Pharmaceutical composition

Abstract

The present invention relates to human immunodeficiency virus (HIV) prevention and treatment. In particular, the present invention relates to a pharmaceutical composition comprising: Cabotegravir; a wetting agent; a stabilizer; and a tension regulator; wherein the Cabotegravir is present in the form of particles having a median mass diameter (X50) of between 2.5 m and 10 m (and including 2.5 m and 10 m).

Description

[0001] sequence list

[0002] This application contains a sequence list, which has been electronically submitted in computer-readable form in XML file format, and is incorporated herein by reference in its entirety. The XML file was created on September 18, 2024, named "70392WO02_Sep_2024", and is 8,199 bytes in size. Technical Field

[0003] This invention relates to the treatment or prevention of human immunodeficiency virus (HIV). Specifically, this invention relates to long-acting treatment or prevention of HIV. Background Technology

[0004] Patients living with HIV often undergo complex treatment regimens involving the daily administration of multiple pills at regular intervals. Patient non-adherence is a known problem associated with these complex HIV treatment regimens and can lead to the emergence of multidrug-resistant strains of HIV.

[0005] The use of long-acting parenteral medications has been established in clinical practice for decades, particularly in the areas of contraception, antipsychotics, and opioid addiction. Recently, long-acting parenteral medications have been proposed as a way to overcome HIV treatment non-adherence issues. Long-acting injectable formulations, some of which have been approved and marketed, such as CABENUVA®, have been shown to prolong post-injection exposure (≥30 days), enabling dosing at monthly and bi-monthly intervals.

[0006] It is desirable to develop injectable suspensions of high-concentration anti-HIV drugs for lower-frequency dosing and to overcome adherence issues in HIV treatment regimens, while maintaining the same or similar injection volume as previous HIV treatment regimens to sustain the patient experience. Similarly, where anti-HIV drugs are available for HIV prevention (e.g., pre-exposure prophylaxis or PrEP), developing injectable suspensions of high-concentration anti-HIV drugs that provide longer-lasting effects could increase adherence due to less frequent dosing. However, high-concentration suspensions often suffer from resuspension difficulties and particle size increase. Furthermore, high-concentration suspensions with larger particle sizes (e.g., micrometers) are more difficult to stabilize in ready-to-use suspensions.

[0007] Lyophilized formulations offer several advantages over ready-to-use suspensions—namely, they avoid resuspension difficulties or failures, maintain product stability, and overcome scale-up issues.

[0008] There is a need in the art for long-acting injectable agents for the treatment or prevention of HIV that can be administered at longer intervals while still achieving the same patient experience, minimizing injection site reactions, and overcoming the known difficulties of high-concentration and / or ready-to-use suspensions. Summary of the Invention

[0009] According to a first aspect of the present invention, a pharmaceutical composition is provided comprising:

[0010] Cabotegravir;

[0011] wetting agent;

[0012] stabilizers; and

[0013] Tension regulator;

[0014] Cabotewe exists in the form of particles with a median mass diameter (X50) between 2.5 µm and 10 µm (including 2.5 µm and 10 µm).

[0015] According to a second aspect of the invention, methods are provided for: (a) treating HIV in a person in need, comprising administering to the person a therapeutically effective amount of a pharmaceutical composition as defined herein; and (b) preventing HIV in a person, comprising administering to the person an effective amount of a pharmaceutical composition as defined herein.

[0016] According to a third aspect of the invention, a pharmaceutical composition as defined herein is provided for the treatment or prevention of HIV.

[0017] According to a fourth aspect of the invention, a kit is provided comprising cabotevir, wherein cabotevir is present in particulate form with a median mass diameter (X50) between 2.5 µm and 10 µm (and including 2.5 µm and 10 µm); a wetting agent; a stabilizer; and a tension modifier.

[0018] The pharmaceutical compositions of the present invention are likely to be advantageous in many respects. The pharmaceutical compositions of the present invention allow for high concentrations of larger-sized cabotevir particles in the composition. These larger-sized particles, in turn, advantageously alter absorption kinetics, thus allowing for ultra-long-acting treatment, which permits longer intervals between dosings compared to existing therapies. This may improve patient compliance and reduce the likelihood of drug-resistant HIV strains. The compositions of the present invention can also reduce injection site reactions, thus improving the patient experience. Finally, the lyophilized compositions of the present invention minimize resuspension failure and maintain product stability and injectability. Attached Figure Description

[0019] Figure 1 and 2 This is a flowchart of an exemplary method for preparing lyophilized compositions as described herein.

[0020] Figure 3A simulation of the median plasma concentration / time plot is shown for individuals designated as male at birth who received an intramuscular loading dose of 3200 mg of cabobetavir (CAB) (a 533 mg / mL cabobetavir formulation in 3 mL double-dose as described in Group 5 of Examples 9 herein), followed by a first maintenance dose of 1600 mg of cabobetavir one month later, and then 1600 mg of cabobetavir every 4 months (a 533 mg / mL cabobetavir formulation in 3 mL as described in Group 5 of Examples 9 herein). This has been overlaid on a graph of the median plasma concentration over time for individuals designated as male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M (every 2 months) (CAB200 marked APRETUDE® in the figure). The black line in the middle of the shaded gray area is the simulated median of the dosing regimen (designated CAB-ULA in the figure). The black line in the middle of the shaded gray area is above the black dashed line (median plasma concentration of CAB200). The lower boundary of the gray band (the simulated 10th percentile of CAB-ULA) is above the lowest dashed line (the simulated 10th percentile of CAB200). Therefore, this indicates that the regimen maintains CAB plasma concentrations higher than the approved Q2M regimen of CAB200 IM gluteal injection.

[0021] Figure 4 The simulation of median plasma concentration / time plots is shown for individuals designated as female at birth who received an intramuscular loading dose of 3200 mg of cabobetavir (a 3 mL twice-dose 533 mg / mL cabobetavir formulation as described in Example 9, Group 5 of this document), followed by a first maintenance dose of 1600 mg of cabobetavir one month later, and then 1600 mg of cabobetavir every 4 months (a 3 mL 533 mg / mL cabobetavir formulation as described in Example 9, Group 5 of this document). This has been overlaid on a graph of median plasma concentrations over time for individuals designated as female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M (every 2 months) (CAB200 marked APRETUDE® in the figure). The black line in the middle of the shaded gray area is the simulated median of the dosing regimen (designated CAB-ULA in the figure). The black line in the middle of the shaded gray area is above the black dashed line (the median of CAB200). The lower boundary of the gray band (the simulated 10th percentile of CAB-ULA) is above the lowest dashed line (the simulated 10th percentile of CAB200). Therefore, this indicates that the regimen maintains CAB plasma concentrations higher than the approved Q2M regimen of CAB200 IM gluteal injection.

[0022] Figure 5This is a simulation of the median plasma concentration / time plot for individuals designated male at birth who received an intramuscular loading dose of 2132 mg cabobetavir (4 mL of 533 mg / mL cabobetavir formulation) and, one month later, a first maintenance dose of 799.5 mg cabobetavir, followed by 799.5 mg cabobetavir (1.5 mL of 533 mg / mL cabobetavir formulation) every 4 months. This has been overlaid on a graph of median plasma concentrations over time for individuals designated male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration for the approved regimen (APRETUDE®). The gray shaded areas represent the 10th to 90th percentiles of plasma concentrations for the simulated regimen. The black solid line represents the median of the simulated dosing regimen.

[0023] Figure 6 This is a simulation of the median plasma concentration / time plot for individuals designated female at birth who received an intramuscular loading dose of 2132 mg cabobetavir (4 mL of 533 mg / mL cabobetavir formulation) and, one month later, a first maintenance dose of 799.5 mg cabobetavir, followed by 799.5 mg cabobetavir (1.5 mL of 533 mg / mL cabobetavir formulation) every 4 months. This has been overlaid on a graph of median plasma concentrations over time for individuals designated female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration for the approved regimen (APRETUDE®). The gray shaded areas represent the 10th to 90th percentiles of plasma concentrations for the simulated regimen. The black solid line represents the median of the simulated dosing regimen.

[0024] Figure 7 A simulation of the median plasma concentration / time plot is shown for individuals designated as male at birth who received an intramuscular loading dose of cabobetavir (two 3 mL doses of 400 mg / mL cabobetavir formulation), followed by a first maintenance dose of 1200 mg cabobetavir one month later, and then 1200 mg cabobetavir (3 mL doses of 400 mg / mL cabobetavir formulation, see Group 3, Example 9 of this document) every 4 months. This has been overlaid on a plot of median plasma concentrations over time for individuals designated as male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line in the middle of the shaded gray area represents the median plasma concentration of the approved regimen (APRETUDE®). The gray shaded area represents the interval of the approved regimen. The black solid line is the median of the simulated dosing regimen, and the black dashed lines above and below it are the upper and lower boundaries of the predicted intervals of the simulated dosing regimen.

[0025] Figure 8 A simulation of the median plasma concentration / time plot is shown for individuals designated as female at birth who received an intramuscular loading dose of cabobetavir (two 3 mL doses of 400 mg / mL cabobetavir formulation), followed by a first maintenance dose of 1200 mg cabobetavir one month later, and then 1200 mg cabobetavir (3 mL doses of 400 mg / mL cabobetavir formulation, see Group 3, Example 9 of this document) every 4 months. This has been overlaid on a graph of median plasma concentrations over time for individuals designated as female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line in the middle of the gray shaded area represents the median plasma concentration of the approved regimen (APRETUDE®). The gray shaded area represents the interval of the approved regimen. The black solid line is the median of the simulated dosing regimen, and the black dashed lines above and below it are the upper and lower boundaries of the predicted intervals of the simulated dosing regimen.

[0026] Figure 9 Showing with Figure 3 The same simulation is shown, but overlaid on the dashed line showing 1.05 µg / mL, instead of the simulation of the approved regimen. The lower boundary of the gray band marked CAB-ULA in the figure (the 10th percentile of the simulation for the dosing regimen shown) is above the horizontal dashed line, i.e., the efficacy benchmark in people designated as male at birth.

[0027] Figure 10 Showing with Figure 4 The same simulation is shown, but overlaid on the dashed line showing 1.39 µg / mL, instead of the simulation of the approved regimen. The lower boundary of the gray band marked CAB-ULA in the figure (the 10th percentile of the simulation for the dosing regimen shown) is above the horizontal blue dashed line, i.e., the efficacy benchmark for people designated as female at birth.

[0028] Figure 11 This is a simulation of the median plasma concentration / time plot for individuals designated as male at birth who received an intramuscular loading dose of 2132 mg cabobetavir (4 mL of 533 mg / mL cabobetavir) and a first maintenance dose of 1066 mg cabobetavir one month later, followed by 1066 mg cabobetavir (2 mL of 533 mg / mL cabobetavir) every 4 months. This has been overlaid on the plot of median plasma concentrations over time for individuals designated as male at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration for the approved regimen (APRETUDE®). The black solid line represents the median of the simulated dosing regimen (labeled Cab-ULA), and the surrounding shaded gray area represents the predicted intervals from the 10th percentile to the 90th percentile for the simulated dosing regimen.

[0029] Figure 12 This is a simulation of the median plasma concentration / time plot for individuals designated female at birth who received an intramuscular loading dose of 2132 mg cabobetavir (4 mL of 533 mg / mL cabobetavir) and a first maintenance dose of 1066 mg cabobetavir one month later, followed by 1066 mg cabobetavir (2 mL of 533 mg / mL cabobetavir) every 4 months. This has been overlaid on the plot of median plasma concentration over time for individuals designated female at birth who have been administered the approved cabobetavir 200 mg / mL formulation Q2M. The black dashed line represents the median plasma concentration for the approved regimen (APRETUDE®). The black solid line represents the median of the simulated dosing regimen (labeled Cab-ULA), and the surrounding shaded gray area represents the predicted interval from the 10th percentile to the 90th percentile for the simulated dosing regimen.

[0030] Figure 13 The concentration-time progression of cabotevir in two nanosuspensions administered intramuscularly in rats at concentrations of 200 mg / mL (CAB200, dashed triangles) and 400 mg / mL (CAB400, continuous circles), respectively, is shown. Data points represent mean ± standard deviation. Invention Details

[0032] definition

[0033] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having a specified number of carbon atoms. For example, the term "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), pentyl and hexyl.

[0034] When the term "alkyl" is used in combination with other substituent groups, such as "halogenated (C10)", it is used in combination with other substituent groups. 1-4 alkyl and hydroxyl (C 1-4 "alkyl", the term "alkyl" is intended to cover divalent straight-chain or branched hydrocarbon groups, where the connecting point is through the alkyl moiety.

[0035] The term "alkylene" refers to a divalent group (C1-C2) derived from, for example, a straight-chain or branched saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 Alkylene groups. Exemplary groups include, but are not limited to, -CH2-, -CH2CH2- and -CH2CH2CH2-.

[0036] The term "cycloalkyl" refers to a non-aromatic, saturated, monocyclic hydrocarbon ring containing a specified number of carbon atoms. For example, a "cycloalkyl" ring can contain 3 to 8 carbon atoms, i.e., C646. 3-8 Cycloalkyl groups. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0037] The term "heteroaryl" refers to a group or portion comprising an aromatic monovalent monocyclic or bicyclic group containing 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The term also covers bicyclic heterocyclic aryl compounds containing an aryl ring portion fused to a heterocyclic alkyl ring portion, comprising 5 to 10 ring atoms, including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Exemplary functional groups include, but are not limited to, furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxacyclopentenyl, dihydrobenzodioxacyclohexenyl, benzothiophene, inazinyl, indoleyl, isoindoleyl, and dihydroindoleyl. Examples of five-membered "heteroaryl" groups include furanyl, thiopheneyl, pyrroleyl, imidazoleyl, pyrazolyl, triazolyl, tetrazolyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, terazolinyl, phthalazinyl, quinazolinyl, 1,5-naphthodinyl, 1,6-naphthodinyl, 1,7-naphthodinyl, 1,8-naphthodinyl, and pteridinyl. Examples of 6-membered "heteroaryl" groups include oxopyridyl, pyridyl, pyridinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" groups include quinolinyl, isoquinolinyl, quinoxalinyl, cenolinyl, phthalazinyl, quinazolinyl, 1,5-naphridinyl, 1,6-naphridinyl, 1,7-naphridinyl, 1,8-naphridinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" groups include benzofuranyl, benzothiophenyl, benzimidazolyl, benzothiazolyl, indazinyl, indoleyl, isoindoleyl, and indazoleyl.

[0038] The terms “halogen” and “halogenated” refer to chlorine, fluorine, bromine, or iodine substituents.

[0039] The term "optionally substituted" means that the group may be unsubstituted or substituted with one or more substituents as defined herein. When referring to a group, the term "substituted" means that a hydrogen atom bonded to a member atom within the group is replaced by one of the defined substituents. Where the group may be chosen from multiple substituents, the chosen groups may be the same or different.

[0040] The term "member atom" refers to one or more atoms that form a chain or ring. When more than one member atom is present in a chain or ring, each member atom is covalently bonded to its adjacent member atom in the chain or ring. Atoms that constitute substituent groups attached to the chain or ring are not member atoms in the chain or ring.

[0041] As used herein, the term "aqueous solution" means any solution containing water or in which the solvent is water. Additionally, "aqueous solution" is used to describe solutions that exhibit characteristics common to water or aqueous solutions, but are not limited to features such as appearance, odor, color, taste, viscosity, pH, absorbance, or physical state at a particular temperature.

[0042] As used in this article, the term "freeze-drying," also known as freeze-drying or cryodesiccation, is a dehydration process that involves freezing products without damaging the physical structure of the substance.

[0043] As used herein, the terms “lyophilized” and “freeze-dried” are used interchangeably and refer to the conditions and / or state of a sample, formulation, or product obtained by lyophilization.

[0044] As may be used interchangeably herein, the terms “lyophilized pharmaceutical composition” and “lyophilized composition” refer to a pharmaceutical composition in lyophilized form as taught herein, such as lyophilized powder.

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compound of this subject matter and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, separately with a suitable base or acid.

[0046] Pharmaceutically acceptable salts include, in particular, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in PH Stahl and CG Wermuth eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2nd ed., Stahl / Wermuth: Wiley-VCH / VHCA, 2011 (see www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html). Suitable pharmaceutically acceptable salts may include acid or base addition salts. Suitable pharmaceutically acceptable salts of the present invention include base addition salts.

[0047] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benzylpenicillin (N-benzylphenylethylamine), benzathine penicillin (N,N'-dibenzylethylenediamine), bis(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, crimidazole (1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidol, lithium, lysine, magnesium, meglumine (N-methylglucosamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine, and zinc.

[0048] As used herein, the term "pharmaceutical composition" means a composition suitable for pharmaceutical use.

[0049] As used herein, the terms “prevention” or “preventing” refer to the avoidance of the disease in subjects who do not have the disease.

[0050] As used herein, “reconstruction” refers to the process of restoring a dried, lyophilized, dehydrated, or concentrated substance to its original or liquid state by adding a solvent to the lyophilized substance, rehydrating the lyophilized substance, and then agitating the mixture of solvent and lyophilized substance. The reconstructed substance can be a product, formulation, sample, raw material, or part of any biological material, but is certainly not limited to substances falling under the common definition of these terms. Reconstruction can be visually assessed. A lyophilized substance is considered reconstructed when a homogeneous suspension is observed. Specifically, a suspension with a turbid appearance is considered appropriately reconstructed.

[0051] As used herein, the term “self-administration” means administration by someone other than a healthcare professional, such as a patient administering a pharmaceutical composition to themselves or others in addition to a healthcare professional administering the composition to them.

[0052] As used in this article, the terms “subject” or “patient” refer to a person.

[0053] As used herein, the term “treatment” or “treating” means to alleviate a particular condition, eliminate or reduce the symptoms of the condition, slow or eliminate the progression, invasion or spread of the condition, and reduce or delay the recurrence of the condition in a previously ill subject.

[0054] As used in this article, the term "diameter" refers to the volume equivalent diameter of a sphere.

[0055] As used in this article, the term “Cmax” refers to the maximum observed plasma concentration.

