment is a Fv, Fab, F(ab') 2 , scFv or a scFV 2 fragment.
  • the broadly neutralising antibody includes an amino acid substitution that increases binding to the FcRn.
  • substitutions are known to the person of ordinary skill in the art, such as substitutions at IgG constant regions T250Q and M428L (see, e.g., Hinton et al., J Immunol, 176:346-356, 2006); M428L and N434S (the"LS" mutation, see, e.g., Zalevsky, et a/., Nature Biotechnology, 28:157-159, 2010); N434A (see, e.g., Petkova et al., Int. Immunol, 18:1759-1769, 2006); T307A, E380A, and N434A (see, e.g., Petkova et al., Int.
  • the disclosed antibodies and antigen binding fragments can be linked to a Fc polypeptide including any of the substitutions listed above, for example, the Fc polypeptide can include the M428L and N434S substitutions.
  • the antibody comprises a recombinant constant domain comprising a modification that increases binding to a neonatal Fc receptor relative to an unmodified constant domain, wherein the recombinant domain is an lgG1 constant domain comprising M428L and N434S mutations.
  • N6-LS is a broadly neutralising antibody, which comprises (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR)1 , a HCDR2, and a HCDR3 of the VH set forth as SEQ ID NO: 1 ; (b) a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR) 1 , a LCDR2, and a LCDR3 of the VL set forth as SEQ ID NO: 2 or a VL comprising an amino acid sequence at least 90 percent identical to one of SEQ ID NO: 2; or (c) a combination of (a) and (b); further comprising an IgGI constant domain comprising M428L and N434S mutations; and wherein the antibody or antigen binding fragment specifically binds to HIV-1 gpl20 and neutralizes HIV-1 infection.
  • VH heavy chain variable region
  • HCDR heavy chain complementarity determining region
  • LCDR3 light chain complement
  • a pharmaceutical composition described herein is administered in combination with a capsid inhibitor, a maturation inhibitor, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) (optionally, rilpivirine).
  • a capsid inhibitor a maturation inhibitor
  • NRTTI nucleoside reverse transcriptase translocation inhibitor
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • the pharmaceutical composition may be administered in combination with a capsid inhibitor.
  • the capsid inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:
  • G 1 is phenyl substituted once with -N(CH 3 )S(O2)CH 3 , -S(O2)C(CH 3 ) 3 , -CHF 2 , -CF 3 , - OCHF 2 , -OCF 3 , or -C(CH 3 ) 2 OH, with the proviso that when G 1 is -CHF 2 or -CF 3 , G 1 is not in the para position or G 1 is one of the following:
  • G 2 and G 3 are independently selected from is H or -CH 3 ;
  • G 4 is H, -CH 3 , or -OCH 3 ;
  • G 4a is -CH 3 , or -OCH 3 ;
  • G 5 is -CH 3 , or CH 2 CH 3 ;
  • G 6 is H, -CH 3 , or CH 2 CH 3 ;
  • G 7 is ethyl, isopropyl, tert-butyl, -CHF 2 , or -CF 3;
  • G 8 is H, methyl, ethyl, -CHF 2 , -CF 3 , -OCH 3 , or -OCH 2 CH 3 ;
  • G 9 is ethyl, isopropyl, cyclopropyl, -CH 2 OH, -OCH 3 ;
  • G 10 is ethyl, isopropyl, cyclopropyl, tert-butyl, -CHF 2 , or -CF 3;
  • G 11 is methyl, -OCH 3 , -CHF 2 , -CF 3 , -S(O 2 )CH 3 ;
  • G 12 is F, -CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -S(O 2 )CH 3 ;
  • G 13 is Ci-C 4 alkyl, Ci-C 6 cycloalkyl, -CH 2 O(Ci-C 3 alkyl);
  • G 14 is H, Ci-C 4 alkyl, -CHF 2 , -CF 3 , -O(Ci-C 3 alkyl);
  • G 15 is H, F, -CH 3 , or OCH 3 ;
  • R 3 is H, F, Cl, -CH 3 , or -OCH 3 ;
  • R 4 is H or Ci-C 3 alkyl wherein Ci-C 3 alkyl is optionally substituted with 1 -3 fluorines;
  • R 5 is Ci-Ce alkyl or C 3 -Ce cycloalkyl;
  • W is selected from: where R 6 is methyl optionally substituted with 1 to 3 fluorines.
