Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions

Definitions

• the invention relates to compounds, pharmaceutical compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides pharmaceutical compositions containing inhibitors of HIV, and methods for using these compositions in the treatment of HIV infection.
• HIV human immunodeficiency virus
• AIDS Acquired immunodeficiency syndrome
• HIV-infected individuals consists of a combination of approved anti-retroviral agents. Close to four dozen drugs are currently approved for HIV infection, either as single agents, fixed dose combinations or single tablet regimens; the latter two containing 2-4 approved agents. These agents belong to a number of different classes, targeting either a viral enzyme or the function of a viral protein during the virus replication cycle.
• agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nudeotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (Pls), integrase strand transfer inhibitors (INSTIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gpl60 protein).
• a pharmacokinetic enhancer cobicistat or ritonavir
• ARVs antiretroviral agents
• WO 2020/084492 and WO 2020/254985 disclose certain Capsid Inhibitor compounds including the two compounds shown below which will be referred to in this application as the compounds of Formula la and Formula lb.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la or a pharmaceutically acceptable salt thereof,
• Formula la wherein the composition comprising polyethylene glycol (PEG) and ethanol.
• the present invention provides a pharmaceutical composition comprising a compound of Formula la or a pharmaceutically acceptable salt thereof,
• Formula la wherein the composition comprises water and contains less than 1% by weight of polyethylene glycol.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of Formula lb or a pharmaceutically acceptable salt thereof,
• Formula lb wherein the composition comprises polyethylene glycol (PEG) and ethanol.
• PEG polyethylene glycol
• the invention provides a pharmaceutical composition comprising a compound of Formula la or a pharmaceutically acceptable salt thereof, Formula lb wherein the composition comprises water and contains less than 1% by weight of polyethylene glycol.
• the present invention provides a method of treating HIV infection in a patient comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention, as described below, to said patient.
• the present invention provides a pharmaceutical composition of the invention, as described below, for use in therapy.
• the present invention provides a pharmaceutical composition of the invention, as described below, for use in treating HIV infection in a patient.
• the present invention provides the use of a pharmaceutical composition of the invention, as described below, in the manufacture of a medicament for the treatment of HIV infection in a patient.
• Figures 1-3 summarize the results of PK experiments described below and summarized in Tables 1-3.
• Figures 4-6 summarize the results of PK experiments described below and summarized in Tables 4-6.
• Figures 7-9 summarize the results of PK experiments described below and summarized in Tables 7-9.
• Figures 10-12 summarize the results of PK experiments described below and summarized in Tables 10-12.
• Figures 13-14 summarize the results of PK experiments described below and summarized in Tables 13-14.
• Figures 15-16 summarize the results of PK experiments described below and summarized in Tables 15-16.
• Figures 17-18 summarize the results of PK experiments described below and summarized in Tables 17-18.
• Figures 19-20 summarize the results of PK experiments described below and summarized in Tables 19-20.
• Figures 21-22 summarize the results of PK experiments described below and summarized in Tables 21-22.
• a compound of Formula la is known by the chemical name N-((S)-l-((3P)-3-(4-chloro- l-methyl-3-(methylsulfonamido)-lH-indazol-7-yl)-4-oxo-7-(6-(trifluoromethyl)pyridin-2-yl)-3,4- dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5- difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cydopenta[l,2-c]pyrazol-l-yl)acetamide.
• a method for making the compound of Formula la is found in published patent application WO 2020/084492.
• a compound of Formula lb is known by the chemical name N-((S)-l-(3-(4-chloro-l- methyl-3-(methylsulfonamido)-lH-indazol-7-yl)-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4- dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3- (difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cydopenta[l,2- c]pyrazol-l-yl)acetamide.
• a method for making the compound of Formula lb is found in published patent application WO 2020/254985.
• compositions of the invention comprise a therapeutically effective amount of a compound of Formula la or a pharmaceutically acceptable salt thereof.
• the compositions of the invention comprise a therapeutically effective amount of a compound of Formula la as a free base.
• compositions of the invention comprise a therapeutically effective amount of a compound of Formula la which is amorphous.