[0056] As used in this article, the term “Ctau” refers to glutathione concentration, which is the concentration reached immediately before the next dose is administered.

[0057] As used in this article, the term "tmax" refers to the time after administration of a substance to the observed maximum plasma concentration (tmax) of that substance.

[0058] As used herein, the term “area under the curve” or “AUC” refers to the area under a concentration-time curve (of a substance in plasma). AUC can be a measure of the integral of the instantaneous concentration over a time interval and has mass*time / volume per unit. AUC is typically calculated using a trapezoidal method (e.g., linear, linear logarithmic). AUC is typically given for time intervals from zero to infinity (AUC(0-inf)) and indicates other time intervals (e.g., AUC(t1,t2), where t1 and t2 are the start and end times of the interval).

[0059] As used herein, the term “about” generally means ±5%, ±10%, ±15%, or ±20% of the value of a number used with it. In one embodiment, the term “about” means ±10% of the value of a number used with it.

[0060] As used herein, the term "CD4 binding site (CD4bs) binding protein" refers to an antibody and other protein constructs, such as domains, capable of binding to the CD4 binding site of the HIV envelope glycoprotein (gp120). In this document, "CD4bs binding protein," "CD4bs binding domain," and "CD4bs antigen-binding protein" are used interchangeably. This does not include natural homologous ligands or receptors. In some embodiments, this document provides monoclonal antibodies and their antigen-binding fragments that bind to and neutralize HIV-1 at the CD4 binding site on gp120. In some embodiments, the CD4bs binding protein comprises N6 and N6LS, or antigen-binding fragments thereof.

[0061] As used herein, the term “antibody” in the broadest sense refers to molecules having immunoglobulin-like domains (e.g., IgG, IgM, IgA, IgD, or IgE), and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugated antibodies; single variable domain (e.g., domain-dependent antibodies (DABs)), 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 forms of “antibody”, see Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136).

[0062] As used interchangeably herein, the terms “full-length antibody or immunoglobulin,” “whole antibody or immunoglobulin,” and “intact antibody or immunoglobulin” refer to heterotetrameric glycoproteins with a molecular weight of approximately 150,000 Daltons. An intact antibody consists of two identical heavy chains (HC) and two identical light chains (LC) linked by covalent disulfide bonds. This H2L2 structure folds to form three functional domains, including two antigen-binding fragments (referred to as “Fab” fragments) and one crystallizable fragment, “Fc.” The Fab fragment consists of a variable domain at the N-terminus (a variable heavy chain (VH) or a variable light chain (VL)) and a constant domain at the C-terminus (CH1 (heavy chain) and CL (light chain)). The Fc fragment consists of two domains formed by the dimerization of paired CH2 and CH3 regions. Fc can induce effector function by binding to receptors on immune cells or by binding to C1q (the first component of the classical complement pathway). The five classes of antibodies—IgM, IgA, IgG, IgE, and IgD—are defined by different heavy chain amino acid sequences, referred to as μ, α, γ, ε, and δ, respectively. Each heavy chain can pair with either a K or λ light chain. Most antibodies in serum belong to the IgG class, and four human IgG isotypes exist (IgG1, IgG2, IgG3, and IgG4), whose sequences differ primarily in their hinge regions.

[0063] Fully human antibodies can be obtained using various methods, such as using yeast-based libraries or transgenic animals (e.g., mice) capable of producing all the components of human antibodies. Yeast containing human antibodies that bind to the antigen of interest on its surface can be selected using FACS (fluorescence-activated cell sorting) based methods or by capturing labeled antigens on beads. Transgenic animals modified to express human immunoglobulin genes can be immunized with the antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. The desired properties of the human antibodies produced using these techniques can then be characterized, such as affinity, spreadability, and selectivity.

[0064] Alternative antibody forms include alternative scaffolds in which one or more CDRs of an antigen-binding protein can be aligned onto a suitable non-immunoglobulin protein scaffold or backbone, such as an affinity protein, SpA scaffold, LDL receptor class A domain, Avimer (see, for example, U.S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301), or EGF domain.

[0065] As used herein, the term "broadly neutralizing antibody" (bnAb) is defined as an antibody that inhibits viral attachment and cell entry by binding to HIV envelope glycoproteins (Env) (e.g., gp160, gp120, gp41), and, as a non-limiting example, exhibits 50% inhibition of infection in vitro against a large group (greater than 100) of HIV-1 envelope pseudotyped viruses and viral isolates of more than 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more. See, for example, U.S. Patent Application Publication No. 20120121597; Burton et al., Broadly Neutralizing Antibodies to HIV and Their Role in Vaccine Design. AnnuRev Immunol. 2016 May 20; 34:635-59.

[0066] As used herein, “CDR” is defined as the amino acid sequence of the complementarity-determining region of an antigen-binding protein. These are hypervariable regions of the heavy and light chains of immunoglobulins. Three heavy chain and three light chain CDRs (or CDR regions) exist in the variable portions of immunoglobulins. Therefore, as used herein, “CDR” refers to all three heavy chain CDRs, all three light chain CDRs, all heavy chain and light chain CDRs, or at least two CDRs.

[0067] Throughout this specification, amino acid residues within the variable domain sequences and variable domain regions of the full-length antigen-binding sequence, such as within the antibody heavy chain or antibody light chain sequences, are numbered according to Kabat numbering conventions. Similarly, the terms “CDR,” “CDRL1,” “CDRL2,” “CDRL3,” “CDRH1,” “CDRH2,” and “CDRH3” used in the examples follow Kabat numbering conventions. For more information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4. th Ed., US Department of Health and Human Services, National Institutes of Health (1987).

[0068] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. Alternative numbering conventions also exist for CDR sequences, such as those detailed in Chothia et al. (1989) Nature 342: 877-883. The structure and protein folding of antigen-binding proteins may mean that other residues are considered part of the CDR sequence, and this will be understood by those skilled in the art.

[0069] Other numbering conventions for CDR sequences available to technicians include the “AbM” (University of Bath) and “Contact” (University College London) methods.

[0070] Table 1 below presents one definition for each CDR or binding unit using each numbering convention. The Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequences. It should be noted that some of the CDR definitions may vary depending on the individual publication used.

[0071] Table 1

[0072]

[0073] As used herein, “antibody half-life” (or “serum 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 a protein 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, a radiolabeled protein is intravenously injected into mice, and its plasma concentration is periodically measured as a function of time (e.g., from approximately 3 minutes to approximately 72 hours after injection). Other methods for pharmacokinetic analysis and determination of the serum half-life of molecules will be familiar to those skilled in the art.

[0074] The antigen-binding protein of the present invention may have amino acid modifications that increase the affinity of a constant domain or fragment thereof for FcRn. Increasing the serum half-life of therapeutic and diagnostic IgG antibodies and other bioactive molecules has numerous benefits, including reducing the amount and / or frequency of administration of these molecules. In one embodiment, the antigen-binding protein of the present invention comprises all or part of an IgG constant domain (FcRn binding portion), said IgG constant domain having one or more of the following amino acid modifications.

[0075] For example, regarding IgG1, M252Y / S254T / T256E (commonly referred to as the "YTE" mutation) and M428L / N434S (commonly referred to as the "LS" mutation) 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 (see IgG1 and Kabat numbering) (Monnet et al.). Serum half-life and FcRn binding can also be prolonged by introducing H433K and N434F mutations (commonly referred to as the "HN" or "Nhance" mutations) (see IgG1) (WO2006 / 130834).

[0076] Invention Statement

[0077] This invention provides a pharmaceutical composition comprising:

[0078] Caboteway;

[0079] wetting agent;

[0080] stabilizers; and

[0081] Tension regulator;

[0082] Cabotewe exists in the form of particles with a median mass diameter (X50) between 2.5 µm and 10 µm (including 2.5 µm and 10 µm).

[0083] For example, embodiments of the present invention provide a pharmaceutical composition comprising cabotevir with a median diameter (X50) between 2.5 µm and 10 µm (and including 2.5 µm and 10 µm); polysorbate 80; sodium CMC; and mannitol.

[0084] The pharmaceutical compositions described herein may be administered via any suitable route. In a preferred embodiment, the composition is administered parenterally (including subcutaneously, intramuscularly, intravenously, or intradermally). In one embodiment, the composition is administered intramuscularly. In another embodiment, the composition is administered subcutaneously.

[0085] Caboteway

[0086] Cabotevir ((3S,11aR)-N-((2,4-difluorophenyl)methyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,11,11a-hexahydro(1,3)oxazolo(3,2-a)pyrido(1,2-d)pyrazin-8-carboxamide) is described in Examples Z-9 of US 8,129,385, which is incorporated herein by reference. Cabotevir is an integrase strand transfer inhibitor (INSTI) exhibiting sub-nanomolar efficacy and antiviral activity against a broad range of HIV-1 strains. Oral administration of cabotevir has demonstrated an acceptable safety and tolerability profile, a long half-life, and minimal drug-drug interactions. Cabotegravir has been proven effective in treating and preventing HIV in both oral and parenteral formulations. See, for example, Margolis DA, Brinson CC, Eron JJ et al., 744 and Rilpivirine as Two Drug Oral Maintenance Therapy: LAI116482 (LATTE) Week 48 Results. 21st Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA, Margolis DA, Podzamczer D, Stellbrink HJ et al., Cabotegravir + Rilpivirine as Long-Acting Maintenance Therapy: LATTE-2 Week 48 Results. 21st 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., ÉCLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Abstract presented in 23 rdCROI; February 22-25, 2016; Boston, MA. Cabotevir has been approved by the U.S. FDA for long-acting prevention of HIV infection with a dosing regimen every two months; and in combination with rilpivirine for long-acting treatment of HIV infection with a dosing regimen every month or every two months.

[0087] Cabotway formula (I) represents:

[0088] (I).

[0089] In embodiments of the present invention, cabotevir exists as a free acid in the pharmaceutical composition.

[0090] The pharmaceutical composition of the present invention comprises particles of crystalline cabotevir. In one embodiment, the X50 value of the cabotevir particles in the pharmaceutical composition is greater than or equal to 2.5 µm and less than or equal to 10 µm (i.e., 2.5 µm ≤ X50 ≤ 10 µm). The particle size distribution can be measured by any suitable method, for example, by laser diffraction as described in the Examples section herein.

[0091] Unwilling to be bound by theory, some believe that larger drug particle size advantageously alters absorption kinetics, thus allowing for ultra-long-acting treatment. They also believe that larger drug particle size advantageously reduces injection site reactions, thereby improving patient experience.

[0092] Furthermore, it is believed that, due to the reduced specific surface area of ​​the drug substance resulting in slower drug reservoir dissolution, injectable microsuspensions can provide additional sustained therapeutic effects beyond those of commercial nanosuspensions. When compared to commercial nanosuspensions, the prolonged dissolution can further enhance patient compliance and treatment efficacy.

[0093] Highly effective hydrophobic compounds such as cabotevir may benefit from increased specific surface area through reduced size, thereby increasing drug dissolution in vivo. However, optimizing the particle size of these compounds can affect the resulting pharmacokinetic properties—smaller crystal sizes of the active substance may dissolve faster than larger crystal sizes due to the increased relative surface area. Therefore, suspensions with larger average particle sizes can exhibit prolonged and more controlled release characteristics from the injected reservoir compared to suspensions with smaller average particle sizes. In one embodiment, the pharmaceutical composition has a prolonged release characteristic of 1 month or longer. In another embodiment, the pharmaceutical composition has a prolonged release characteristic of 2 months or longer. In another embodiment, the pharmaceutical composition has a prolonged release characteristic of 3 months or longer. In another embodiment, the pharmaceutical composition has a prolonged release characteristic of 4 months or longer. In another embodiment, the pharmaceutical composition has a prolonged release characteristic of 5 months or longer. In another embodiment, the pharmaceutical composition has a prolonged release characteristic of 6 months or longer.

[0094] In one embodiment, the pharmaceutical composition contains about 100 to about 800 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition contains about 200 mg / mL to about 700 mg / mL, about 300 mg / mL to about 650 mg / mL, about 400 mg / mL to about 600 mg / mL, about 450 mg / mL to about 600 mg / mL, about 500 mg / mL to about 600 mg / mL, about 550 mg / mL to about 600 mg / mL, about 400 mg / mL, about 500 mg / mL, or about 533 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition contains about 400 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition contains about 533 mg / mL of cabobetavir.

[0095] In one embodiment, the pharmaceutical composition has been reconstituted from a lyophilized powder and contains about 100 to about 800 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition, after reconstitution, contains about 200 mg / mL to about 700 mg / mL, about 300 mg / mL to about 650 mg / mL, about 400 mg / mL to about 600 mg / mL, about 400, about 500, or about 533 mg / mL of cabobetavir. In one embodiment, the pharmaceutical composition, after reconstitution, contains about 400 mg / mL of cabobetavir. In a further embodiment, the pharmaceutical composition, after reconstitution, contains about 533 mg / mL of cabobetavir. In yet another embodiment, the pharmaceutical composition contains 533 mg / mL of cabobetavir.

[0096] In another embodiment, the pharmaceutical composition contains cabotevir in an amount between about 300 mg and about 4800 mg. In one embodiment, the pharmaceutical composition contains cabotevir in an amount between about 350 mg and about 4000 mg. In one embodiment, the pharmaceutical composition contains cabotevir in an amount between about 375 mg and about 3200 mg. In one embodiment, the pharmaceutical composition contains cabotevir in an amount between about 400 mg and about 2000 mg. In one embodiment, the pharmaceutical composition contains 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 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, or about 1200 mg. mg, approximately 1225 mg, approximately 1250 mg, approximately 1275 mg, approximately 1300 mg, approximately 1325 mg, approximately 1350 mg, approximately 1375 mg, approximately 1400 mg, approximately 1425 mg, approximately 1450 mg, approximately 1475 mg, approximately 1500 mg, approximately 1525 mg, approximately 1550 mg, approximately 1575 mg, approximately 1600 mg, approximately 1625 mg, approximately 1650 mg, approximately 1675 mg, approximately 1700 mg, approximately 1725 mg, approximately 1750 mg, approximately 1775 mg, approximately 1800 mg, approximately 1825 mg, approximately 1850 mg, approximately 1875 mg, approximately 1900 mg, approximately 1925 mg, approximately 1950 mg, approximately 1975 mg, approximately 2000 mg, approximately 2025 mg, approximately 2050 mg, approximately 2075 mg mg, approximately 2100 mg, approximately 2125 mg, approximately 2150 mg, approximately 2175 mg, approximately 2200 mg, approximately 2225 mg, approximately 2250 mg, approximately 2275 mg, approximately 2300 mg, approximately 2325 mg, approximately 2350 mg, approximately 2375 mg, approximately 2400 mg, approximately 2425 mg, approximately 2450 mg, approximately 2475 mg, approximately 2500 mg, approximately 2525 mg, approximately 2550 mg, approximately 2575 mg, approximately 2600 mgCabozantvir in amounts of approximately 2625 mg, approximately 2650 mg, approximately 2675 mg, approximately 2700 mg, approximately 2725 mg, approximately 2750 mg, approximately 2775 mg, approximately 2800 mg, approximately 2825 mg, approximately 2850 mg, approximately 2875 mg, approximately 2900 mg, approximately 2925 mg, approximately 2950 mg, approximately 2975 mg, approximately 3000 mg, approximately 3025 mg, approximately 3050 mg, approximately 3075 mg, approximately 3100 mg, approximately 3125 mg, approximately 3150 mg, approximately 3175 mg, or approximately 3200 mg. In one embodiment, the pharmaceutical composition contains approximately 800 mg of cabozantvir. In one embodiment, the pharmaceutical composition contains approximately 1600 mg of cabozantvir. In one embodiment, the pharmaceutical composition contains approximately 2665 mg of cabozantvir. In one embodiment, the pharmaceutical composition contains about 3200 mg of cabotevir. In one embodiment, the pharmaceutical composition contains about 4000 mg of cabotevir. In one embodiment, the pharmaceutical composition contains about 4800 mg of cabotevir.

[0097] wetting agent

[0098] Wetting agents, or surfactants, are compounds that, when dissolved in a liquid, reduce the surface tension of gaseous, liquid, or solid surfaces within that liquid. They are typically amphiphilic and can contribute to wetting and enhancing the manufacturability of pharmaceutical products. Furthermore, surfactants can impart long-term stability to products through steric or electrostatic repulsion. Nonionic surfactants are preferred over ionic surfactants because they are generally nontoxic, non-irritating, and inert. Examples of surfactants include, but are not limited to: polysorbate 20 (Tween-20), polysorbate 80 (Tween-80), sorbitol monolaurate (Span-20), sorbitol monooleate (Span-80), poloxamer 188 (Kolliphor P188), poloxamer 338 (Kolliphor P338), and poloxamer 407 (Kolliphor P407).

[0099] In one embodiment, the pharmaceutical composition of the present invention comprises polysorbate 80 (PS80) as a wetting agent.

[0100] PS80 (IUPAC name: Polyoxyethylene (20) dehydrated sorbitan monooleate; CAS No. 9005-65-6) is a nonionic surfactant and emulsifier derived from polyethoxylated dehydrated sorbitan and oleic acid. The hydrophilic group in PS80 is a polyether, also known as a polyoxyethylene group, which is a polymer of ethylene oxide. In the nomenclature of polysorbates, the number following "polysorbate" (e.g., "polysorbate 80") indicates the lipophilic group, in this case, oleic acid. The structure of PS80 is provided by formula (II):

[0101] (II)

[0102] The inventors unexpectedly discovered that the use of PS80 in lyophilized microsuspensions resulted in superior in vivo performance, tolerability, and greater production flexibility.

[0103] In one embodiment, the pharmaceutical composition contains a wetting agent of about 0.1 mg / mL to about 150 mg / mL. In a further embodiment, the pharmaceutical composition contains a wetting agent of about 1 mg / mL to about 80 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2.5 mg / mL to about 6 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

[0104] In one embodiment, the pharmaceutical composition contains about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 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, 5.7, 5.8, 5.9, or 6.0 mg / mL of wetting agent. In another embodiment, the pharmaceutical composition contains about 3.0 mg / mL of wetting agent. In another embodiment, the pharmaceutical composition contains about 4.0 mg / mL of wetting agent. In yet another embodiment, the pharmaceutical composition contains about 5.3 mg / mL of wetting agent.