  • the capsid inhibitor is Compound 2 pharmaceutically acceptable salt thereof.
  • Compound 2 is described in patent application number PCT/IB2020/055653 as Example 1 , which example is incorporated herein by reference.
  • the capsid inhibitor is lenacapavir.
  • the pharmaceutical composition may be administered in combination with a maturation inhibitor.
  • the maturation inhibitor is a compound of Formula (IV) or a pharmaceutically acceptable salt thereof: Formula (IV) wherein Ri is isopropenyl or isopropyl;
  • A is -Ci-e alkyl-ORo; wherein R o is heteroaryl-Q 0;
  • Qo is selected from the group of -H, -CN, -Ci- 6 alkyl, -COOH, -Ph, -OC1-6 alkyl, -halo, -CF 3
  • R 2 is -H, -C1-6 alkyl, -alkylsubstituted C1-6 alkyl or-arylsubstituted C1-6 alkyl;
  • W is absent, or is -CH 2 - or -CO-;
  • R3 is -H, -C1-6 alkyl or -alkylsubstituted C1-6 alkyl
  • R 4 is selected from the group of -H, -Ci- 6 alkyl, -Ci- 6 alkyl-C 3 -6 cycloalkyl, -Ci- 6 substituted -C1-6 alkyl, -Ci- 6 alkyl-Qi , -Ci-6 alkyl-C 3 -6cycloalkyl-Qi , aryl, heteroaryl, substituted heteroaryl, -COR 6 , -SO 2 R 7 , -SO 2 NR 2 R 2 , and wherein G is selected from the group of -O-, -SO 2 - and -NRI 2 -; wherein Qi is selected from the group of -C1-6 alkyl, - C1-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF 3 , -OR 2 , -COOR 2 , -NRsRg, -CONRsRg and -SO 2 R 7 ; Rs is selected
  • Re is selected from the group of -H, -C1-6 alkyl, -C1-6 alkyl-substitutedalkyl, -C3-6 cycloalkyl, -C3-6 substitutedcycloalkyl-Q2, -Ci- 6 alkyl-O 2 , -C1-6 alkyl-substitutedalkyl-Q2,-C3-6 cycloalkyl- Q 2 , aryl-Q 2 , -NR13R14, and -OR15; wherein Q 2 is selected from the group of aryl, heteroaryl, substituted heteroaryl, - OR2, -COOR2, -NR 8 R 9 , SO2R7, -CONHSO2R3, and -CONHSO2NR2R2;
  • R 7 is selected from the group of -H, -Ci- 6 alkyl, -Ci- 6 substituted alkyl, -C3-6 cycloalkyl, -CF 3 , aryl, and heteroaryl;
  • Rs and R 9 are independently selected from the group of -H, -C1-6 alkyl, -C1-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C1-6 alkyl-O 2 , and -COOR3, or Rs and R 9 are taken together with the adjacent N to form a cycle selected from the group of:
  • M is selected from the group of -R15, -SO2R2, -SO2NR2R2, -OH and -NR2R12;
  • V is selected from the group of -CR10R11-, -SO2-, -O- and -NR12-; with the proviso that only one of Rs or R 9 can be -COOR 3 ; Rio and Rn are independently selected from the group of -H, -Ci- 6 alkyl, -Ci- 6 substituted alkyl and -C 3 -6 cycloalkyl;
  • R12 is selected from the group of -H, -Ci- 6 alkyl, -alkylsubstituted Ci- 6 alkyl, - CONR2R2, -SO2R3, and -SO2NR2R2;
  • R13 and R14 are independently selected from the group of -H, -C1-6 alkyl, -C3-6 cycloalkyl, - C1-6 substituted alkyl, -C1-6 alkyl-Q 3 , -Ci-6 alkyl-C3-6cycloalkyl-Q 3 , and C1-6 substituted alkyl- Q 3 ;
  • Q 3 is selected from the group of heteroaryl, substituted heteroaryl, -NR2R12, - CONR2R2, -COOR2, -OR2, and -SO2R3;
  • R15 is selected from the group of -Ci- 6 alkyl, -C 3.6 cycloalkyl, -Ci- 6 substituted alkyl, -Ci- 6 alkyl-Qs, -Ci-6 alkyl-C3-6cycloalkyl-Q 3 and -Ci- 6 substituted alkyl-Q 3;
  • R is selected from the group of -H, -Ci- 6 alkyl, -NR 2 R 2 , and -COOR 2 ; with the proviso that when V is -NR12-; R16 is not -NR2R2; and
  • R17 is selected from the group of -H, -C1-6 alkyl, -COOR3, and aryl.