• compositions of the invention comprise a therapeutically effective amount of a compound of Formula lb or a pharmaceutically acceptable salt thereof.
• compositions of the invention comprise a therapeutically effective amount of a compound of Formula lb as a free base.
• compositions of the invention comprise a therapeutically effective amount of a compound of Formula lb which is amorphous.
• terapéuticaally effective amount in reference to a compound, its salt, or a pharmaceutical composition of the invention comprising said compound or its salt, or other pharmaceutically-active agent or composition, means an amount of the compound, its salt or a pharmaceutical composition of the invention comprising said compound or its salt, sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
• a therapeutically effective amount of a compound of Formula la or Formula lb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of Formula la or the compound of Formula lb, or its salt, in a quantity that, when administered to a patient in need thereof, is sufficient to modulate the activity of HIV capsid such that the disease condition which is mediated by that activity is treated, including reduced, alleviated, or prevented.
• a therapeutically effective amount of a compound, its salt or a pharmaceutical composition comprising the compound or its salt will vary with the particular compound chosen (e.g., consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
• a composition of this invention comprises polyethylene glycol and ethanol. It will be understood by the skilled artisan that he chemical formula for polyethylene glycol (PEG) can be generally written as H-(O-CH2-CH2)n-OH. In one embodiment, the composition of the invention is a homogeneous solution.
• the invention provides a composition further comprising water. In another embodiment, the invention provides a composition further comprising lecithin. In yet another embodiment, the invention provides a composition further comprising propylene glycol. In still another embodiment, the invention provides a composition further comprising benzyl alcohol. In still yet another embodiment, the invention provides a composition further comprising benzyl benzoate. In another embodiment, the invention provides a composition further comprising sucrose acetate isobutyrate (SAIB). In yet another embodiment, the invention provides a composition further comprising sesame oil.
• SAIB sucrose acetate isobutyrate
• the invention provides a composition further comprising one or more components which are water, lecithin, propylene glycol, benzyl alcohol, benzyl benzoate, SAIB, or sesame oil.
• the invention provides a composition further comprising one or more components which are water, lecithin, propylene glycol, benzyl alcohol, benzyl benzoate, or sesame oil.
• the invention provides a composition further comprising one or more components which are water, lecithin, propylene glycol, benzyl alcohol, or sesame oil.
• the invention provides a composition further comprising one or more components which are propylene glycol, benzyl alcohol, or sesame oil.
• the lecithin is egg-based. In another embodiment, the lecithin is soy-based and is about 80 weight% phosphatidylcholine or is about 100 weight% phosphatidylcholine.
• the average molecular weight of polyethylene glycol is about 200 (PEG 200).
• the average molecular weight of polyethylene glycol is about 300 (PEG 300).
• the average molecular weight of polyethylene glycol is about 400 (PEG 400).
• the amount of a component present in the composition is expressed as a weight% relative to total mass of the formulation.
• the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition expressed as weight% is between about 5-50%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 5-30%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 5-35%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is about 10-25%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is about 10-30%.
• the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 15-30%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 20-30%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 25-35%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 30-40%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 35-45%. In one embodiment of the invention, the amount of a compound of Formula la, or a pharmaceutically acceptable salt thereof, present in the composition is between about 40-50%.
• the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 5-50%.
• the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 5-30%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 5-35%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 10- 25%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 10- 30%.
• the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 15- 30%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 20- 30%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 25- 35%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 30- 40%.
• the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 35- 45%. In one embodiment of the invention, the amount of a compound of Formula lb, or a pharmaceutically acceptable salt thereof, present in the composition is between about 40- 50%.
• compositions of the invention are administered subcutaneously.
• the invention provides a homogeneous solution for subcutaneous administration. In one embodiment, the invention provides a homogeneous solution comprising an amorphous form of a compound of Formula la for subcutaneous administration. In one embodiment, the invention provides a homogeneous solution comprising an amorphous form of a compound of Formula lb for subcutaneous administration.