[0105] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains a wetting agent of about 0.1 mg / mL to about 150 mg / mL. In a further embodiment, the pharmaceutical composition, after reconstitution, contains a wetting agent of about 1 mg / mL to about 80 mg / mL, about 2 mg / mL to about 40 mg / mL, about 2.5 mg / mL to about 6 mg / mL, or about 2.5 mg / mL to about 5 mg / mL.

[0106] In one embodiment, the pharmaceutical composition has been reconstituted from a lyophilized powder and contains a wetting agent of about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 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, 5.7, 5.8, 5.9, or 6.0 mg / mL. In another embodiment, the pharmaceutical composition contains a wetting agent of about 3.0 mg / mL after reconstitution. In yet another embodiment, the pharmaceutical composition contains a wetting agent of about 4.0 mg / mL after reconstitution. In another embodiment, the pharmaceutical composition contains about 5.3 mg / mL of wetting agent after reconstitution.

[0107] In one embodiment, the pharmaceutical composition contains about 0.1 mg to about 900 mg of a wetting agent. In another embodiment, the pharmaceutical composition contains about 0.5 mg to about 200 mg of a wetting agent. In another embodiment, the pharmaceutical composition contains about 1.0 mg to about 100 mg of a wetting agent. In another embodiment, the pharmaceutical composition contains about 2.0 mg to about 50 mg of a wetting agent. In yet 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, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 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, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7 1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 1 1.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15 9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 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、21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42. 6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45. 1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47. The composition comprises a wetting agent of 6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0 mg. In one embodiment, the pharmaceutical composition comprises about 5.9 mg of wetting agent. In another embodiment, the pharmaceutical composition comprises about 8.0 mg of wetting agent.

[0108] In one embodiment, the weight ratio of the wetting agent to cabotevir is in the range of 1:10 to 1:400. In another embodiment, the weight ratio of the wetting agent to cabotevir is in the range of 1:50 to 1:200. In yet another embodiment, the weight ratio of the wetting agent to cabotevir is 1:100 to 1:150. In another embodiment, the weight ratio of the wetting agent to cabotevir 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. The ratios are approximately 1:124, 1:125, 1:126, 1:127, 1:128, 1:129, 1:130, 1:131, 1:132, 1:133, 1:134, 1:135, 1:136, 1:137, 1:138, 1:139, 1:140, 1:141, 1:142, 1:143, 1:144, 1:145, 1:146, 1:147, 1:148, 1:149, or 1:150. In another embodiment, the weight ratio of the wetting agent to cabotevir is approximately 1:100. In another embodiment, the weight ratio of the wetting agent to cabotevir is approximately 1:105. In another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:110. In another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:115. In yet another embodiment, the weight ratio of the wetting agent to cabotevir is about 1:136.

[0109] stabilizer

[0110] Stabilizers are ingredients added to help maintain key product properties throughout their shelf life. In the case of suspensions, stabilizers can be used to induce charge effects, increase steric stabilization, increase the viscosity of the medium, etc. These factors can maintain particle size, product resuspendability, and / or improve manufacturability. Examples of stabilizers include, but are not limited to, sodium carboxymethyl cellulose (CMC), polyethylene glycol 3350, polyethylene glycol 4000, povidone K12, and povidone K17.

[0111] In one embodiment, the pharmaceutical composition of the present invention comprises sodium CMC as a stabilizer.

[0112] In one embodiment, the pharmaceutical composition contains about 0.1 to about 150 mg / mL of a stabilizer. In a further embodiment, the pharmaceutical composition contains about 1 mg / mL to about 25 mg / mL, about 2 mg / mL to about 15 mg / mL, about 2 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 10 mg / mL of a stabilizer.

[0113] In one embodiment, the pharmaceutical composition contains about (in mg / mL) 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 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, 5.7 The pharmaceutical composition contains stabilizers of approximately 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In another embodiment, the pharmaceutical composition contains about 3.7 mg / mL of stabilizer. In another embodiment, the pharmaceutical composition contains about 5.0 mg / mL of stabilizer. In another embodiment, the pharmaceutical composition contains about 6.7 mg / mL of stabilizer.

[0114] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains a stabilizer of about 0.1 to about 150 mg / mL. In a further embodiment, the pharmaceutical composition, after reconstitution, contains a stabilizer of about 1 mg / mL to about 25 mg / mL, about 2 mg / mL to about 15 mg / mL, about 2 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 10 mg / mL.

[0115] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains approximately (in mg / mL) 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 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 The pharmaceutical composition contains a stabilizer of 6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0. In another embodiment, the pharmaceutical composition contains about 3.7 mg / mL of stabilizer after reconstitution. In yet another embodiment, the pharmaceutical composition contains about 5.0 mg / mL of stabilizer after reconstitution. In another embodiment, the pharmaceutical composition contains approximately 6.7 mg / mL of stabilizer after reconstitution.

[0116] In one embodiment, the pharmaceutical composition contains about 0.1 mg to about 300 mg of stabilizer. In another embodiment, the pharmaceutical composition contains about 1.0 mg to about 200 mg of stabilizer. In another embodiment, the pharmaceutical composition contains about 2.0 mg to about 100 mg of stabilizer. In another embodiment, the pharmaceutical composition contains about 4.0 mg to about 50 mg of stabilizer. In yet another embodiment, 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, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9 1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 1 3.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17 5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4, 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 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, 21.6、21.7、21.8、21.9、22.0、22.1、22.2、22.3、22.4、22.5、22.6、22.7、22.8、22.9、23.0、23.1、23.2、23.3、23.4、23.5、23.6、23.7、23.8、23.9、24.0、24.1、24.2、24.3、24.4、24.5、24.6、24.7、24.8、24.9、25.0、25.1、25.2、25.3、25.4、25.5、25.6、25.7、25.8、25.9、26.0、26.1、26.2、26.3、26.4、26.5、26.6、26.7、26.8、26.9、27.0、27.1、27.2、27.3、27.4、27.5、27.6、27.7、27.8、27.9、28.0、28.1、28.2、28.3、28.4、28.5、28.6、28.7、28.8、28.9、29.0、29.1、29.2、29.3、29.4、29.5、29.6、29.7、29.8、29.9、30.0、30.1、30.2、30.3、30.4、30.5、30.6、30.7、30.8、30.9、31.0、31.1、31.2、31.3、31.4、31.5、31.6、31.7、31.8、31.9、32.0、32.1、32.2、32.3、32.4、32.5、32.6、32.7、32.8、32.9、33.0、33.1、33.2、33.3、33.4、33.5、33.6、33.7、33.8、33.9、34.0、34.1、34.2、34.3、34.4、34.5、34.6、34.7、34.8、34.9、35.0、35.1、35.2、35.3、35.4、35.5、35.6、35.7、35.8、35.9、36.0、36.1、36.2、36.3、36.4、36.5、36.6、36.7、36.8、36.9、37.0、37.1、37.2、37.3、37.4、37.5、37.6、37.7、37.8、37.9、38.0、38.1、38.2、38.3、38.4、38.5、38.6、38.7、38.8、38.9、39.0、39.1、39.2、39.3、39.4、39.5、39.6、39.7、39.8、39.9、40.0、40.1、40.2、40.3、40.4、40.5、40.6、40.7、40.8、40.9、41.0、41.2、41.3、41.4、41.5、41.6、41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45. The stabilizer comprises 9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0. In one embodiment, the pharmaceutical composition comprises about 7.4 mg of stabilizer. In another embodiment, the pharmaceutical composition comprises about 10.0 mg of stabilizer. .

[0117] In one embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:10 to 1:400. In another embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:40 to 1:200. In yet another embodiment, the weight ratio of the stabilizer to cabotevir is in the range of 1:70 to 1:120. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:70, 1:71, 1:72, 1:73, 1:74, 1:75, 1:76, 1:77, 1:78, 1:79, 1:80, 1:81, 1:82, 1:83, 1:84, 1:85, 1:86, 1:87, 1:88, 1:89, 1:90, 1:91, 1:92, 1:93, 1:94, or approximately 1... The ratios are approximately 1:95, 1:96, 1:97, 1:98, 1:99, 1:100, 1:101, 1:102, 1:103, 1:104, 1:105, 1:106, 1:107, 1:108, 1:109, 1:110, 1:111, 1:112, 1:113, 1:114, 1:115, 1:116, 1:117, 1:118, 1:119, or 1:120. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:80. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:100. In another embodiment, the weight ratio of the stabilizer to cabotevir is approximately 1:101. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:102. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:103. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:104. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:105. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:106. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:107. In another embodiment, the weight ratio of the stabilizer to cabosorbide is about 1:108.

[0118] Tension regulator

[0119] The role of the tension modifier is to provide and maintain stable tension in the pharmaceutical compositions disclosed herein. In some embodiments, the tension modifier also acts as a non-aqueous solvent, solubilizer, and / or stabilizer. In this case, if the primary purpose of the tension modifier is stability, it may be used at a concentration higher than that required for tension, or if the primary purpose of the tension modifier is tension regulation, it may be used at a concentration higher than that required for stability.

[0120] In some embodiments, the tonic modifier is a pharmaceutically acceptable inorganic chloride, such as potassium chloride, sodium chloride, magnesium chloride, or calcium chloride. In still other embodiments, the tonic modifier is a sugar, such as mannitol, sorbitol, lactose, trehalose, raffinose, dextrose, maltose, galactose, sucrose, or polysucrose. In a further aspect, the tonic modifier is mannitol. In other aspects, the tonic modifier is a non-aqueous polar aprotic or protic material, such as polyethylene glycol, N,N-dimethylacetamide, N-methylpyrrolidone, glycerol, propylene glycol, ethanol, tert-butanol, benzyl alcohol, benzyl benzoate, dimethyl sulfoxide, or glycerol. In a further aspect, the tonic modifier is a polymer, such as polyethylene glycol, polygalacturonic acid, galacturonic acid, polyvinylpyrrolidone (PVP), such as PEG 300, PEG 400, PEG 3350, PEG 6000, or PEG 8000. In other respects, tension modifiers are amino acids, such as lysine, arginine, glycine, methionine, or other amino acids. In yet another respect, tension modifiers are cyclodextrins, such as dextran, Ficoll, and polyvinylpyrrolidone, as well as other similar excipients and combinations thereof.

[0121] In one embodiment, the pharmaceutical composition of the present invention comprises mannitol as a tension modulator.

[0122] In one embodiment, the pharmaceutical composition contains about 0.1 to about 250 mg / mL of a tension modulator. In a further embodiment, the pharmaceutical composition contains about 1 mg / mL to about 150 mg / mL, about 10 mg / mL to about 125 mg / mL, about 15 mg / mL to about 60 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 20 mg / mL to about 40 mg / mL of a tension modulator.

[0123] In one embodiment, the pharmaceutical composition contains approximately (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, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24. 8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 2 9.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42 1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47.4, 4 The pharmaceutical composition contains a tension modifier at concentrations of 7.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0. In another embodiment, the pharmaceutical composition contains about 25.9 mg / mL of a tension modifier. In another embodiment, the pharmaceutical composition contains about 35.0 mg / mL of a tension modifier. In yet another embodiment, the pharmaceutical composition contains about 46.6 mg / mL of a tension modifier.

[0124] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains about 0.1 to about 250 mg / mL of a tonic modulator. In a further embodiment, the pharmaceutical composition, after reconstitution, contains about 1 mg / mL to about 150 mg / mL, about 10 mg / mL to about 125 mg / mL, about 15 mg / mL to about 60 mg / mL, about 15 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 20 mg / mL to about 40 mg / mL of a tonic modulator.

[0125] In one embodiment, the pharmaceutical composition has been reconstituted from lyophilized powder and contains approximately (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, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1, 26.2, 26.3, 26.4, 26.5, 26.6 26.7, 26.8, 26.9, 27.0, 27.1, 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1, 31.2, 31.3, 31.4, 31.5, 31. 6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34. 1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36. 6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 4 1.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3, 47 The pharmaceutical composition contains a tonic modulator at concentrations of 4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.0. In another embodiment, the pharmaceutical composition, after reconstitution, contains about 25.9 mg / mL of a tonic modulator. In another embodiment, the pharmaceutical composition, after reconstitution, contains about 35.0 mg / mL of a tonic modulator. In yet another embodiment, the pharmaceutical composition, after reconstitution, contains about 46.6 mg / mL of a tonic modulator.

[0126] In one embodiment, the pharmaceutical composition contains about 0.1 mg to about 400 mg of a tension modulator. In another embodiment, the pharmaceutical composition contains about 1.0 mg to about 300 mg of a tension modulator. In another embodiment, the pharmaceutical composition contains about 10 mg to about 100 mg of a tension modulator. In another embodiment, the pharmaceutical composition contains about 35 mg to about 80 mg of a tension modulator. In yet 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, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1, 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1, 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 44.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47. 2, 47.3, 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1, 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1, 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, 51.0, 51.1, 51.2, 51.3、51.4、51.5、51.6、51.7、51.8、51.9、52.0、52.1、52.2、52.3、52.4、52.5、52.6、52.7、52.8、52.9、53.0、53.1、53.2、53.3、53.4、53.5、53.6、53.7、53.8、53.9、54.0、54.1、54.2、54.3、54.4、54.5、54.6、54.7、54.8、54.9、55.0、55.1、55.2、55.3、55.4、55.5、55.6、55.7、55.8、55.9、56.0、56.1、56.2、56.3、56.4、56.5、56.6、56.7、56.8、56.9、57.0、57.1、57.2、57.3、57.4、57.5、57.6、57.7、57.8、57.9、58.0、58.1、58.2、58.3、58.4、58.5、58.6、58.7、58.8、58.9、59.0、59.1、59.2、59.3、59.4、59.5、59.6、59.7、59.8、59.9、60.0、60.1、60.2、60.3、60.4、60.5、60.6、60.7、60.8、60.9、61.0、61.1、61.2、61.3、61.4、61.5、61.6、61.7、61.8、61.9、62.0、62.1、62.2、62.3、62.4、62.5、62.6、62.7、62.8、62.9、63.0、63.1、63.2、63.3、63.4、63.5、63.6、63.7、63.8、63.9、64.0、64.1、64.2、64.3、64.4、64.5、64.6、64.7、64.8、64.9、65.0、65.1、65.2、65.3、65.4、65.5、65.6、65.7、65.8、65.9、66.0、66.1、66.2、66.3、66.4、66.5、66.6、66.7、66.8、66.9、67.0、67.1、67.2、67.3、67.4、67.5、67.6、67.7、67.8、67.9、68.0、68.1、68.2、68.3、68.4、68.5、68.6、68.7、68.8、68.9、69.0、69.1、69.2、69.3、69.4、69.5、69.6、69.7、69.8、69.9、70.0、70.1、70.2、70.3、70.4、70.5、70.6、70.7、70.8、70.9、71.0、71.1、71.2、71.3, 71.4, 71.5, 71.6, 71.7, 71.8, 71.9, 72.0, 72.1, 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.8, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.7, 73.8, 73.9, 74.0, 74.1, 74.2, 74.3, 74.4, 74.5, 74.6, 74.7, 74.8, 74.9, 75.0, 75.1, 75.2, 75.3, 75.4, 75.5, 75.6, 75.7 The composition comprises a tension modulator in the following proportions: 75.8, 75.9, 76.0, 76.1, 76.2, 76.3, 76.4, 76.5, 76.6, 76.7, 76.8, 76.9, 77.0, 77.1, 77.2, 77.3, 77.4, 77.5, 77.6, 77.7, 77.8, 77.9, 78.0, 78.1, 78.2, 78.3, 78.4, 78.5, 78.6, 78.7, 78.8, 78.9, 79.0, 79.1, 79.2, 79.3, 79.4, 79.5, 79.6, 79.7, 79.8, 79.9, or 80.0. In one embodiment, the pharmaceutical composition comprises about 51.8 mg of the tension modulator. In one embodiment, the pharmaceutical composition comprises about 70 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 105 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 140 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 175 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 210 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 245 mg of a tension modulator. In one embodiment, the pharmaceutical composition comprises about 280 mg of a tension modulator.

[0127] In one embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:1 to 1:100. In another embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:5 to 1:50. In another embodiment, the weight ratio of the tension modifier to cabobetavir is in the range of 1:8 to 1:25. In another embodiment, the weight ratio of the tension modifier to cabobetavir 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. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:8. In another embodiment, the weight ratio of the tension modifier to cabobetavir is about 1:9. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:10. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:11. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:12. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:13. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:14. In another embodiment, the weight ratio of the tension modifier to cabobetavir is approximately 1:15.

[0128] Cabotway particle size

[0129] The dissolution properties of a pharmaceutical composition are particularly affected by the particle size and particle size distribution of the active pharmaceutical ingredient (i.e., cabotevir).

[0130] As used herein, X50 (or “X50 value”) is the diameter of Cabotene particles in micrometers, at which 50% by volume of Cabotene particles 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.

[0131] As used herein, X90 (or “X90 value”) is the diameter of a Cabotevir particle in micrometers, at which 90% by volume of Cabotevir particles have a smaller diameter and 10% by volume have a larger diameter.

[0132] As used herein, X10 (or “X10 value”) is the diameter of the cabotubevir particle in micrometers, at which 10% by volume of cabotubevir particles have a smaller diameter and 90% by volume have a larger diameter.

[0133] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabobetavir particles have a particle diameter less than or equal to 25 µm (i.e., X90 is 25 µm). In one embodiment, the X90 value of the cabobetavir particles in the pharmaceutical composition is greater than or equal to 5 µm and less than or equal to 25 µm (i.e., 5 µm ≤ X90 ≤ 25 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabobetavir particles have a particle diameter less than or equal to 20 µm (i.e., X90 is 20 µm). In one embodiment, the X90 value of the cabobetavir particles in the pharmaceutical composition is greater than or equal to 6 µm and less than or equal to 20 µm (i.e., 6 µm ≤ X90 ≤ 20 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabobetavir particles have a particle diameter less than or equal to 18 µm (i.e., X90 is 18 µm). In one embodiment, the X90 value of the cabotevir particles of the pharmaceutical composition is greater than or equal to 7 µm and less than or equal to 18 µm (i.e., 7 µm ≤ X90 ≤ 18 µm).