  • the pharmaceutical composition may be administered in combination with an NRTTI.
  • NRTTI is a compound of the formula (V): Formula (V) wherein: R 1 is: wherein:
  • X is selected from the group consisting of NH 2 , F and Cl;
  • R 5 is selected from the group consisting of H and (C1-C14) alkyl
  • R 2 and R 3 join together to form a C 3 to C 28 cyclic structure; and with the proviso that when R 2 is (C1-C14 alkyl) at least one of R 3 , R 5 and R 6 is not H.
  • the present invention provides methods for (a) treatment of HIV in a human in need thereof comprising administering to said human a therapeutically effective amount of a pharmaceutical composition as defined herein; and (b) prevention of HIV in a human comprising administering to said human an effective amount of a pharmaceutical composition as defined herein.
  • the method comprises administering the pharmaceutical composition parenterally.
  • the pharmaceutical composition is administered intramuscularly.
  • the pharmaceutical composition is administered subcutaneously.
  • the method comprises administering around 1 mL to around 8 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 1 mL of the pharmaceutical composition to a patient. In another embodiment the method comprises administering around 2 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 3 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 4 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 5 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 6 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 7 mL of the pharmaceutical composition to a patient. In an embodiment the method comprises administering around 8 mL of the pharmaceutical composition to a patient.
  • the pharmaceutical composition is administered in more than one injection.
  • the pharmaceutical composition is administered in two or more injections, which may be simultaneously or consecutively administered. For example, two separate injections of 3 mL (for a total of 6 mL) of the pharmaceutical composition may be consecutively administered to the patient.
  • the pharmaceutical composition is administered in two injections.
  • about 300 mg to about 3200 mg of cabotegravir is administered to the patient in the pharmaceutical composition.
  • the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and about 800 mg to about 1600 mg of cabotegravir is administered to the patient. In an embodiment, the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and 800 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and 1200 mg of cabotegravir is administered to the patient.
  • the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 1200 to about 3200 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 1600 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 2400 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 3200 mg of cabotegravir is administered to the patient.
  • the pharmaceutical composition is administered to a patient once every 1 , 2, 3, 4, 5, or 6 months. In an embodiment, the pharmaceutical composition is administered to the human once every month. In an alternative embodiment, the pharmaceutical composition is administered once every two months. In an alternative embodiment, the pharmaceutical composition is administered once every three months. In an alternative embodiment, the pharmaceutical composition is administered once every four months. In an alternative embodiment, the pharmaceutical composition is administered once every five months. In an alternative embodiment, the pharmaceutical composition is administered once every six months.
  • the pharmaceutical composition may be administered by any suitable means.
  • pharmaceutical composition may be administered subcutaneously.
  • the pharmaceutical composition may be administered subcutaneously by another (e.g., by a healthcare professional) or may be self-administered by a patient.
  • the pharmaceutical composition may be administered subcutaneously via injection.
  • the pharmaceutical composition is administered subcutaneously via injection.
  • the pharmaceutical composition is administered or self-administered once monthly by subcutaneous injection.
  • the pharmaceutical composition is administered or self-administered once every two months by subcutaneous injection.
  • the pharmaceutical composition is administered or selfadministered once every three months by subcutaneous injection.
  • the pharmaceutical composition is administered or self-administered once every four months by subcutaneous injection.
  • the pharmaceutical composition is administered or self-administered once every five months by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or selfadministered once every six months by subcutaneous injection. In an embodiment, the pharmaceutical composition is administered or self-administered in one injection. In another embodiment, the pharmaceutical composition is administered or self-administered in two or more injections, which may be simultaneously or consecutively administered. In an embodiment, the pharmaceutical composition is administered or self-administered in two injections.