[0134] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabotevir particles (X90) have a particle diameter less than or equal to 7.0 µm, 7.1 µm, 7.2 µm, 7.3 µm, 7.4 µm, 7.5 µm, 7.6 µm, 7.7 µm, 7.8 µm, 7.9 µm, 8.0 µm, 8.1 µm, 8.2 µm, 8.3 µm, 8.4 µm, 8.5 µm, 8.6 µm, 8.7 µm, 8.8 µm, 8.9 µm, 9.0 µm, 9.1 µm, 9.2 µm, 9.3 µm, 9.4 µm, 9.5 µm, 9.6 µm, 9.7 µm, 9.8 µm, 9.9 µm, 10.0 µm, 10.1 µm, 10.2 µm, 10.3 µm, 10.4 µm, 10.5 µm, 10.6 µm, 10.7 µm, 10.8 µm, 10.9 µm, 10.0 µm, 10.1 µm, 10.2 µm, 10.3 ...9 µm, 10.9 µm, 10.9 µm, 10.0 µm, 10.9 µm, 10.9 µm, 10.9 µm, 10.9 µm, 10.9 µm, 10.9 µm, 1 µm, 10.4 µm, 10.5 µm, 10.6 µm, 10.7 µm, 10.8 µm, 10.9 µm, 11.0 µm, 11.1 µm, 11.2 µm, 11.3 µm, 11.4 µm, 11.5 µm, 11.6 µm, 11.7 µm, 11.8 µm, 11.9 µm, 12.0 µm, 12.1 µm, 12.2 µm, 12.3 µm, 12.4 µm, 12.5 µm, 12.6 µm, 12.7µm, 12.8 µm, 12.9 µm, 13.0 µm, 13.1 µm, 13.2 µm, 13.3 µm, 13.4 µm, 13.5 µm, 13.6 µm, 13.7 µm, 13.8 µm, 13.9 µm, 14.0 µm, 14.1 µm, 14.2 µm, 14.3 µm, 14.4 µm, 14.5 µm, 14.6µm, 14.7 µm, 14.8 µm, 14.9 µm, 15.0 µm, 15.1 µm, 15.2 µm, 15.3 µm, 15.4 µm, 15.5 µm, 15.6 µm, 15.7 µm, 15.8 µm, 15.9 µm, 16.0 µm, 16.1 µm, 16.2 µm, 16.3 µm, 16.4 µm, 16.5µm, 16.6 µm, 16.7 µm, 16.8 µm, 16.9 µm, 17.0 µm, 17.1 µm, 17.2 µm, 17.3 µm, 17.4 µm, 17.5 µm, 17.6 µm, 17.7 µm, 17.8 µm, 17.9 µm, or 18.0 µm. In another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabotevir particles (X90) have a particle diameter of less than or equal to 9 µm (i.e., X90 is 9 µm).In another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabotevir particles (X90) have a particle diameter of less than or equal to 14 µm (i.e., X90 is 14 µm). In another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 90% of the cabotevir particles (X90) have a particle diameter of less than or equal to 17 µm (i.e., X90 is 17 µm).

[0135] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 50% of the cabobetavir particles have a particle diameter less than or equal to 10 µm (i.e., X50 is 10 µm). In one embodiment, the X50 value of the cabobetavir particles in the pharmaceutical composition is greater than or equal to 2.5 µm and less than or equal to 10 µm (i.e., 2.5 µm ≤ X50 ≤ 10 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 50% of the cabobetavir particles have a particle diameter less than or equal to 8.5 µm (i.e., X50 is 8.5 µm). In one embodiment, the X50 value of the cabobetavir particles in the pharmaceutical composition is greater than or equal to 3 µm and less than or equal to 8.5 µm (i.e., 3 µm ≤ X50 ≤ 8.5 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 50% of the cabobetavir particles have a particle diameter less than or equal to 8 µm (i.e., X50 is 8 µm). In one embodiment, the X50 value of the cabotabevir particles of the pharmaceutical composition is greater than or equal to 3.5 µm and less than or equal to 8 µm (i.e., 3.5 µm ≤ X50 ≤ 8 µm). In another embodiment, the X50 value of the cabotabevir particles of the pharmaceutical composition is greater than or equal to 3 µm and less than or equal to 6 µm (i.e., 3 µm ≤ X50 ≤ 6 µm).

[0136] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 50% of the cabotevir particles (X50) have a particle diameter less than or equal to 3.0 µm, 3.1 µm, 3.2 µm, 3.3 µm, 3.4 µm, 3.5 µm, 3.6 µm, 3.7 µm, 3.8 µm, 3.9 µm, 4.0 µm, 4.1 µm, 4.2 µm, 4.3 µm, 4.4 µm, 4.5 µm, 4.6 µm, 4.7 µm, 4.8 µm, 4.9 µm, 5.0 µm, 5.1 µm, 5.2 µm, 5.3 µm, 5.4 µm, 5.5 µm, 5.6 µm, 5.7 µm, 5.8 µm, 5.9 µm, 6.0 µm, 6.1 µm, 6.2 µm, 6.3 µm, 6.4 µm, etc. The particle size distribution of the pharmaceutical composition is 6.5 µm, 6.6 µm, 6.7 µm, 6.8 µm, 6.9 µm, 7.0 µm, 7.1 µm, 7.2 µm, 7.3 µm, 7.4 µm, 7.5 µm, 7.6 µm, 7.7 µm, 7.8 µm, 7.9 µm, or 8.0 µm. In another embodiment, the particle size distribution of the pharmaceutical composition (by volume) is such that 50% of the cabotevir particles (X50) have a particle diameter of less than or equal to 4 µm (i.e., X50 is 4 µm). In another embodiment, the particle size distribution of the pharmaceutical composition (by volume) is such that 50% of the cabotevir particles (X50) have a particle diameter of less than or equal to 6 µm (i.e., X50 is 6 µm).

[0137] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 10% of the cabotabevir particles have a particle diameter less than or equal to 4 µm (i.e., x10 = 4 µm). In one embodiment, the x10 value of the cabotabevir particles in the pharmaceutical composition is greater than or equal to 0.5 µm and less than or equal to 4 µm (i.e., 0.5 µm ≤ x10 ≤ 4 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 10% of the cabotabevir particles have a particle diameter less than or equal to 3.5 µm. In one embodiment, the x10 value of the cabotabevir particles in the pharmaceutical composition is greater than or equal to 1 µm and less than or equal to 3.5 µm (i.e., 1 µm ≤ x10 ≤ 3.5 µm). In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that 10% of the cabotabevir particles have a particle diameter less than or equal to 3 µm. In one embodiment, the X10 value of the cabotevir particles of the pharmaceutical composition is greater than or equal to 1.5 µm and less than or equal to 3 µm (i.e., 1.5 µm ≤ X10 ≤ 3 µm).

[0138] In one embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that the particle diameter of 10% cabotevir particles (X10) is less than or equal to 1.0 µm, 1.1 µm, 1.2 µm, 1.3 µm, 1.4 µm, 1.5 µm, 1.6 µm, 1.7 µm, 1.8 µm, 1.9 µm, 2.0 µm, 2.1 µm, 2.2 µm, 2.3 µm, 2.4 µm, 2.5 µm, 2.6 µm, 2.7 µm, 2.8 µm, 2.9 µm, 3.0 µm, 3.1 µm, 3.2 µm, 3.3 µm, 3.4 µm, 3.5 µm, 3.6 µm, 3.7 µm, 3.8 µm, 3.9 µm, or 4.0 µm. In another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that the particle diameter of 10% of the cabotabevir particles (X10) is less than or equal to 1.7 µm (i.e., X10 is 1.7 µm). In another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that the particle diameter of 10% of the cabotabevir particles (X10) is less than or equal to 2.2 µm (i.e., X10 is 2.2 µm). In yet another embodiment, the particle size distribution (by volume) of the pharmaceutical composition is such that the particle diameter of 10% of the cabotabevir particles (X10) is less than or equal to 2.6 µm (i.e., X10 is 2.6 µm).

[0139] In one embodiment, all X90, X50, and X10 values ​​described herein are volumetric and determined by laser diffraction. Laser diffraction is sensitive to particle volume and provides the volume-average particle size, which, if the density is constant, is equivalent to the weight-average particle size. It will be apparent to those skilled in the art that results from particle size distribution determined by one technique can be correlated with results from another technique, for example, based on experience from routine experiments. Furthermore, particle size distribution can also be determined by microscopy, particularly electron microscopy or scanning electron microscopy.

[0140] freeze-dried form

[0141] For aqueous drug suspensions, one pathway to long-term failure is irreversible product sedimentation, which prevents these systems from easily resuspending within the expected product shelf life. In these physically unstable conditions, drug concentrations may be uneven in the vial at administration, potentially leading to inconsistent product dosages for patients. The physical stability of suspensions can be greatly affected by the size of the suspended particles. Particle sizes reduced to below a few hundred nanometers can be stabilized by a variety of factors, such as Brownian motion, spatial stability through excipients, electrical stability, flocculation, etc., all of which minimize the effects of van der Waals forces between particles that could lead to irreversible product sedimentation. However, particles in the micrometer range, due to their relatively large size, may experience greater sedimentation rates and forces, which can overwhelm the stabilizing forces that separate the particles. If these hydrophobic particles interact directly with each other in an aqueous environment, particle aggregation—leading to irreversible sedimentation—is likely to occur. Therefore, the inventors' discovery of lyophilized formulations of cabotevir in micrometer particles (as opposed to nanoparticles) is both surprising and unexpected, as reversible sedimentation of the micrometer particles has been observed. In fact, the sedimentation of the cabotevir microparticle suspension, previously thought to be irreversible, surprisingly showed to be reversible after freeze-drying. Due to this reversibility, the freeze-dried cabotevir microparticle suspension (or microsuspension) unexpectedly extended its shelf life (e.g., at least two years when stored at up to 30°C).

[0142] Freeze-drying includes at least a freezing step and a sublimation step. Freeze-drying can be used to prepare pharmaceutical products and their intermediates. During freezing, the material is cooled to a temperature in which the solid, liquid, and gas phases of the material can exist. Active pharmaceutical ingredients (APIs) can be freeze-dried to achieve chemical and physical stability that allows for storage at room temperature. This differs from traditional methods that utilize heat to evaporate water. The advantages of freeze-drying may include, but are not limited to, enhanced stability of the dried powder, removal of water without overheating the product, and enhanced product stability in a dry state.

[0143] In an exemplary method for preparing the lyophilized formulation of the present invention, micronized cabotevir free acid is packaged in an antistatic linear low-density polyethylene bag. The packaged cabotevir is sealed in a corrugated plastic box and subjected to gamma irradiation as a bioburden reduction step, referred to as gamma-irradiated cabotevir. The gamma-irradiated cabotevir is dispersed in a filtered aqueous medium containing a stabilizer (e.g., sodium CMC), a tensiating agent (e.g., mannitol), and a wetting agent (e.g., PS80). The resulting suspension is filled into washed, sterilized / pyrogen-free 10 mL Type I clear glass vials. The container materials are then treated: the vials are depyrogenated by dry heat, and the stoppers and overseals are sterilized by steam. The product vials are lyophilized, backwashed with nitrogen, sealed with halogenated butyl rubber stoppers, and secured with an aluminum overseal seal. The sealed vials are finally sterilized by gamma irradiation. See also Figure 1 and Figure 2 .

[0144] As demonstrated in the embodiments illustrating certain representative embodiments of the invention, the inventors have developed lyophilized pharmaceutical compositions and methods for obtaining said compositions (which allow for larger-sized cabotevir particles). The data provided herein indicate that such lyophilized pharmaceutical compositions reduce injection site reactions and contribute to improved pharmacokinetic properties, thus addressing one or more of the aforementioned problems in the art.

[0145] In one embodiment, the lyophilized pharmaceutical composition is a suspension. The lyophilized pharmaceutical composition is advantageously suspended in an aqueous or non-aqueous solution during reconstitution, i.e., all or substantially all, for example, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or 100% of the lyophilized pharmaceutical composition is suspended during reconstitution.

[0146] Reconstruction can be assessed visually. A homogeneous suspension is considered reconstructed when the lyophilized material is observed. In particular, a suspension with a turbid appearance is considered appropriately reconstructed.

[0147] It will be apparent to those skilled in the art that the pharmaceutical compositions described herein can be reconstituted to desired concentrations in aqueous or non-aqueous solutions. For example, the pharmaceutical compositions described in Examples 1-3 below can be reconstituted in 1.7 mL of water to achieve a cabotevir concentration of 400 mg / mL. Similarly, the same pharmaceutical compositions described in Examples 1-3 below can be reconstituted in 1.1 mL of water to achieve a cabotevir concentration of 533 mg / mL.

[0148] In one embodiment, this disclosure provides a lyophilized pharmaceutical composition comprising cabobotevir, wherein cabobotevir is present in particulate form with a median mass diameter (X50) between 2.5 μm and 10 μm (and including 2.5 μm and 10 μm); a wetting agent; a stabilizer; and a tension modifier; wherein, when reconstituted in an aqueous solution, the formulation has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less. In another embodiment, this disclosure provides a lyophilized pharmaceutical composition comprising cabobotevir, wherein cabobotevir is present in particulate form with a median mass diameter (X50) between 2.5 µm and 10 µm (and including 2.5 μm and 10 μm); PS80; sodium CMC; and mannitol; wherein, when reconstituted in an aqueous or non-aqueous solution, the formulation has a reconstitution time of 15 minutes or less, 10 minutes or less, or 5 minutes or less.

[0149] Exemplary Implementation

[0150] In one embodiment, the pharmaceutical composition comprises cabotevir, mannitol, PS80, and CMC sodium; wherein cabotevir is present in particulate form with a median mass diameter (X50) between 2.5 µm and 10 µm (and including 2.5 µm and 10 µm).

[0151] In one embodiment, the pharmaceutical composition comprises:

[0152]

[0153] While the above embodiments describe vials containing 800 mg of cabotevir, various vial sizes can accommodate larger or smaller amounts of cabotevir, with the amounts of stabilizers (e.g., sodium carboxymethyl cellulose), tension modifiers (e.g., mannitol), and wetting agents (e.g., polysorbate 80) varying proportionally. The reconstitution filling volume can be adjusted to achieve the desired cabotevir concentration. In one embodiment, the pharmaceutical composition is prepared in vials of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mL. In one embodiment, the pharmaceutical composition is prepared in a 25 mL vial. It is believed that 25 mL vials improve the lyophilization, reconstitution time, and vial extraction of the pharmaceutical composition.

[0154] In one embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X50 = 6 µm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X10 = 2.2 µm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X90 = 17 µm); 51.8 mg mannitol; 5.9 mg PS80; and 7.4 mg CMC sodium.

[0155] In one embodiment, the pharmaceutical composition comprises 800 mg cabotevir (X50 = 6 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg (X10 = 2.6 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabotevir (X90 = 14 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium.

[0156] In one embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X50 = 4 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X10 = 1.7 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium. In yet another embodiment, the pharmaceutical composition comprises 800 mg cabobotevir (X90 = 9 µm); 70.0 mg mannitol; 8.0 mg PS80; and 10.0 mg CMC sodium.

[0157] In another embodiment, the pharmaceutical composition comprises cabotevir, wherein cabotevir is present in particulate form with an X50 value greater than or equal to 3.5 µm and less than or equal to 8 µm; PS80; CMC sodium; and mannitol; wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.75.

[0158] In another embodiment, the pharmaceutical composition comprises cabotevir, wherein cabotevir is present in particulate form with an X50 value greater than or equal to 3.5 µm and less than or equal to 8 µm; PS80; CMC sodium; and mannitol; wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.9.

[0159] In another embodiment, the pharmaceutical composition, after lyophilization and reconstitution, is as described in Tables 2a-1 and 2a-2:

[0160] Table 2a-1

[0161]

[0162] Table 2a-2

[0163]

[0164] In another embodiment, the pharmaceutical composition, after lyophilization and reconstitution, is as described in Tables 2b-1 and 2b-2:

[0165] Table 2b-1

[0166]

[0167] Table 2b-2

[0168]

[0169] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 2c:

[0170] Table 2c

[0171]

[0172] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 2d:

[0173] Table 2d

[0174]

[0175] In another embodiment, the pharmaceutical composition, after lyophilization and reconstruction with 1.7 or 1.1 mL of water, is as described in Table 2e:

[0176] Table 2e

[0177]

[0178] pH

[0179] In one embodiment, the pharmaceutical composition of the present invention has a pH of about 4 or higher. If the composition is administered by injection, a pH of about 4 or higher relieves the patient's pain. In one embodiment, the pharmaceutical composition of the present invention has a pH of about 6.5. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 4 to about 8. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 5 to about 7. In an alternative embodiment, the pH of the pharmaceutical composition is in the range of about 6 to about 7.

[0180] Optional co-application

[0181] In one embodiment, the pharmaceutical composition described herein is administered in combination with a broad-spectrum neutralizing antibody. In some embodiments, the broad-spectrum neutralizing antibody is selected from VRC01, VRC01-LS, N6, N6LS, VRC07, and VRC07-523. Examples of VRC01 disclosed are described in U.S. Patent No. 8,637,036. Examples of VRC01-LS disclosed are described in WO 2012 / 106578. Examples of N6 and N6LS disclosed are described in WO 2016 / 196975. Examples of VRC07 and VRC07-523 disclosed are described in U.S. Patent No. 8,637,036, U.S. Patent Publication No. 2014 / 0322163 A1, WO 2016 / 196975, and WO 2017 / 79479.

[0182] In one embodiment, the broad-spectrum neutralizing antibody is an isolated N6 monoclonal antibody or its antigen-binding fragment comprising a heavy chain complementarity-determining region (CDRH) having the CDRH1 amino acid sequence of SEQ ID NO: 1, the CDRH2 amino acid sequence of SEQ ID NO: 2, and the CDRH3 amino acid sequence of SEQ ID NO: 3; and a light chain complementarity-determining region (CDRL) having the CDRL1 amino acid sequence of SEQ ID NO: 4, the CDRL2 amino acid sequence of SEQ ID NO: 5, and the CDRH3 amino acid sequence of SEQ ID NO: 6.

[0183] In one embodiment, the broad-spectrum neutralizing antibody is an isolated N6LS monoclonal antibody or antigen-binding fragment comprising a heavy chain complementarity-determining region (CDRH) having the amino acid sequences of CDRH1 (SEQ ID NO: 1), CDRH2 (SEQ ID NO: 2), and CDRH3 (SEQ ID NO: 3); a light chain complementarity-determining region (CDRL) having the amino acid sequences of CDRL1 (SEQ ID NO: 4), CDRL2 (SEQ ID NO: 5), and CDRH3 (SEQ ID NO: 6); and a recombinant constant domain containing the M428L and N434S mutations. In some embodiments, the antigen-binding fragment is an Fv, Fab, F(ab')2, scFv, or scFV2 ​​fragment.

[0184] In some implementations, the broad-spectrum neutralizing antibody contains amino acid substitutions that increase binding to FcRn. Several such substitutions are known to those skilled in the art, such as substitutions at T250Q and M428L in the IgG constant region (see, e.g., Hinton et al., J Immunol, 176:346-356, 2006); substitutions at M428L and N434S (“LS” mutation, see, e.g., Zalevsky et al., Nature Biotechnology, 28:157-159, 2010); substitutions at N434A (see, e.g., Petkova et al., Int. Immunol, 18:1759-1769, 2006); T307A, E380A, and N434A (see, e.g., Petkova et al., Int. Immunol, 18:1759-1769, 2006); and M252Y, S254T, and T256E (see, e.g., Dall'Acqua et al., J. Biol. Chem., 281:23514-23524, 2006). The disclosed antibody and antigen-binding fragment can be linked to an Fc peptide comprising any of the substitutions listed above, for example, the Fc peptide may comprise M428L and N434S substitutions. In some embodiments, the antibody comprises a recombinant constant domain comprising modifications that increase binding to the neonatal Fc receptor relative to an unmodified constant domain, wherein the recombinant domain is an IgG1 constant domain comprising M428L and N434S mutations.

[0185] In one embodiment, the neutralizing antibody is N6-LS. N6-LS is a broad-spectrum neutralizing antibody comprising (a) a VH containing heavy chain complementarity-determining regions (HCDR)1, HCDR2, and HCDR3 of the heavy chain variable region (VH) as shown in SEQ ID NO: 1; (b) a VL containing light chain complementarity-determining regions (LCDR)1, LCDR2, and LCDR3 of the light chain variable region (VL) as shown in SEQ ID NO: 2, or a VL containing an amino acid sequence having 90% identity with one of SEQ ID NO: 2; or (c) a combination of (a) and (b); the antibody further comprising an IgG1 constant domain including M428L and N434S mutations; and wherein the antibody or antigen-binding fragment specifically binds to HIV-1 gpl20 and neutralizes HIV-1 infection.

[0186] In one embodiment, the 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).

[0187] The pharmaceutical composition may be administered in combination with a capsid inhibitor. In one embodiment, the capsid inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0188]

[0189] Equation (III)

[0190] in:

[0191] G 1 It is a phenyl group that is substituted once by the following: -N(CH3)S(O2)CH3, -S(O2)C(CH3)3, -CHF2, -CF3, -OCHF2, -OCF3 or -C(CH3)2OH, provided that G ... 1 When it is -CHF2 or -CF3, G 1 Not in alignment, or G 1 It is one of the following:

[0192] ;

[0193] G 2 and G 3 Independently selected from H or -CH3;

[0194] G 4 It is H, -CH3, or -OCH3;

[0195] G 4a It is -CH3 or -OCH3;

[0196] G 5 It is -CH3 or CH2CH3;

[0197] G 6 It is H, -CH3, or CH2CH3;

[0198] G 7 It is ethyl, isopropyl, tert-butyl, -CHF2, or -CF3;

[0199] G 8 It is H, methyl, ethyl, -CHF2, -CF3, -OCH3 or -OCH2CH3;

[0200] G 9 It is ethyl, isopropyl, cyclopropyl, -CH2OH, -OCH3;

[0201] G 10 It is ethyl, isopropyl, cyclopropyl, tert-butyl, -CHF2, or -CF3;

[0202] G 11 These are methyl, -OCH3, -CHF2, -CF3, -S(O2)CH3;

[0203] G 12 It is F, -CH3, -CHF2, -CF3, -OCH3, -S(O2)CH3;

[0204] G 13 It is C1-C4 alkyl, C1-C6 cycloalkyl, -CH2O (C1-C3 alkyl);

[0205] G 14 It is H, C1-C4 alkyl, -CHF2, -CF3, -O (C1-C3 alkyl);

[0206] G 15 It is H, F, -CH3, or OCH3;

[0207] R 3 It is H, F, Cl, -CH3, or -OCH3;

[0208] R 4It is an H or C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with 1-3 fluorine atoms;

[0209] R 5 It is a C1-C6 alkyl or a C3-C6 cycloalkyl;

[0210] W is selected from:

[0211]

[0212] Where R 6 The methyl group is optionally substituted with 1-3 fluorine atoms.

[0213] Compound (III) is described in WO 2020 / 084492, which is incorporated herein by reference. In one embodiment, the capsid inhibitor is compound 1 or a pharmaceutically acceptable salt thereof. Compound 1 is described in WO 2020 / 084492 as Example 59, which is incorporated herein by reference.

[0214] Compound 1.

[0215] In one embodiment, the capsid inhibitor is compound 2 or a pharmaceutically acceptable salt thereof. Compound 2 is described as Example 1 in patent application number PCT / IB2020 / 055653, which is incorporated herein by reference.

[0216] Compound 2.

[0217] In an alternative implementation, the capsid inhibitor is lenacapavir.

[0218] This pharmaceutical composition can be administered in combination with a maturation inhibitor. In one embodiment, the maturation inhibitor is a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0219] Formula (IV)

[0220] Where R1 is isopropenyl or isopropyl;

[0221] A is -C 1-6 Alkyl-ORO;

[0222] Where R0 is heteroaryl-Q0;

[0223] Q0 is selected from -H, -CN, -C 1-6 Alkyl, -COOH, -Ph, -OC 1-6 Alkyl, -halogen, -CF3,

[0224] Y is selected from -COOR2, -C(O)NR2SO2R3, -C(O)NHSO2NR2R2, -SO2NR2C(O)R2, -tetrazole, and -CONHOH.

[0225] Where n = 1 - 6;

[0226] R2 is -H, -C 1-6 Alkyl, -alkyl substituted C 1-6 alkyl or -aryl substituted C 1-6 alkyl;

[0227] W does not exist, or it is either -CH2- or -CO-;

[0228] R3 is -H, -C 1-6 alkyl or -alkyl substituted C 1-6 alkyl;

[0229] R4 is selected from -H, -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl, -C 1-6 Replacement -C 1-6 Alkyl, -C 1-6 Alkyl-Q1, -C 1-6 Alkyl-C 3-6 Cycloalkyl-Q1, aryl, heteroaryl, substituted heteroaryl, -COR6, -SO2R7, -SO2NR2R2 and

[0230] ,

[0231] G is selected from –O-, -SO2-, and -NR. 12 -;

[0232] Q1 is selected from -C 1-6 Alkyl, -C 1-6 Fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF3, -OR2, -COOR2, -NR8R9, -CONR8R9 and -SO2R7;

[0233] R5 is selected from -H, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -C 1-6 Alkyl-substituted alkyl, -C 1-6 Alkyl groups -NR8R9, -COR3, -SO2R7, and -SO2NR2R2;

[0234] The condition is that when W is -CO-, R4 or R5 is not -COR6;

[0235] A further condition is that only one R4 or R5 is selected from -COR6, -COCOR6, -SO2R7, and -SO2NR2R2;

[0236] R6 is selected from -H, -C 1-6 Alkyl, -C 1-6 Alkyl-substituted alkyl, -C 3-6 cycloalkyl, -C 3-6 Substituted cycloalkyl-Q2,-C 1-6 Alkyl-Q2, -C 1-6 Alkyl-substituted alkyl groups -Q2, -C 3-6 Cycloalkyl-Q2, aryl-Q2, -NR 13 R 14 and -OR 15 ;

[0237] Q2 is selected from aryl, heteroaryl, substituted heteroaryl, -OR2, -COOR2, -NR8R9, -SO2R7, -CONHSO2R3 and -CONHSO2NR2R2;

[0238] R7 is selected from –H, -C 1-6 Alkyl, -C 1-6 Substituted alkyl groups, -C 3-6 cycloalkyl, -CF3, aryl, and heteroaryl groups;

[0239] R8 and R9 are independently selected from -H and -C. 1-6 Alkyl, -C 1-6 Substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C 1-6 Alkyl groups -Q2 and -COOR3,

[0240] Alternatively, R8 and R9 together with the adjacent N form a ring selected from the following:

[0241]

[0242] M is selected from –R 15 , -SO2R2, -SO2NR2R2, -OH and –NR2R 12 ;

[0243] V is selected from –CR 10 R 11 -, -SO2-, -O- and –NR 12 -;

[0244] The condition is that only one of R8 or R9 can be -COOR3;

[0245] R 10 and R 11 Independently selected from -H, -C1-6 Alkyl, -C 1-6 Substituted alkyl groups and -C 3-6 cycloalkyl;

[0246] R 12 Selected from -H, -C 1-6 Alkyl, -alkyl substituted C 1-6 Alkyl groups, -CONR2R2, -SO2R3, and -SO2NR2R2;

[0247] R 13 and R 14 Independently selected from -H, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -C 1-6 Substituted alkyl groups, -C 1-6 Alkyl-Q3, -C 1-6 Alkyl-C 3-6 cycloalkyl-Q3 and C 1-6 Substituted alkyl group - Q3;

[0248] Q3 is selected from heteroaryl, substituted heteroaryl, and -NR2R. 12 -CONR2R2, -COOR2, -OR2, and -SO2R3;

[0249] R 15 Selected from -C 1-6 Alkyl, -C 3-6 cycloalkyl, -C 1-6 Substituted alkyl groups, -C 1-6 Alkyl-Q3, -C 1-6 Alkyl-C 3-6 cycloalkyl-Q3 and -C 1-6 Substituted alkyl group - Q3;

[0250] R 16 Selected from -H, -C 1-6 Alkyl groups, -NR2R2, and -COOR2;

[0251] The condition is that when V is –NR 12 -time; R 16 Not –NR2R2; and

[0252] R 17 Selected from -H, -C 1-6 Alkyl, -COOR3 and aryl.

[0253] Compound (IV) is described in WO 2017 / 134596, which is incorporated herein by reference. In one embodiment, the maturation inhibitor is compound 3. Compound 3 is described in WO 2017 / 134596 as Example 25, which is incorporated herein by reference.

[0254] Compound 3.

[0255] This pharmaceutical composition can be used in combination with NRTTI. In one embodiment, NRTTI is a compound of formula (V):

[0256] Formula (V)

[0257] in:

[0258] R 1 yes:

[0259]

[0260] in:

[0261] X is selected from NH2, F, and Cl;

[0262] R 5 Selected from H and (C1-C) 14 )alkyl;

[0263] R 6 Selected from H and -(C=O)-(C1-C 14 )alkyl;

[0264] R 2 Selected from (C1-C) 24 Alkyl group; (CH2) n1 -O-(CH2CH2O) n2 -(C1-C 14 Alkyl group), where n1 and n2 are integers independently selected from 1 to 4; -R 7 -NH-(C=O)-R 8 , where R 7 It can be (C1-C) 14 )alkyl, and R 8 It can be independently selected from H and (C1-C) 14 )alkyl; -R 9 -(C6-C 14 ) aryl, wherein R 9 It is a bond or (C1-C6) alkyl group; -R 10 -(C3-C 14 )cycloalkyl, wherein R 10 It is a bond or (C1-C6) alkyl; -(C1-C 20 )alkylene-(C=O)-OR 11 , where R 11 Optional from H and (C1-C) 20 )alkyl;

[0265]

[0266] and;

[0267] R 3 Selected from H, -(C=O)-(C1-C 24 )alkyl, -(C=O)-O-(C1-C 24 )alkyl; and C3-C 14 cycloalkyl; or

[0268] R 2 and R 3 Connected together to form C3 to C 28 The ring structure; and

[0269] The condition is that when R 2 For (C1-C 14 When alkyl), R 3 R 5 and R 6 At least one of them is not H.

[0270] Compound 3 is disclosed in WO 2020 / 178767, which is incorporated herein by reference. In one embodiment, the pharmaceutical composition of the present invention is combined with compound 4. Compound 4 is described in WO 2020 / 178767 as Example 18, which is incorporated herein by reference.

[0271] Compound 4

[0272] In an alternative implementation, NRTTI is Islatravir.

[0273] Methods of treating and preventing HIV

[0274] In a second aspect, the present invention provides a method for (a) treating HIV in a person in need, comprising administering to the person a therapeutically effective amount of a pharmaceutical composition as defined herein; and (b) preventing HIV in a person, comprising administering to the person an effective amount of a pharmaceutical composition as defined herein.

[0275] In one embodiment, the method includes parenteral administration of the pharmaceutical composition. In one embodiment, the pharmaceutical composition is administered intramuscularly. In one embodiment, the pharmaceutical composition is administered subcutaneously.

[0276] In one embodiment, the method includes administering about 1 mL to about 8 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 1 mL of the pharmaceutical composition to a patient. In another embodiment, the method includes administering about 2 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 3 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 4 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 5 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 6 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 7 mL of the pharmaceutical composition to a patient. In one embodiment, the method includes administering about 8 mL of the pharmaceutical composition to a patient.

[0277] In one embodiment, the pharmaceutical composition is administered with more than one injection. In one embodiment, the pharmaceutical composition is administered with two or more injections, which may be administered simultaneously or consecutively. For example, the pharmaceutical composition may be administered to a patient twice consecutively as a single injection (6 mL in total). In one embodiment, the pharmaceutical composition is administered with two injections. In one embodiment, the pharmaceutical composition is administered as a 1 mL injection. In one embodiment, the pharmaceutical composition is administered as a 2 mL injection. In one embodiment, the pharmaceutical composition is administered as a 3 mL injection.

[0278] In one embodiment, the patient is given about 300 mg to about 3200 mg of cabotevir in the pharmaceutical composition.

[0279] In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered about 800 mg to about 1600 mg of cabostatin. In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered 800 mg of cabostatin. In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered 1200 mg of cabostatin.

[0280] In one embodiment, the drug composition has a cabobetavir concentration of about 533 mg / mL, and about 1200 to about 3200 mg of cabobetavir is administered to a patient. In one embodiment, the drug composition has a cabobetavir concentration of about 533 mg / mL, and about 1600 mg of cabobetavir is administered to a patient. In one embodiment, the drug composition contains about 1600 mg of cabobetavir in a 3 mL injection. In one embodiment, the drug composition has a cabobetavir concentration of about 533 mg / mL, and about 2400 mg of cabobetavir is administered to a patient. In one embodiment, the drug composition contains about 2400 mg of cabobetavir in two 2 mL injections. In one embodiment, the drug composition has a cabobetavir concentration of about 533 mg / mL, and about 3200 mg of cabobetavir is administered to a patient. In one embodiment, the drug composition contains about 3200 mg of cabobetavir in three 3 mL injections.

[0281] In one embodiment, the pharmaceutical composition is administered to a patient every 1, 2, 3, 4, 5, or 6 months. In one embodiment, the pharmaceutical composition is administered to a person monthly. In an alternative embodiment, the pharmaceutical composition is administered every two months. In an alternative embodiment, the pharmaceutical composition is administered every three months. In an alternative embodiment, the pharmaceutical composition is administered every four months. In an alternative embodiment, the pharmaceutical composition is administered every five months. In an alternative embodiment, the pharmaceutical composition is administered every six months. In an alternative embodiment, the pharmaceutical composition is administered every 15 to 24 weeks. In one embodiment, the pharmaceutical composition is administered every 15 to 20 weeks or every 15 to 19 weeks.

[0282] In one embodiment, the pharmaceutical composition is administered once every 16 to 18 weeks. In another embodiment, the pharmaceutical composition is administered once every 16 weeks, or once every 17 weeks, or once every 18 weeks.

[0283] In one implementation, the pharmaceutical composition may be administered by any suitable method.

[0284] In one embodiment, the pharmaceutical composition may be administered subcutaneously. In this embodiment, the pharmaceutical composition may be administered subcutaneously by another person (e.g., a healthcare professional) or may be self-administered by the patient. In this embodiment, the pharmaceutical composition may be administered subcutaneously by injection. In one embodiment, the pharmaceutical composition is administered subcutaneously by injection. In one embodiment of the invention, the pharmaceutical composition is administered or self-administered monthly by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self-administered every two months by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self-administered every three months by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self-administered every four months by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self-administered every five months by subcutaneous injection. In another embodiment, the pharmaceutical composition is administered or self-administered every six months by subcutaneous injection. In one embodiment, the pharmaceutical composition is administered or self-administered with a single injection. In another embodiment, the pharmaceutical composition is administered or self-administered with two or more injections, which may be administered simultaneously or consecutively. In one embodiment, the pharmaceutical composition is administered or self-administered with two injections.