  • the pharmaceutical composition is administered intramuscularly via injection.
  • the pharmaceutical composition may be administered intramuscularly by another (e.g., by a healthcare professional) or may be self-administered by a patient.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every month.
  • the pharmaceutical composition is administered or selfadministered intramuscularly via injection once every two months.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every three months.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every four months.
  • the pharmaceutical composition is administered or self-administered intramuscularly via injection once every five months. In another embodiment, the pharmaceutical composition is administered or self-administered intramuscularly via injection once every six months. In an embodiment the intramuscular injection is administered by a healthcare professional. In an embodiment, the pharmaceutical composition is intramuscularly administered in one injection during a visit with a healthcare professional. In another embodiment, the pharmaceutical composition is intramuscularly administered in two or more injections, which may be simultaneously or consecutively administered, during one visit with a healthcare professional. In an embodiment, the pharmaceutical composition is intramuscularly administered in two injections, which may be simultaneously or consecutively administered, during one visit with a healthcare professional.
  • the pharmaceutical composition is intramuscularly self-administered in one injection. In another embodiment, the pharmaceutical composition is intramuscularly selfadministered in two or more injections, which may be simultaneously or consecutively selfadministered. In an embodiment, the pharmaceutical composition is intramuscularly selfadministered in two injections, which may be simultaneously or consecutively selfadministered. 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. Marketed medicines are currently available to treat HIV.
  • compositions of the present invention are administered in combination with N6-LS.
  • N6-LS is described above.
  • compositions of the present invention are administered in combination with a capsid inhibitor, a maturation inhibitor or a nucleoside reverse transcriptase translocation inhibitor (NRTTI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) (optionally, rilpivirine).
  • a capsid inhibitor a maturation inhibitor or a nucleoside reverse transcriptase translocation inhibitor (NRTTI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) (optionally, rilpivirine).
  • NRTTI nucleoside reverse transcriptase translocation inhibitor
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • the present invention provides a pharmaceutical composition defined herein for use in the treatment or prevention of HIV.
  • 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 around 1 mL to around 8 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 1 mL of the pharmaceutical composition to a patient. In another embodiment the use comprises administering around 2 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 3 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 4 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 5 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 6 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 7 mL of the pharmaceutical composition to a patient. In an embodiment the use comprises administering around 8 mL of the pharmaceutical composition to a patient.
  • the use comprises administering the pharmaceutical composition in more than one injection. In an embodiment, the use comprises administering the pharmaceutical composition in two or more injections, which may be simultaneously or consecutively administered. For example, two separate injections of 3 mL (for a total of 6 mL) of the pharmaceutical composition may be consecutively administered to the patient. In an embodiment, the use comprises administering the pharmaceutical composition in two injections.
  • about 300 mg to about 3200 mg of cabotegravir is administered to the patient in the pharmaceutical composition.
  • the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and about 800 mg to about 1600 mg of cabotegravir is administered to the patient. In an embodiment, the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and 800 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 400 mg/mL and 1200 mg of cabotegravir is administered to the patient.
  • the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 1200 to about 3200 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 1600 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 2400 mg of cabotegravir is administered to the patient. In an embodiment the pharmaceutical composition has a cabotegravir concentration of about 533 mg/mL and about 3200 mg of cabotegravir is administered to the patient.
  • the use comprises administering the pharmaceutical to a patient once every 1 , 2, 3, 4, 5, or 6 months. In an embodiment the use comprises administering the pharmaceutical composition to a patient once every month. In an alternative embodiment, the use comprises administering the pharmaceutical composition once every two months. In an alternative embodiment the use comprises administering the pharmaceutical composition once every three months. In an alternative embodiment the use comprises administering the pharmaceutical composition once every four months. In an alternative embodiment the use comprises administering the pharmaceutical composition once every five months. In an alternative embodiment the use comprises administering the pharmaceutical composition once every six months.
  • use comprises administering the pharmaceutical composition by any suitable means.