[0285] In another embodiment, the pharmaceutical composition is administered via intramuscular injection. In this embodiment, the pharmaceutical composition may be administered intramuscularly by another person (e.g., a healthcare professional) or may be self-administered by the patient. In one embodiment of the invention, the pharmaceutical composition is administered or self-administered monthly via intramuscular injection. In another embodiment, the pharmaceutical composition is administered or self-administered every two months via intramuscular injection. In another embodiment, the pharmaceutical composition is administered or self-administered every three months via intramuscular injection. In another embodiment, the pharmaceutical composition is administered or self-administered every four months via intramuscular injection. In another embodiment, the pharmaceutical composition is administered or self-administered every five months via intramuscular injection. In another embodiment, the pharmaceutical composition is administered or self-administered every six months via intramuscular injection. In one embodiment, the intramuscular injection is administered by a healthcare professional. In one embodiment, the pharmaceutical composition is administered as a single intramuscular injection during a visit with a healthcare professional. In another embodiment, the pharmaceutical composition is administered as two or more intramuscular injections during a single visit with a healthcare professional, which may be administered simultaneously or consecutively. In one embodiment, the pharmaceutical composition is administered as two intramuscular injections during a single visit with a healthcare professional, which may be administered simultaneously or consecutively. In another embodiment, the pharmaceutical composition is self-administered via a single intramuscular injection. In another embodiment, the pharmaceutical composition is self-administered via two or more intramuscular injections, which may be administered simultaneously or consecutively. In one embodiment, the pharmaceutical composition is self-administered via two intramuscular injections, which may be administered simultaneously or consecutively.

[0286] In one embodiment, the pharmaceutical composition of the present invention is administered in combination with other pharmaceutical compositions as components of a multi-drug treatment regimen. In one embodiment, the other pharmaceutical composition is a drug for treating or preventing HIV. Marketed drugs are currently available for the treatment of HIV.

[0287] In one embodiment, the pharmaceutical composition of the present invention is administered in combination with N6-LS. N6-LS is as described above.

[0288] In one embodiment, the pharmaceutical composition of the present invention is 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).

[0289] Uses for treating or preventing HIV

[0290] In a third aspect, the present invention provides pharmaceutical compositions as defined herein for the treatment or prevention of HIV.

[0291] In one embodiment, the use includes parenteral administration of the pharmaceutical composition. In one embodiment, the pharmaceutical composition is suitable for use as an injectable composition. In one embodiment, the use includes intramuscular administration of the pharmaceutical composition. In another embodiment, the use includes subcutaneous administration of the pharmaceutical composition.

[0292] In one embodiment, the use includes administering about 1 mL to about 8 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 1 mL of the pharmaceutical composition to a patient. In another embodiment, the use includes administering about 2 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 3 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 4 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 5 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 6 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 7 mL of the pharmaceutical composition to a patient. In one embodiment, the use includes administering about 8 mL of the pharmaceutical composition to a patient.

[0293] In one embodiment, the use includes administering the pharmaceutical composition with more than one injection. In another embodiment, the use includes administering the pharmaceutical composition with two or more injections, which may be administered simultaneously or consecutively. For example, a patient may be given two consecutive 3 mL (total 6 mL) injections of the pharmaceutical composition. In one embodiment, the use includes administering the pharmaceutical composition with two injections.

[0294] In one embodiment, the patient is given about 300 mg to about 3200 mg of cabotevir in the pharmaceutical composition.

[0295] In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered about 800 mg to about 1600 mg of cabostatin. In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered 800 mg of cabostatin. In one embodiment, the drug composition has a cabostatin concentration of about 400 mg / mL, and the patient is administered 1200 mg of cabostatin.

[0296] In one embodiment, the drug composition has a cabostatin concentration of about 533 mg / mL, and about 1200 to about 3200 mg of cabostatin is administered to the patient. In one embodiment, the drug composition has a cabostatin concentration of about 533 mg / mL, and about 1600 mg of cabostatin is administered to the patient. In one embodiment, the drug composition has a cabostatin concentration of about 533 mg / mL, and about 2400 mg of cabostatin is administered to the patient. In one embodiment, the drug composition has a cabostatin concentration of about 533 mg / mL, and about 3200 mg of cabostatin is administered to the patient.

[0297] In one embodiment, the use includes administering the drug to a patient once every 1, 2, 3, 4, 5, or 6 months. In one embodiment, the use includes administering the drug composition to a patient once a month. In an alternative embodiment, the use includes administering the drug composition once every two months. In an alternative embodiment, the use includes administering the drug composition once every three months. In an alternative embodiment, the use includes administering the drug composition once every four months. In an alternative embodiment, the use includes administering the drug composition once every five months. In an alternative embodiment, the use includes administering the drug composition once every six months.

[0298] In one embodiment, the use includes administering the pharmaceutical composition by any suitable means.

[0299] In one embodiment, the use includes self-administration of the pharmaceutical composition by a patient. In another embodiment, the use may include subcutaneous administration of the pharmaceutical composition via injection. In one embodiment of the invention, the use includes self-administration of the pharmaceutical composition once a month via subcutaneous injection. In another embodiment, the use includes self-administration of the pharmaceutical composition once every two months via subcutaneous injection. In another embodiment, the use includes self-administration of the pharmaceutical composition once every three months via subcutaneous injection. In another embodiment, the use includes self-administration of the pharmaceutical composition once every four months via subcutaneous injection. In another embodiment, the use includes self-administration of the pharmaceutical composition once every five months via subcutaneous injection. In another embodiment, the use includes self-administration of the pharmaceutical composition once every six months via subcutaneous injection. In one embodiment, the use includes self-administration of the pharmaceutical composition with a single injection. In another embodiment, the use includes self-administration of the pharmaceutical composition with two or more injections, which may be administered simultaneously or consecutively. In one embodiment, the use includes self-administration of the pharmaceutical composition with two injections.

[0300] In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection. In one embodiment of the invention, the use includes intramuscular administration of the pharmaceutical composition by injection once a month. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once every two months. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once every three months. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once every four months. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once every five months. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once every six months. In one embodiment, the intramuscular injection is administered by a healthcare professional. In one embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection once during a visit with a healthcare professional. In another embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection twice or more during a single visit with a healthcare professional, which may be administered simultaneously or consecutively. In one embodiment, the use includes intramuscular administration of the pharmaceutical composition by injection twice during a single visit with a healthcare professional.

[0301] In one embodiment of the invention, the use includes administering the pharmaceutical composition of the invention in combination with other pharmaceutical compositions as components of a multi-drug treatment regimen. In one embodiment, the other pharmaceutical composition is a medicine for treating or preventing HIV. Marketed medicines are currently available for treating HIV.

[0302] In one embodiment, the use includes administering the pharmaceutical composition of the present invention in combination with N6-LS. N6-LS is as described above.

[0303] In one embodiment, the use includes administering the pharmaceutical composition of the invention 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).

[0304] Reagent test kit

[0305] A fourth aspect of the invention provides a kit comprising cabotevir, wherein cabotevir is present in particulate form with an X50 value greater than or equal to 2.5 µm and less than or equal to 10 µm; a wetting agent; a stabilizer; and a tension modifier.

[0306] In one embodiment, the present invention provides a kit comprising a container containing a pharmaceutical composition according to the invention as a lyophilized powder. In one embodiment, the kit further comprises a container containing a liquid suitable for generating a reconstituted solution. In one embodiment, a suitable liquid is water. In one embodiment, a suitable liquid is water, and the container containing water is a pre-filled syringe. In one embodiment, the kit further comprises a needle suitable for dispensing water from the pre-filled syringe into the container containing the lyophilized composition of the invention. In an alternative embodiment, the kit comprises a needle suitable for injecting the reconstituted solution into a patient in need. In still a further embodiment, the kit comprises a needle suitable for dispensing water from the pre-filled syringe into the container containing the lyophilized composition of the invention and injecting the reconstituted solution into a patient in need. In one embodiment, the kit further comprises a leaflet containing instructions for use.

[0307] In one embodiment, the kit comprises a syringe or vial containing the composition of the present invention.

[0308] In one embodiment, the present invention provides a method for preparing a reconstituted solution, the method comprising providing a kit as described herein and contacting a lyophilized composition with a suitable liquid to produce a reconstituted solution. In one embodiment, the suitable liquid is an aqueous solvent. In another embodiment, the suitable liquid is water. In yet another embodiment, the suitable liquid is a non-aqueous solvent.

[0309] This disclosure further provides the following implementation schemes:

[0310] (a) A parenteral drug composition comprising a wetting agent, a stabilizer, a tension modifier and an effective amount of cabotevir for long-term treatment of HIV infection or for prevention of HIV infection in an individual at risk of HIV infection, wherein the composition is administered intermittently at intervals of at least one month.

[0311] (b) The composition according to (a), wherein the composition is applied once every 2 months.

[0312] (c) The composition according to (a), wherein the composition is applied once every 3 months.

[0313] (d) The composition according to (a), wherein the composition is applied once every 4 months.

[0314] (e) The composition according to (a), wherein the composition is applied once every 5 months.

[0315] (f) The composition according to (a), wherein the composition is applied once every 6 months.

[0316] (g) The composition according to any one of (a) to (f), wherein the wetting agent is polysorbate 80, the stabilizer is sodium carboxymethyl cellulose, and the tension modifier is mannitol.

[0317] (h) The composition according to any one of (a) to (g), wherein an effective amount of cabotevir is selected such that the plasma concentration of cabotevir in the subject remains at a level between a maximum plasma level and a minimum plasma level during an extended time period, the maximum plasma level being the plasma level that causes significant side effects, and the minimum plasma level being the lowest plasma level that causes cabotevir to provide effective treatment or prevention of HIV infection.

[0318] (i) the composition according to (h), wherein the subject’s plasma level is maintained at or above about 150 ng / ml, particularly at or above about 600 ng / ml.

[0319] (j) The composition according to any one of (a) to (i), wherein the composition is administered subcutaneously or intramuscularly.

[0320] The dosage of cabotevir administered (which is the amount of cabotevir used in the parenteral composition of the present invention) can be selected such that: the plasma concentration of cabotevir in humans is maintained above the trough plasma concentration (Ctau); or the plasma concentration in humans is maintained at or above Ctau of the approved 200 mg / mL cabotevir regimen (i.e., in the APRETUDE® dosing regimen).

[0321] Trough plasma level (Ctau) refers to trough plasma concentration, which is the concentration reached immediately before the next dose is administered. The Ctau value represents the lowest plasma drug level. Ctau can be measured in any suitable manner.

[0322] The inventors have discovered that, in order to maintain an effective dosing regimen for the treatment or prevention of HIV, the dose of cabozantvir (which is the amount of cabozantvir in the pharmaceutical composition used in this invention) should maintain Ctau at a level higher than the 10th percentile of Ctau observed in Phase 3 studies 201738 (HPTN 083) (for individuals designated as male at birth (1.05 μg / mL)) and 201739 (HPTN 084) (for individuals designated as female at birth (1.39 μg / mL)). The 10th percentile of Ctau observed in the mentioned Phase 3 studies is a sex-specific PrEP benchmark, which was achieved in at least 90% of participants.

[0323] The inventors have also discovered that, in order to maintain an effective dosing regimen for the treatment or prevention of HIV, in both individuals designated as male at birth and individuals designated as female at birth, the dose of cabotevir needs to maintain a median and 10th percentile of Ctau higher than the median and 10th percentile of Ctau for the approved 200 mg / mL intramuscular regimen of cabotevir (APRETUDE®).

[0324] Human cabotevir plasma levels can be maintained above these Ctau levels because at lower levels the drug may no longer be effective, increasing the risk of HIV transmission and potentially making it suboptimal for treatment in HIV-infected subjects. Higher cabotevir plasma levels help prevent the development of HIV mutations while maintaining a safety margin.

[0325] Implementation Plan

[0326] The following is a non-exhaustive list of embodiments of this disclosure:

[0327] Implementation Scheme 1: A pharmaceutical composition comprising:

[0328] Caboteway;

[0329] wetting agent;

[0330] stabilizers; and

[0331] Tension regulator;

[0332] Cabotewe exists in the form of particles with a median mass diameter (X50) between 2.5 µm and 10 µm (including 2.5 µm and 10 µm).

[0333] Implementation Scheme 2: The pharmaceutical composition according to Implementation Scheme 1, wherein the wetting agent is selected from polysorbate 20, polysorbate 80, sorbitol monolaurate, sorbitol monooleate, poloxamer 188, poloxamer 338 and poloxamer 407.

[0334] Implementation Scheme 3: The pharmaceutical composition according to Implementation Scheme 1 or Implementation Scheme 2, wherein the wetting agent is polysorbate 80.

[0335] Implementation Scheme 4: The pharmaceutical composition according to any one of Implementation Schemes 1-3, wherein the stabilizer is selected from sodium carboxymethyl cellulose, polyethylene glycol 3350, polyethylene glycol 4000, povidone K12 and povidone K17.

[0336] Implementation Scheme 5: The pharmaceutical composition according to any one of Implementation Schemes 1-4, wherein the stabilizer is sodium carboxymethyl cellulose.

[0337] Implementation Scheme 6: A pharmaceutical composition according to any one of Implementation Schemes 1-5, wherein the tension modifier is selected from mannitol, sorbitol, lactose, trehalose, raffinose, dextrose, maltose, galactose, sucrose, and polysucrose.

[0338] Implementation Scheme 7: The pharmaceutical composition according to any one of Implementation Schemes 1-6, wherein the tension modifier is mannitol.

[0339] Implementation Scheme 8: The pharmaceutical composition according to any one of Implementation Schemes 1-7, wherein the X90 value of the cabotevir particles is greater than or equal to 5 µm and less than or equal to 25 µm.

[0340] Implementation Scheme 9: The pharmaceutical composition according to any one of Implementation Schemes 1-8, wherein the X50 value of the cabotevir particles is greater than or equal to 3 µm and less than or equal to 8.5 µm.

[0341] Implementation Scheme 10: The pharmaceutical composition according to Implementation Scheme 9, wherein the X50 value of the cabotevir particles is greater than or equal to 3 µm and less than or equal to 8.5 µm, and wherein the X90 value of the cabotevir particles is greater than or equal to 6 µm and less than or equal to 20 µm.

[0342] Implementation Scheme 11: The pharmaceutical composition according to any one of Implementation Schemes 1-10, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 µm and less than or equal to 8.0 µm.

[0343] Implementation Scheme 12: The pharmaceutical composition according to any one of Implementation Schemes 1-11, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 µm and less than or equal to 8.0 µm, and wherein the X90 value of the cabotevir particles is greater than or equal to 7.0 µm and less than or equal to 18.0 µm.

[0344] Implementation Scheme 13: A pharmaceutical composition according to any one of Implementation Schemes 1-12, wherein cabotevir is present in an amount of about 300 mg to about 1800 mg.

[0345] Implementation Scheme 14: A pharmaceutical composition according to any one of Implementation Schemes 1-12, wherein cabotevir is present in an amount of about 350 mg to about 1650 mg.

[0346] Implementation Scheme 15: A pharmaceutical composition according to any one of Implementation Schemes 1-12, wherein cabotevir is present in an amount of about 800 mg.

[0347] Implementation Scheme 16: A pharmaceutical composition according to any one of Implementation Schemes 1-12, wherein cabotevir is present in an amount of about 1600 mg.

[0348] Implementation Scheme 17: A pharmaceutical composition according to any one of Implementation Schemes 1-16, wherein the weight ratio of the wetting agent to cabotevir is in the range of about 1:10 to about 1:400.

[0349] Implementation Scheme 18: A pharmaceutical composition according to any one of Implementation Schemes 1-17, wherein the weight ratio of the wetting agent to cabotevir is in the range of about 1:50 to about 1:200.

[0350] Implementation Scheme 19: A pharmaceutical composition according to any one of Implementation Schemes 1-18, wherein the weight ratio of the wetting agent to cabotevir is in the range of about 1:100 to about 1:150.

[0351] Implementation Scheme 20: A pharmaceutical composition according to any one of Implementation Schemes 1-19, wherein the weight ratio of the stabilizer to cabotevir is in the range of about 1:10 to about 1:400.

[0352] Implementation Scheme 21: A pharmaceutical composition according to any one of Implementation Schemes 1-20, wherein the weight ratio of the stabilizer to cabotevir is in the range of about 1:40 to about 1:200.

[0353] Implementation Scheme 22: The pharmaceutical composition according to any one of Implementation Schemes 1-21, wherein the weight ratio of the stabilizer to cabotevir is in the range of about 1:70 to about 1:120.

[0354] Implementation Scheme 23: The pharmaceutical composition according to any one of Implementation Schemes 1-22, wherein the weight ratio of the tension modifier to cabotevir is in the range of about 1:1 to about 1:100.

[0355] Implementation Scheme 24: A pharmaceutical composition according to any one of Implementation Schemes 1-23, wherein the weight ratio of the tension modifier to cabotevir is in the range of about 1:5 to about 1:50.

[0356] Implementation Scheme 25: A pharmaceutical composition according to any one of Implementation Schemes 1-24, wherein the weight ratio of the tension modifier to cabotevir is in the range of about 1:8 to about 1:25.

[0357] Implementation Scheme 26: A pharmaceutical composition according to any one of Implementation Schemes 1-25, wherein the wetting agent is polysorbate 80, wherein the stabilizer is sodium carboxymethyl cellulose, wherein the tension modifier is mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.75.

[0358] Implementation Scheme 27: A pharmaceutical composition according to any one of Implementation Schemes 1-25, wherein the wetting agent is polysorbate 80, wherein the stabilizer is sodium carboxymethyl cellulose, wherein the tension modifier is mannitol, and wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.9.

[0359] Implementation Scheme 28: A pharmaceutical composition according to any one of Implementation Schemes 1-27, wherein the pharmaceutical composition is provided as a lyophilized powder.

[0360] Implementation Scheme 29: A pharmaceutical composition according to any one of Implementation Schemes 1-28, wherein the concentration of cabotevir is in the range of about 100 mg / mL to about 800 mg / mL.

[0361] Implementation Scheme 30: The pharmaceutical composition according to Implementation Scheme 29, wherein the concentration of cabotevir is in the range of about 200 mg / mL to about 700 mg / mL.

[0362] Implementation Scheme 31: The pharmaceutical composition according to Implementation Scheme 29, wherein the concentration of cabotevir is in the range of about 300 mg / mL to about 650 mg / mL.

[0363] Implementation Scheme 32: The pharmaceutical composition according to Implementation Scheme 29, wherein the concentration of cabotevir is about 400 mg / mL.

[0364] Implementation Scheme 33: The pharmaceutical composition according to Implementation Scheme 29, wherein the concentration of cabotevir is about 533 mg / mL.

[0365] Implementation Scheme 34: A pharmaceutical composition according to any one of Implementation Schemes 1-33, wherein the pharmaceutical composition comprises:

[0366] (a) Reconstitute from lyophilized powder using a suitable liquid, or

[0367] (b) Provided as a liquid composition.

[0368] Implementation Scheme 35: The pharmaceutical composition according to Implementation Scheme 34, wherein the suitable liquid is an aqueous solvent.

[0369] Implementation Scheme 36: The pharmaceutical composition according to Implementation Scheme 34 or Implementation Scheme 35, wherein the suitable liquid is water.

[0370] Implementation Scheme 37: The pharmaceutical composition according to Implementation Scheme 34, wherein the suitable liquid is a non-aqueous solvent.

[0371] Implementation Scheme 38: A pharmaceutical composition according to any one of Implementation Schemes 1-37, wherein the pharmaceutical composition is formulated as a parenteral pharmaceutical composition.

[0372] Implementation Scheme 39: A pharmaceutical composition according to any one of Implementation Schemes 1-38, wherein the pharmaceutical composition is suitable for injection.

[0373] Implementation Scheme 40: The pharmaceutical composition according to Implementation Scheme 39, wherein the pharmaceutical composition is suitable for subcutaneous, subdermal or intramuscular injection.

[0374] Implementation Plan 41: A pharmaceutical composition according to any one of Implementation Plans 1-40, used for the treatment or prevention of HIV.

[0375] Implementation Scheme 42: A pharmaceutical composition for use according to Implementation Scheme 41, wherein the use includes the step of administering the pharmaceutical composition subcutaneously or intramuscularly to a human body.

[0376] Implementation Scheme 43: A pharmaceutical composition for use according to Implementation Scheme 42, wherein cabotevir is administered to a human at a dose of about 300 mg to about 3200 mg.

[0377] Implementation Scheme 44: A pharmaceutical composition for the use described in Implementation Scheme 42 or Implementation Scheme 43, wherein the use includes administering the pharmaceutical composition to a person once a month, once every two months, once every three months, once every four months, once every five months, or once every six months.

[0378] Implementation Scheme 45: A pharmaceutical composition for treating HIV according to Implementation Scheme 38, wherein the pharmaceutical composition is administered in combination with one or more nucleoside reverse transcriptase inhibitors (NRTTIs), one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs), one or more capsid inhibitors and / or one or more broad-spectrum neutralizing antibodies (bNAb).

[0379] Implementation Scheme 46: A method for treating HIV in a person in need, the method comprising administering to the person a therapeutically effective amount of a pharmaceutical composition according to any one of Implementation Schemes 1-41.

[0380] Implementation Scheme 47: A method for preventing HIV in a person, the method comprising administering to the person an effective amount of a pharmaceutical composition according to any one of Implementation Schemes 1-41.

[0381] Implementation Scheme 48: The method according to Implementation Scheme 46 or Implementation Scheme 47, wherein the method includes the step of administering the pharmaceutical composition subcutaneously or intramuscularly.

[0382] Implementation Scheme 49: The method according to any one of Implementation Schemes 46-48, wherein about 300 mg to about 3200 mg of cabotevir is administered to a person.

[0383] Implementation Scheme 50: The method according to any one of Implementation Schemes 46-49, wherein the method comprises administering the pharmaceutical composition to the person once a month, once every two months, once every three months, once every four months, once every five months, or once every six months.

[0384] Implementation Scheme 51: The method according to any one of Implementation Schemes 46-50, wherein the method comprises administering the pharmaceutical composition intramuscularly to a human every 4 months.

[0385] Implementation Scheme 52: The method according to any one of Implementation Schemes 46-51, wherein the method comprises administering the pharmaceutical composition in combination with one or more nucleoside reverse transcriptase inhibitors (NRTTIs), one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs), one or more capsid inhibitors and / or one or more broadly neutralizing antibodies (bnAbs).

[0386] Implementation Scheme 53: A kit comprising a container containing a pharmaceutical composition according to any one of Implementation Schemes 1-45 as a lyophilized powder.

[0387] Implementation Scheme 54: The kit according to Implementation Scheme 53, wherein the kit further comprises a container containing water.

[0388] Implementation Scheme 55: A method for preparing a reconstitution solution, the method comprising providing the kit of Implementation Scheme 53 and contacting the lyophilized composition with a suitable liquid to produce a reconstitution solution.

[0389] Implementation Scheme 56: The method according to Implementation Scheme 55, wherein the suitable liquid is an aqueous solvent.

[0390] Implementation Scheme 57: The method according to Implementation Scheme 55 or Implementation Scheme 56, wherein the suitable liquid is water.

[0391] Implementation Scheme 58: The method according to Implementation Scheme 55, wherein the suitable liquid is a non-aqueous solvent. Example

[0392] Comparative Example (Example 8 of WO 2021 / 116872A1):

[0393] A long-acting suspension containing 200 mg / mL cabotevir, 20 mg / mL PS20, and 20 mg / mL PEG3350 was studied to test the stability of cabotevir at concentrations increased to 400 mg / mL.

[0394] Suspensions were prepared in 250 mL batches using Netzsch miniCer and 0.3 mm YTZ beads. A range of excipient concentrations were explored.

[0395] A formulation mediator was prepared by dissolving polysorbate 20 (Croda), polyethylene glycol 3350 (Clariant), and mannitol (Roquette Freres) in water for injection (WFI) and filtering the solution through a 0.2 µm filter. The formulation mediator was then added to cabotevir (free acid) to prepare a 400 mg / mL crude suspension. The crude suspension was circulated at 73–145 mL / min through a wet bead mill (Netzsch MiniCer) containing 0.30 mm YTZ beads (Nikkato Corp) set at 29.7 Hz until a desired median particle diameter of less than 0.25 µm, as measured by laser diffraction, was achieved. The wet bead mill was cooled to maintain a temperature between 1 °C and 25 °C. The suspension was then filled into Type I glass vials, flushed with nitrogen, stoppered (FM457 stopper), and sealed. The filled suspension was finally sterilized by gamma irradiation at a minimum dose of 25 kGy.

[0396] 30 mg / mL PS20, 20 mg / mL PEG3350, and 19 mg / mL mannitol, and 400 mg / mL cabotevir were prepared. The γ-irradiated suspensions in vials were placed upright and stored at 40°C / 75% RH. Suspension suitability was tested after 1 month and 3 months of storage. Table 3 shows the particle size (µm) of the 400 mg / mL cabotevir formulation with 30 mg / mL PS20, 30 mg / mL PEG3350, and 19 mg / mL mannitol after preparation and after 1 month of storage at 40°C / 75% RH. The particle size increased at 1 month compared to the initial time point (Table 3). At 3 months, the suspension became a non-recoverable gel and could not be removed from the vial with a syringe.

[0397] Table 3

[0398]

[0399] Other suspensions containing cabotevir, PS20, and PEG3350 were prepared at the concentrations shown in Table 4. Experiments 1, 2, and 5 were prepared using the method described above for 20 mg / mL PS20 and PEG3350. In Experiment 3, the suspension was first ground with PS20 (without PEG3350), followed by the addition of PEG3350, at which point 400 mg / mL cabotevir was ground with 30 mg / mL PS20. After grinding, a concentrated solution of PEG3350 (400 mg / mL) was added to dilute the 400 mg / mL suspension to 360 mg / mL cabotevir, 27 mg / mL PS20, and 27 mg / mL mannitol. All compositions were prepared in 250 mL batches using a Netzsch miniCer and 0.3 mm YTZ beads.

[0400] Table 4

[0401]

[0402] * Dilute 400 mg / mL by 10% to obtain 360 mg / mL cabotevir and 27 mg / mL PS20.

[0403] In experiments 1, 2, 4, and 5, the suspensions thickened into a paste and were non-recoverable during wet bead milling on a miniCer. In experiment 3, the suspension thickened and could not be stirred within 5 minutes of adding 400 mg / mL PEG3350 solution. The combination of PS20 and PEG3350 with 400 mg / mL cabotevir did not produce a physically stable suspension.

[0404] Experimental Examples

[0405] In the following description of embodiments, specific implementations are described. These implementations are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other implementations and logical or other variations may be made without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure.

[0406] The following scheme describes the measurement of cabotewe particle size in the microsuspension in the following examples.

[0407] Solution Description

[0408] • A method for measuring particle size using laser diffraction (USP) was developed. <429> ).

[0409] • Reconstitute the lyophilized product with water for injection (WFI) (the volume of WFI is determined by the desired concentration of the reconstituted suspension).

[0410] • Clean and fill the Malvern Mastersizer 3000 laser diffractometer with deionized water using an MV instrument.

[0411] • The dispersion stirring speed is 2000 rpm, the particle refractive index is 1.67, the particle absorption index (imaginary part of the refractive index) is 0.01, and it has a general-purpose analysis mode with normal sensitivity. The refractive index of the dispersant (DI water) is 1.33. The measurement time and background time are both 10 seconds, and two measurements are obtained for each aliquot of the sample.

[0412] • Comparisons were performed and the background was measured.

[0413] • The suspension is stirred (as shown in the examples below) to ensure that all particles are suspended in the drug product vial.

[0414] • Draw ~0.2 mL of contents using a 1 mL syringe fitted with a needle (18 G).

[0415] Add two drops of suspension to a microcentrifuge tube containing 0.5 mL of a 6.6% w / v P338 aqueous solution.

[0416] • Gently vortex to ensure uniform dispersion of the drug product in P338 dispersant.

[0417] • Add an appropriate amount of the dispersion to the instrument until 5%-7% masking is achieved.

[0418] • Allow the test suspension to circulate in the instrument for approximately 30 seconds before starting the measurement.

[0419] • Perform measurements and rinse the instrument with deionized water after each measurement.

[0420] • Repeat this process three times for each new aliquot of the sample and calculate the average value obtained from the volume distribution.

[0421] Example 1

[0422] Table 5

[0423]

[0424] Table 5 shows exemplary pharmaceutical compositions of the present invention (also described as “suspensions” in these examples) prepared using the following methods.

[0425] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 4.8 kg of 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 containers were rinsed with additional water into a mixing container, and the mixed medium solution was brought to a final weight of 6.06 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target X50 = 5–6 µm particle size) was added to 3.0 kg of the filtered medium and mixed to form a homogeneous suspension. The mixed suspension was degassed while stirring until it reached its target batch volume, and then the suspension was 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 time at a slow climatization rate of + / - 1°C / min), initial drying at approximately 150 mTorr at -10°C (slow climatization rate: 0.15°C / min) for at least 23 hours, and secondary drying at approximately 150 mTorr at 25°C (slow climatization rate: 0.58°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly shaken to resuspend before administration.

[0426] Example 2

[0427] Table 6

[0428]

[0429] Table 6 shows exemplary pharmaceutical compositions of the present invention (the pharmaceutical compositions are also described as “suspensions” in these examples) prepared using the following methods.

[0430] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 3.4 kg of 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 containers were rinsed with additional water into the mixing container, and the mixed medium solution was brought to a final weight of 4.50 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target X50 = 5–6 µm particle size) was added to the 3.0 kg of filtered medium and mixed to form a homogeneous suspension. The mixed suspension was degassed while stirring until it reached its target batch volume, and then the suspension was filled into vials. The product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -10°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each time at a slow rate of + / - 1°C / min), initial drying at approximately 150 mTorr at -5°C (slow rate: 1°C / min) for at least 20 hours, and secondary drying at approximately 150 mTorr at 40°C (slow rate: 1°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly shaken to resuspend before administration.

[0431] Example 3

[0432] Table 7

[0433]

[0434] Table 7 shows exemplary pharmaceutical compositions of the present invention (the pharmaceutical compositions are also described as “suspensions” in these examples) which were prepared using the following methods.

[0435] The formulation medium was prepared by dissolving / diluting 24.0 g of polysorbate 80 (“PS80”) (Croda) in approximately 300 g of water. Separately, 30.0 g of sodium carboxymethyl cellulose (“NaCMC”) (Ashland, 7L2P) and 210.0 g of mannitol (Roquette Freres) were dissolved in 3.4 kg of 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 containers were rinsed with additional water into the mixing container, and the mixed medium solution was brought to a final weight of 4.50 kg and filtered through a 0.2 μm filter. 1.6 kg of cabotevir micronized free acid (target X50 = 3–4 µm particle size) was added to the 3.0 kg filtered medium and mixed to form a homogeneous suspension. The mixed suspension was degassed while stirring until it reached its target batch volume, and then the suspension was filled into vials. The product was lyophilized by freezing at -45°C for at least 2 hours, annealing at -10°C for at least 2 hours, refreezing at -45°C for at least 2 hours (each time at a slow rate of + / - 1°C / min), initial drying at approximately 150 mTorr at -5°C (slow rate: 1°C / min) for at least 20 hours, and secondary drying at approximately 150 mTorr at 40°C (slow rate: 1°C / min) for at least 6 hours. The lyophilized vials were backwashed with nitrogen to approximately 600 Torr, sealed, and sterilized by gamma irradiation at a minimum dose of 25 kGy. The formulation was reconstituted with WFI and briefly shaken to resuspend before administration.

[0436] Table 8 below applies to Examples 4-6.

[0437] Table 8

[0438]

[0439] Example 4: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 80, and mannitol

[0440] A formulation mediator was prepared by dissolving 2.10 g PS80 (Croda), 2.63 g NaCMC (Ashland), and 18.38 g mannitol (Roquette Freres) in 369.6 g WFI, and filtering the solution through a 0.2 µm filter. The formulation mediator was added to 210 g cabotevir (free acid) to prepare a crude suspension of 400 mg / mL. The suspension was capped and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0441] Table 9: Batch #1 (400 mg / mL Cabotevir; 0.4 w / v% PS80; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0442]

[0443] Note:

[0444] AmbH ambient humidity

[0445] RH (Relative Humidity)

[0446] - This indicates that testing was not scheduled at these time points.

[0447] NGT = not greater than

[0448] NLT = not less than

[0449] Example 5: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 20, and mannitol

[0450] A formulation mediator was prepared by dissolving 2.10 g of polysorbate 20 (Croda), 2.63 g of sodium CMC (Ashland), and 18.38 g of mannitol (Roquette Freres) in 550.9 g of WFI, and filtering the solution through a 0.2 µm filter. The formulation mediator was added to 210 g of cabotevir (free acid) to prepare a crude suspension of 300 mg / mL. The suspension was capped and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0451] Table 10: Batch #2 (400 mg / mL Cabotevir; 0.4 w / v% PS20; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0452]

[0453] Note:

[0454] AmbH ambient humidity

[0455] RH (Relative Humidity)

[0456] - This indicates that testing was not scheduled at these time points.

[0457] NGT = not greater than

[0458] NLT = not less than

[0459] Example 6: Stability of a composition comprising cabotevir, sodium carboxymethyl cellulose, poloxamer 338, and mannitol

[0460] A formulation mediator was prepared by dissolving 2.10 g poloxamer 338 (BASF), 2.63 g sodium CMC (Ashland), and 18.38 g mannitol (Roquette Freres) in 369.6 g WFI, and filtering the solution through a 0.2 µm filter. The formulation mediator was added to 210 g cabotevir (free acid) to prepare a crude suspension of 400 mg / mL. The suspension was capped and stirred for 2 hours. The suspension was filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 400 mg / mL.

[0461] Table 11: Batch #3 (400 mg / mL Cabotevir; 0.4 w / v% P338; 0.5 w / v% NaCMC; 3.5 w / v% Mannitol)

[0462]

[0463] Note:

[0464] AmbH ambient humidity

[0465] RH (Relative Humidity)

[0466] - This indicates that testing was not scheduled at these time points.

[0467] NGT = not greater than

[0468] NLT = not less than

[0469] Example 7: Stability of compositions comprising cabotevir, sodium carboxymethyl cellulose, polysorbate 80, and mannitol

[0470] A formulation medium was prepared by dissolving 1.04 g PS80 (Croda), 1.30 g NaCMC (Ashland; 7LF), and 9.1 g mannitol (Roquette Freres) in 183.4 g WFI. A crude suspension of 400 mg / mL was prepared by adding 195.0 mL of the formulation medium to 104.0 g cabotevir (free acid). The suspension was capped and stirred for 2 hours. The suspension was then filled into Type I glass vials and lyophilized as described in Examples 1-3. The lyophilized suspension was reconstituted to a cabotevir concentration of 533 mg / mL.

[0471] Table 12: Batch #1 (533 mg / mL Cabotevir; 0.53 w / v% PS80; 0.67 w / v% NaCMC; 4.66 w / v% Mannitol)

[0472]

[0473] Note:

[0474] AmbH ambient humidity

[0475] RH (Relative Humidity)

[0476] - This indicates that testing was not scheduled at these time points.

[0477] NGT = not greater than

[0478] NLT = not less than

[0479] Example 8: In vivo pharmacokinetic study in rats of a composition comprising cabotevir, sodium carboxymethyl cellulose, mannitol, and polysorbate 80 or poloxamer 338:

[0480] The preparation of the compositions was described in Examples 4 and 6. The formulations were administered subcutaneously in the intrascapular region at a dose of 30 mg / kg in nine male Sprague Dawley rats. Briefly, two cabotabine nanosuspensions (different in excipient composition) were administered subcutaneously at a target dose of 30 mg / kg via a single injection to each rat. Similarly, two micron-sized lyophilized cabotabine powder formulations with different excipient compositions were reconstituted to a concentration of 400 mg / mL using WFI and administered subcutaneously via a single injection to each rat at a target dose of 30 mg / kg. Details of the formulations are described in Table 13.

[0481] Table 13: Details of suspension formulations of test articles administered in animal PK studies

[0482]

[0483] Table 14 shows the plasma pharmacokinetics of cabotevir in preclinical studies and the statistical analysis by t-tests of several pharmacokinetic parameters. The lyophilized formulation from group 3, compared to the nanosuspension formulation from group 1, highlights a significantly lower Cg. max (1.8 times) and extended t 1 / 2 (1.5 times). Furthermore, compared to the formulation from group 4, the lyophilized formulation from group 3 showed improved t... 1 / 2 .