  • the use comprises the patient self-administering the pharmaceutical composition. In this embodiment the use may comprise administering the pharmaceutical composition subcutaneously via injection. In one embodiment of the invention the use comprises self-administering the pharmaceutical composition once monthly by subcutaneous injection. In another embodiment, the use comprises selfadministering the pharmaceutical composition once every two months by subcutaneous injection. In another embodiment, the use comprises self-administering the pharmaceutical composition once every three months by subcutaneous injection. In another embodiment, the use comprises self-administering the pharmaceutical composition once every four months by subcutaneous injection. In another embodiment, the use comprises self-administering the pharmaceutical composition once every five months by subcutaneous injection. In another embodiment, the use comprises selfadministering the pharmaceutical composition once every six months by subcutaneous injection.
  • the use comprises self-administering the pharmaceutical composition in one injection. In another embodiment, the use comprises selfadministering the pharmaceutical composition in two or more injections, which may be simultaneously or consecutively administered. In an embodiment, the use comprises selfadministering the pharmaceutical composition in two injections.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every month.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every two months.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every three months.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every four months.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every five months.
  • the use comprises administering the pharmaceutical composition intramuscularly via injection once every six months.
  • the intramuscular injection is administered by a healthcare professional.
  • the use comprises intramuscularly administering the pharmaceutical composition in one injection during a visit with a healthcare professional. In another embodiment, the use comprises intramuscularly administering the pharmaceutical composition in two or more injections, which may be simultaneously or consecutively administered, during one visit with a healthcare professional. In an embodiment, the use comprises intramuscularly administering the pharmaceutical composition in two injections during one visit with a healthcare professional.
  • use comprises administering the pharmaceutical compositions of the present invention 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. Marketed medicines are currently available to treat HIV.
  • the use comprises administering the pharmaceutical compositions of the present invention in combination with N6-LS.
  • N6-LS is described above.
  • the use comprises administering the pharmaceutical compositions of the present invention in combination with a capsid inhibitor, a maturation inhibitor or a nucleoside reverse transcriptase translocation inhibitor (NRTTI), or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (optionally, rilpivirine).
  • a capsid inhibitor a maturation inhibitor or a nucleoside reverse transcriptase translocation inhibitor (NRTTI), or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (optionally, rilpivirine).
  • NRTTI nucleoside reverse transcriptase translocation inhibitor
  • NRTI nonnucleoside reverse transcriptase inhibitor
  • the present invention provides a kit comprising cabotegravir, wherein cabotegravir is present in the form of particles having an X50 value greater than or equal to 2.5 pm and less than or equal to 10 pm; a wetting agent; a stabilizer; and a tonicity adjuster.
  • the kit comprises a syringe or vial comprising a composition of the invention as well as a leaflet comprising use instructions.
  • the present invention provides a method of preparing a reconstituted solution, the method comprising providing the kit as described here and contacting the lyophilized composition with a suitable liquid to produce a reconstituted solution.
  • a suitable liquid is an aqueous solvent.
  • the suitable liquid is water.
  • the suitable liquid is a non-aqueous solvent.
  • Dispersion stirring speed was 2000 rpm
  • particle refractive index was 1 .67
  • particle absorption Index (imaginary part of refractive index) was 0.01
  • General Purpose analysis mode with normal sensitivity dispersant (DI water) refractive index was 1.33
  • measurement time and background time were both 10 seconds, and 2 measurements were acquired by the instrument per aliquot.
  • Table 3 shows an exemplary pharmaceutical composition of the invention (pharmaceutical compositions are also described in these examples as “suspensions”), which was made using the following method.
  • a formulation vehicle was prepared by dissolving/diluting 24.0g polysorbate 80 (“PS80”) (Croda) in about 300g water.
  • PS80 polysorbate 80
  • 30.0g sodium carboxymethylcellulose (“NaCMC”) (Ashland, 7L2P)
  • 210.0g mannitol Roquette Freres
  • the weighing and dilution vessels were rinsed into the compounding vessel with additional water and the compounded vehicle solution was brought to a final weight of 6.06kg and filtered through a 0.2pm filter.
  • the compounded suspension was deaerated while stirring until it reached its target batch volume, and the suspension was then filled into vials.
  • the product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -18°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a ramp rate of +/- 1°C/min), primary drying at -10°C (ramp rate: 0.15°C/min) for at least 20 hours at approximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.5°C/min) for at least 6 hours at approximately 150 mTorr.