[0484] Table 14: Pharmacokinetic parameters of cabotevir and statistical analysis by t-test in the PK study of Example 8

[0485]

[0486] # The data comes from 8 animals (excluding 1 animal as an outlier).

[0487] The p-value calculated based on the significance of the one-tailed unpaired t-test is: * = 0.01 <p<0.05; ** = 0.001<p<0.01; *** = 0.0001<p<0.001; p<0.0001

[0488] Tolerance was assessed as part of the study, with particular attention to injection site reactions, and the results are summarized in Table 15. The incidence of edema and crusting was extremely low and observed in a small number of animals over a short period. Nevertheless, minor differences were recorded among the four groups, with lower frequencies of edema observed in groups 3 and 4, particularly group 3.

[0489] Table 15: Observation results of injection site reaction

[0490]

[0491] Example 9

[0492] Example 9 evaluated the safety, tolerability, and pharmacokinetics of a single-dose administration of the pharmaceutical composition of the present invention in 57 healthy adult participants. The lyophilized formulation of Example 9 is provided in Tables 16a and 16b below:

[0493] Table 16a

[0494]

[0495] Water is removed during the production process.

[0496] Nitrogen was used as a processing aid during vial sealing.

[0497] Table 16b

[0498]

[0499] Water is removed during the production process.

[0500] Nitrogen was used as a processing aid during vial sealing.

[0501] Table 17 below describes the Cabotewe particle size (micrometers) determined by diffraction:

[0502] Table 17

[0503]

[0504] The vials containing the formulation from Table 16a were reconstituted with 1.7 mL of water to obtain a suspension with a cabotevir concentration of 400 mg / mL. The formulation from Table 16a was administered in two groups: 800 mg (2 mL of 400 mg / mL suspension) via the subcutaneous (SC) abdominal route (group C1; 8 participants) and via the intramuscular (IM) (gluteus medius) route (group C2; 8 participants).

[0505] The vials containing the formulation in Table 16b were reconstituted with 1.7 mL of water to obtain a suspension with a cabotevir concentration of 400 mg / mL, or with 1.1 mL of water to obtain a suspension with a cabotevir concentration of 533 mg / mL. The dosages of the formulations in Table 16b were administered in three groups: 1200 mg (3 mL of 400 mg / mL suspension) via the subcutaneous (SC) abdominal route (Group C3; 8 participants), 1200 mg (3 mL of 400 mg / mL suspension) via the intramuscular (IM) (gluteus medius) route (Group C4; 8 participants), 1600 mg (3 mL of 533 mg / mL suspension) via the intramuscular (IM) (gluteus medius) route (Group C5; 16 participants), 2400 mg (4.5 mL of 533 mg / mL suspension) via the IM route administered in 2.2 mL in one gluteus medius muscle (left or right) and in 2.3 mL in another gluteus medius muscle (right or left) (Group C6; 9 participants), and 3200 mg (6 mL of 533 mg / mL suspension) via the IM route administered in 3 mL in each gluteus medius muscle (left and right, respectively) (Group C7; 7 participants).

[0506] Safety and tolerability

[0507] The safety and tolerability characteristics of the pharmaceutical compositions of Tables 16a and 16b administered in Example 9 were acceptable. Adverse events (AEs) occurred in 63-100% of participants (Table 18). Injection site reactions (ISRs) were the most common AEs, and most were Grade 1 (Table 19). Overall, fewer ISRs were reported after IM administration compared to SC administration; however, ISRs were predominantly Grade 1 (Table 19). No Grade 4 or serious AEs were reported in groups C1 through C7.

[0508] Table 18: Summary of the most frequent (≥2 participants across groups) AEs (ISR and non-ISR) by group

[0509]

[0510] Table 19: ISR Summary

[0511]

[0512]

[0513] a. If an end date is missing, the ISR duration is not calculated.

[0514] Example 10

[0515] PK and Simulation

[0516] The plasma Cmax of cabotevir following a single SC (abdomen) or IM (gluteal muscle) injection of the pharmaceutical composition described in Examples 9, Groups 1-5, was lower than that following a single IM injection of APRETUDE®, while the plasma Cmax following bilateral IM gluteal muscle injections (2.3 mL in one gluteus medius muscle (left or right) and 2.2 mL in the other gluteus medius muscle (right or left); total 4.5 mL) was comparable to that following a single IM injection of APRETUDE®. Based on the observed PK data in Examples 9, Groups 1-5, the predicted t1 / 2 after SC and IM injections in these groups were the t1 / 2 of APRETUDE® (Q2M cabotevir 200 mg / mL). 1 / 2 >6x (SC injection) and >2x (IM injection). There is insufficient data to determine the t after administration of the cabotevir pharmaceutical composition described in Group 6 or 7 of Example 9. 1 / 2 .

[0517] Table 20. Plasma pharmacokinetic and safety results in healthy adult participant groups C1–C7

[0518]

[0519] a Values ​​reported as geometric mean (%CVb). *Not yet calculable.

[0520] simulation

[0521] Based on PK data following intramuscular (IM) injection of cabotegravir (CAB) at 200 mg / mL, a population pharmacokinetics (PopPK) model of cabotegravir was established. This PK data was obtained from 16 historical studies. (Population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult HIV-1-infected and uninfected subjects. HanK, Baker M, Lovern M, Paul P, Xiong Y, Patel P, Moore KP, Seal CS, Cutrell AG, D'Amico RD, Benn PD, Landovitz RJ, Marzinke MA, Spreen WR, Ford SL. Br JClin Pharmacol. 2022 Oct;88(10):4607-4622. doi: 10.1111 / bcp.15439. Epub 2022Jul 4. PMID: Collected from 35695476 and updated based on 19 studies (LAI116585, LAI117010, LAI117011, LAI117020, 201741, 201479, 201480, 205696, LAI116482 (LATTE), LAI115428, LAI116815, 200056 (LATTE-2), 201120 (ECLAIR), 201103 (HPTN077), 201584 (FLAIR), 201585 (ATLAS), 207966 (ATLAS-2M), 201738 (HPTN 083) and 201739 (HPTN084)). The PopPK model was built using a total of 34,850 CAB plasma concentrations collected from 2,694 participants at different time points. Findings:

[0522] • The long-acting intramuscular gluteal absorption rate constant (KA2) was 46.5% lower in people designated as female at birth than in people designated as male at birth.

[0523] • In individuals designated as male at birth, the KA2 level was 50.8% higher with fractionated injections, but in individuals designated as female at birth, KA2 levels were not affected by fractionated injections.

[0524] • KA2 decreases with increasing BMI, and for the same increase in BMI, the decrease is greater in people designated as male at birth than in people designated as female at birth.

[0525] • The longer the needle, the lower the KA2.

[0526] • After adjusting for all covariates, KA2 was 22.8% higher in Study 201120 (ECLAIR) than in other studies.

[0527] • The apparent central clearance rate (CL / F) is 16.4% higher among current smokers.

[0528] Based on observed PK data from the study discussed in Example 9, the typical half-life (t) of the 533 mg / mL formulation was determined. 1 / 2 The value was set at 25 weeks, and the typical half-life (t) of the 400 mg / mL formulation was... 1 / 2 The PopPK model was modified by setting the value to twice the corresponding APRETUDE® value to simulate the cabotevir formulation used in Example 9. Assumptions:

[0529] • Following intramuscular injection of the formulation from Example 9 with a cabotevir concentration of 533 mg / mL, t½ was 25 weeks.

[0530] • For the formulation with a concentration of 400 mg / mL, after intramuscular injection of the formulation in Example 9, the t½ is twice that of APRETUDE®.

[0531] • The effects of body weight, BMI, and smoking status on PK, all variability (e.g., inter-individual variability and residual variability), and bioavailability were the same as those of 200 mg / mL IM intramuscular injection in the buttock.

[0532] • The PK after the formulation in Example 9 was administered via fractionated 1-minute intramuscular injection into both sides of the body was the same as that after a single 1-minute intramuscular injection of the formulation in Example 9.

[0533] The simulation was conducted as follows: Covariates (including weight, BMI, and smoking status) were resampled 5000 times from the distributions of these covariates for men and women, generating 5000 virtual male subjects and 5000 virtual female subjects. Individual PK parameters for the virtual subjects were calculated using subject-specific covariates and subject-specific non-MEM inter-individual error (ETA) sampled from the distribution determined by the estimated variance-covariate matrix of inter-individual variability from the final population PK model. Concentration versus time curves for the virtual subjects were calculated using the individual PK parameters. Residual variability (EPS) was included in the simulation. The median and 10th percentile and 90th percentile (80% prediction interval) of the simulated concentration versus time curves for the virtual men and women were calculated.

[0534] Adequate dose is defined as a dose that meets the following criteria:

[0535] 1. Among individuals designated as male at birth and those designated as female at birth, the median and 10th percentile of maintenance trough CAB plasma concentration (Ctau) above 200 mg / mL CAB IM gluteal intramuscular injection were obtained using the approved Q2M regimen.

[0536] 2. Maintained Ctau levels above the sex-specific PrEP benchmark in over 90% of participants. The sex-specific PrEP benchmark was the 10th percentile of Ctau in individuals designated as male at birth (1.05 μg / mL) observed in phase 3 study 201738 (HPTN 083) and individuals designated as female at birth (1.39 μg / mL) observed in study 201739 (HPTN 084).

[0537] Simulations showed that in individuals designated as male or female at birth, a maintenance dose of 1.5 mL of 533 mg / mL cabotevir (799.5 mg cabotevir) was effective. Figure 5 and 6 ) or 3 mL of 400 mg / mL cabotevir (1200 mg cabotevir) Figure 7 and 8 The Q4M regimen of intramuscular CAB injection in the gluteal region does not maintain CAB plasma concentrations higher than the approved Q2M regimen of intramuscular CAB injection in the gluteal region at 200 mg / mL.

[0538] People who were designated as male at birth ( Figure 11 ) and those designated as female at birth ( Figure 12In this context, a Q4M regimen consisting of a loading dose of at least 2132 mg (4 mL) and a maintenance dose of at least 1066 mg (2 mL) administered intramuscularly via gluteal injection, starting 1 month after the loading dose, will meet criterion 1, namely, maintaining CAB plasma concentrations higher than the approved Q2M regimen of CAB200 IM intramuscular injection via gluteal injection.

[0539] A Q4M regimen consisting of a loading dose of at least 3200 mg (3 mL + 3 mL) and a maintenance dose of at least 1600 mg (3 mL) administered intramuscularly via gluteal injection, starting one month after the loading dose, will meet two criteria:

[0540] • People who were designated as male at birth ( Figure 3 and those who were designated as female at birth ( Figure 4 In this study, the Q2M regimen of maintaining CAB plasma concentrations above the approved CAB200 IM gluteal injection was used.

[0541] • More than 90% of people were designated as male at birth ( Figure 9 ) and those designated as female at birth ( Figure 10 Ctau levels were maintained above 1.05 μg / mL and 1.39 μg / mL, respectively. Figure 9 and Figure 10 As shown, the lower boundary of the gray band (the 10th percentile of the simulated CAB-ULA) is above the horizontal dashed line (the baseline).

[0542] Example 11

[0543] In vivo pharmacokinetic studies of combinations of different drug concentrations in rats

[0544] The pharmacokinetics of two nanosuspension formulations at different cabotevir concentrations (drug loads) were evaluated via intramuscular administration in male Sprague Dawley rats. Briefly, approximately 200 mg / mL (Group 1) and 400 mg / mL (Group 2) of the two cabotevir nanosuspensions (which also differed in excipient composition) were administered intramuscularly in each rat via a single injection of a target dose of 10 mg / kg. Details of the formulations and particle size distribution are reported in Table 21.

[0545] Table 21. Details of the suspension formulation of the test article administered in Example 11 of the animal PK study.

[0546]

[0547] Figure 13The mean plasma concentration-time course of cabobotevir in Example 11 of the PK study is displayed on a semi-logarithmic scale. Compared to the nanosuspension from Group 1 with a similar particle size distribution but a lower cabobotevir concentration (200 mg / mL), (t... 1 / 2 =162 ± 18h), approximately 400 mg / mL nano-suspension formulation from group 2 (t 1 / 2 = 224 ± 47 h) with a significantly prolonged apparent terminal half-life (1.4-fold). CAB200 nano-suspension formulation (200 mg / mL cabotevir) is represented by a dashed line with a triangle, and CAB400 nano-suspension formulation (400 mg / mL cabotevir) is represented by a solid line with a circle. Data points represent mean ± standard deviation.

[0548] Preclinical data from Example 11 (see Example 11) Figure 13 It is emphasized that a higher concentration of cabotevir in the formulation has a greater impact on the apparent terminal t 1 / 2 The positive effects of concentration are fully utilized in lyophilized delivery to further extend the duration of action, exceeding the goals achievable with micron-sized particle sizes. This effect allows cabotevir to achieve a longer duration of action without requiring significantly larger particle sizes, which could lead to injectability problems (Samaradi et al.), such as needle clogging.

[0549] In addition, higher cabotevir concentrations in pharmaceutical products allow for smaller injection volumes for the same dosage, which is preferred for patients.

[0550] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications mentioned in this specification are incorporated herein by reference to the extent that they are not consistent with this description in their entirety.

[0551] As will be understood from the foregoing, although specific embodiments have been described herein for illustrative purposes, various modifications may be made without departing from the spirit and scope of this disclosure. Therefore, this disclosure is not limited except for the appended claims.

[0552] sequence list

[0553]

Claims

1. A pharmaceutical composition comprising: Caboteway; A wetting agent, wherein the wetting agent is polysorbate 80 (PS80); Stabilizer, wherein the stabilizer is sodium carboxymethyl cellulose (CMC); and A tension modifier, wherein the tension modifier is mannitol; Cabotewe exists as particles with a median mass diameter (X50) between 2.5 µm and 10 µm (including the endpoints).

2. The pharmaceutical composition according to claim 1, wherein cabotevir is present in the form of particles with a median diameter (X50) greater than or equal to 3 µm and less than or equal to 8.5 µm.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the X50 value of the cabotevir particles is greater than or equal to 3.5 µm and less than or equal to 8.0 µm, and wherein the X90 value of the cabotevir particles is greater than or equal to 7.0 µm and less than or equal to 18.0 µm.

4. The pharmaceutical composition according to any one of claims 1-3, wherein cabotevir is present in an amount of about 350 mg to about 1650 mg.

5. The pharmaceutical composition according to any one of claims 1-4, wherein cabotevir is present in an amount of about 800 mg.

6. The pharmaceutical composition according to any one of claims 1-4, wherein cabotevir is present in an amount of about 1600 mg.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the weight ratio of the wetting agent to cabotevir is in the range of about 1:100 to about 1:150; The weight ratio of the stabilizer to cabotevir is in the range of about 1:70 to about 1:120; and The weight ratio of the tension modifier to cabotevir is in the range of about 1:8 to about 1:

25.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 100:1:1.25:8.

75.

9. The pharmaceutical composition according to any one of claims 1-7, wherein the weight ratio of cabotevir:PS80:CMC sodium:mannitol is about 400:3:3.7:25.

9.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is provided as a lyophilized powder.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the concentration of cabotevir is in the range of about 300 mg / mL to about 650 mg / mL.

12. The pharmaceutical composition according to claim 11, wherein the concentration of cabotevir is about 400 mg / mL.

13. The pharmaceutical composition according to claim 11, wherein the concentration of cabotevir is about 533 mg / mL.

14. The pharmaceutical composition according to any one of claims 1-13, wherein the pharmaceutical composition comprises: (a) Reconstitute from lyophilized powder using a suitable liquid, or (b) Provided as a liquid composition.

15. The pharmaceutical composition according to any one of claims 1-14, wherein the pharmaceutical composition is formulated as a parenteral pharmaceutical composition.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is suitable for subcutaneous, subdermal, or intramuscular injection.

17. The pharmaceutical composition according to any one of claims 1-16, for the treatment or prevention of HIV.

18. The pharmaceutical composition for use according to claim 17, wherein the use comprises the step of administering the pharmaceutical composition subcutaneously or intramuscularly to a human body.

19. The pharmaceutical composition for use according to claim 18, wherein the human is administered about 300 mg to about 3200 mg of cabotevir.

20. The pharmaceutical composition for the use according to claim 18 or claim 19, wherein the use comprises administering the pharmaceutical composition to the person once a month, once every two months, once every three months, once every four months, once every five months, or once every six months.

21. The pharmaceutical composition for treating HIV according to any one of claims 17-20, wherein the pharmaceutical composition is administered in combination with one or more nucleoside reverse transcriptase inhibitors (NRTTIs), one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs), one or more capsid inhibitors, and / or one or more broad-spectrum neutralizing antibodies (bnAbs).

22. A method of treating HIV in a person in need, comprising administering to said person a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1-21.

23. A method for preventing HIV in a human, comprising administering to the human an effective amount of the pharmaceutical composition according to any one of claims 1-20.

24. The method of claim 22 or claim 23, wherein the method comprises the step of administering the pharmaceutical composition subcutaneously or intramuscularly.

25. The method according to any one of claims 22-24, wherein the person is administered about 300 mg to about 3200 mg of cabotevir.

26. The method according to any one of claims 22-25, wherein the method comprises administering the pharmaceutical composition to the person once a month, once every two months, once every three months, once every four months, once every five months, or once every six months.

27. The method according to any one of claims 22 and 24-26, wherein the method comprises administering the pharmaceutical composition in combination with one or more nucleoside reverse transcriptase inhibitors (NRTTIs), one or more non-nucleoside reverse transcriptase inhibitors (NNRTIs), one or more capsid inhibitors and / or one or more broadly neutralizing antibodies (bnAbs).

28. A kit comprising a container containing, as a lyophilized powder, a pharmaceutical composition according to any one of claims 1-21.

29. A method for preparing a reconstitution solution, the method comprising providing the kit of claim 28 and contacting a lyophilized composition with a suitable liquid to produce a reconstitution solution.

30. The pharmaceutical composition of claim 14, the kit of claim 28, or the method of claim 29, wherein the suitable liquid is water.

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