  • the lyophilized vials were backflushed with nitrogen to about 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25kGy.
  • the formulation is reconstituted with WFI and briefly shaken to resuspend prior to administration.
  • Table 4 shows an exemplary pharmaceutical composition of the invention (pharmaceutical compositions are also described in these examples as “suspensions”), which was made using the following method.
  • a formulation vehicle was prepared by dissolving/diluting 24.0g polysorbate 80 (“PS80”) (Croda) in about 300g water. Separately, 30.0g sodium carboxymethylcellulose (“NaCMC”) (Ashland, 7L2P) and 210.0g mannitol (Roquette Freres) were dissolved in 3.4kg water for injection (WFI). Once the NaCMC and mannitol were dissolved, the PS80 solution was added to the NaCMC-mannitol solution with stirring. The weighing and dilution vessels were rinsed into the compounding vessel with additional water and the compounded vehicle solution was brought to a final weight of 4.50kg and filtered through a 0.2pm filter.
  • PS80 polysorbate 80
  • the product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -18°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a ramp rate of +/- 1°C/min), primary drying at -10°C (ramp rate: 0.15°C/min) for at least 20 hours at approximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.5°C/min) for at least 6 hours at approximately 150 mTorr.
  • the lyophilized vials were backflushed with nitrogen to about 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25kGy.
  • the formulation is reconstituted with WFI and briefly shaken to resuspend prior to administration.
  • Table 5 shows an exemplary pharmaceutical composition of the invention (pharmaceutical compositions are also described in these examples as “suspensions”), which was made using the following method.
  • a formulation vehicle was prepared by dissolving/diluting 24.0g polysorbate 80 (“PS80”) (Croda) in about 300g water. Separately, 30.0g sodium carboxymethylcellulose (“NaCMC”) (Ashland, 7L2P) and 210.0g mannitol (Roquette Freres) were dissolved in 3.4kg water for injection (WFI). Once the NaCMC and mannitol were dissolved, the PS80 solution was added to the NaCMC-mannitol solution with stirring. The weighing and dilution vessels were rinsed into the compounding vessel with additional water and the compounded vehicle solution was brought to a final weight of 4.50kg and filtered through a 0.2pm filter.
  • PS80 polysorbate 80
  • the product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -18°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each transition at a ramp rate of +/- 1°C/min), primary drying at -10°C (ramp rate: 0.15°C/min) for at least 20 hours at approximately 150 mTorr, and secondary drying at 25°C (ramp rate: 0.5°C/min) for at least 6 hours at approximately 150 mTorr.
  • the lyophilized vials were backflushed with nitrogen to about 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25kGy.
  • the formulation is reconstituted with WFI and briefly shaken to resuspend prior to administration.
  • Example 4 Stability of a composition comprising cabotegravir, sodium carboxymethylcellulose, polysorbate 80 and mannitol
  • a formulation vehicle was prepared by dissolving 2.10g PS80 (Croda), 2.63g NaCMC (Ashland), and 18.38g mannitol (Roquette Freres) in 369.6g WFI and filtering the solution through a 0.2pm filter.
  • the formulation vehicle was added to 210g Cabotegravir (free acid) to prepare a 400 mg/mL coarse suspension.
  • the suspension was covered and stirred for 2 hrs.
  • the suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3.
  • the lyophilized suspension was reconstituted to a cabotegravir concentration of 400 mg/mL.
  • Example 5 Stability of a composition comprising cabotegravir, sodium carboxymethylcellulose, polysorbate 20 and mannitol
  • a formulation vehicle was prepared by dissolving 2.10g polysorbate 20 (Croda), 2.63g sodium CMC (Ashland), and 18.38g mannitol (Roquette Freres) in 550.9g WFI and filtering the solution through a 0.2pm filter.
  • the formulation vehicle was added to 210g cabotegravir (free acid) to prepare a 300 mg/mL coarse suspension.
  • the suspension was covered and stirred for 2 hrs.
  • the suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3.
  • the lyophilized suspension was reconstituted to a cabotegravir concentration of 400 mg/mL.
  • Example 6 Stability of a composition comprising cabotegravir, sodium carboxymethylcellulose, poloxamer 338 and mannitol
  • a formulation vehicle was prepared by dissolving 2.10g poloxamer 338 (BASF), 2.63g sodium CMC (Ashland), and 18.38g mannitol (Roquette Freres) in 369.6g WFI and filtering the solution through a 0.2pm filter.
  • the formulation vehicle was added to 210g Cabotegravir (free acid) to prepare a 400 mg/mL coarse suspension.
  • the suspension was covered and stirred for 2 hrs.
  • the suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3.
  • the lyophilized suspension was reconstituted to a cabotegravir concentration of 400 mg/mL.
  • Example 7 In vivo rat pharmacokinetic study for compositions comprising cabotegravir, sodium carboxymethylcellulose, mannitol and either polysorbate 80 or poloxamer 338:
  • composition preparation was described in Examples 4 and 6. Formulations were dosed in 9 Sprague Dawley male rats at 30mg/kg in the subcutaneous space of the intrascapular region. Briefly, two nanosuspension formulations of Cabotegravir at 200 (group 1 ) and 400 mg/mL (group 2), also differing in excipient composition, were administered subcutaneously through a single injection at target dose of 30mg/kg in each rat. Similarly, two lyophilized powder formulations of Cabotegravir at micron-size, differing in excipient composition, were reconstituted with WFI to 400mg/mL concentration and administered subcutaneously through a single injection at target dose of 30mg/kg in each rat. Details of the formulations are described in Table 10.
  • Table 10 Suspension formulations details for test articles dosed in animal PK study
  • Table 11 shows Cabotegravir plasma pharmacokinetics for a preclinical study and statistical analysis through t-test for several pharmacokinetic parameters.
  • the lyophilized formulation from Group 3 highlights a significantly reduced C ma x (1 .8 folds) and extended ti/2 (1 .5 folds) compared to the nanosuspension formulation from Group 1 .
  • the lyophilized formulation from Group 3 demonstrates improved ti/ 2 compared to formulation from Group 4.
  • Example 8 evaluated the safety, tolerability and pharmacokinetics of single-dose administration of a pharmaceutical composition of the invention in 16 healthy adult participants.
  • the formulation of Example 8 is provided in Table 13 below:
  • Nitrogen is utilized as a processing aid during vial stoppering.
  • Table 13 The formulation of Table 13 was administered in two cohorts: 800 mg (2 ml of 400 mg/mL suspension) via the subcutaneous (SC) abdominal route (Cohort C1 ; 8 participants) and via the intramuscular (IM) (gluteus maxims) route (Cohort C2; 8 participants).
  • SC subcutaneous
  • IM intramuscular
  • Table 15 Summary of most frequent (>2 participants in either cohort) AEs (ISR and non-ISR) by cohort Table 16: Summary of ISRs a. ISR duration is not calculated if end date is missing.

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Abstract

La présente invention concerne la prévention et le traitement du virus de l'immunodéficience humaine (VIH). L'invention concerne en particulier une composition pharmaceutique comprenant : du cabotégravir ; un agent mouillant ; un stabilisant ; et un ajusteur de tonicité ; le cabotégravir étant présent sous la forme de particules ayant un diamètre médian en masse (X50) compris entre (et y compris) 2,5 et 10 µm.
PCT/IB2023/059640 2020-03-01 2023-09-27 Composition pharmaceutique de cabotégravir Pending WO2025068743A1 (fr)

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TW113136400A TW202529766A (zh) 2023-09-27 2024-09-25 醫藥組合物
PCT/IB2024/059356 WO2025068912A1 (fr) 2023-09-27 2024-09-25 Compositions pharmaceutiques
AU2024353051A AU2024353051A1 (en) 2023-09-27 2024-09-25 Pharmaceutical compositions
US18/895,498 US20250099464A1 (en) 2023-09-27 2024-09-25 Pharmaceutical compositions
ARP240102571A AR133924A1 (es) 2020-03-01 2024-09-25 Composiciones farmacéuticas
IL327150A IL327150A (en) 2023-09-27 2024-09-25 Pharmaceutical preparations
CN202480061613.8A CN121909019A (zh) 2023-09-27 2024-09-25 药物组合物
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WO2025181723A1 (fr) * 2024-03-01 2025-09-04 ViiV Healthcare UK (No.3) Limited Schéma posologique

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