• the invention provides a heterogeneous suspension for subcutaneous administration. In one embodiment, the invention provides a heterogeneous suspension comprising an amorphous form of a compound of Formula la for subcutaneous administration. In one embodiment, the invention provides a heterogeneous suspension comprising an amorphous form of a compound of Formula lb for subcutaneous administration.
• compositions of the invention are administered intramuscularly.
• compositions of the invention are administered intravenously.
• compositions of the invention comprise a vehicle or carrier, which is an inert medium used as a solvent or diluent in which the active agent, Formula la or Formula lb, is formulated or administered.
• Suitable vehicles for the compositions of this invention include, but are not limited to, ethanol (up to about 35 weight%), polyethylene glycol (up to about 85 weight%), modified polyethylene glycol (up to about 85 weight%), propylene glycol (up to about 60 weight%), N-Methyl-2-pyrrolidone (NMP) (up to about weight%), Dimethylacetamide (DMA) (up to about 50%), dimethylsulfoxide (DMSO) (up to about 5 weight %), water, ethyl lactate, dimethyl isosorbide, and the like. It will be understood that one or more solvents may comprise the vehicle for a particular pharmaceutical composition.
• compositions of the invention optionally comprise an oil.
• oils for the compositions of this invention include, but are not limited to, sesame oil, soyabean oil, castor oil, medium chain triglyceride, safflower oil, and the like.
• the oil is present in an amount of from about 0 to about 50 weight%.
• the oil is present in an amount of up to about 100 weight%.
• the invention provides a homogeneous solution comprising an oil.
• compositions of the invention optionally comprise a surfactant.
• Suitable surfactants include, but are not limited to, a phospholipid (up to about 25 weight%), a poloxamer (up to about 7 weight%), a polysorbate (up to about 7 weight%), a sorbitan ester (aka spans) (up to about 7 weight%), and the like.
• the invention provides a composition comprising a phospholipid surfactant.
• the invention provides a composition comprising a phospholipid surfactant which is lecithin.
• the invention provides a composition comprising Poloxamer 338.
• the invention provides a composition comprising Poloxamer 188.
• the invention provides a composition comprising Poloxamer 338 or Poloxamer 188.
• the invention provides a heterogeneous suspension comprising a surfactant. In one embodiment, the invention provides a heterogeneous suspension comprising a surfactant. In one embodiment, the invention provides a heterogeneous suspension comprising lecithin. In one embodiment, the invention provides a heterogeneous suspension comprising Poloxamer 338. In one embodiment, the invention provides a heterogeneous suspension comprising Poloxamer 188. In one embodiment, the invention provides a heterogeneous suspension comprising Poloxamer 338 or Poloxamer 188.
• composition of the invention optionally comprises an iso-osmolarity/tonicity agent.
• Suitable iso-osmolarity/tonicity agents include but are not limited to, mannitol (about 1 to about 5 weight%), trehalose (about 7 to about 10 weight%), sucrose (about 7 to about 10 weight%), glucose (about 3 to about 5 weight%), dextrose (about 3 to about 5 weight%), sodium chloride (about 0.45 to about 0.9 weight%), potassium chloride (about 0.45 to about 0.9 weight%), and the like.
• the invention provides a heterogeneous suspension comprising mannitol.
• compositions of the invention optionally comprise a buffering agent.
• Suitable buffering agents for the compositions of the invention include, but are not limited to, acetate, citrate, tartrate, malic acid and its salt, NaOH and HCI, format histidine, phosphate, TRIS, borate, and the like.
• the invention provides a composition comprising a buffering agent in the amount of about 1 mM to about 20 mM.
• the invention provides a composition which is a micro-suspension.
• the invention provides a micro-suspension composition comprising a viscosity modifying agent.
• Suitable viscosity modifying agents for the compositions of the invention include, but are not limited to, sodium carboxymethyl cellulose, hyaluronic acids, PVP-K-12, K-19, hydroxy ethyl starch, and the like.
• the invention provides a composition comprising levels of viscosity modifying agents from 0 to about 1 weight%.
• the invention provides a micro-suspension composition comprising a bulking agent.
• Suitable bulking agents for the compositions of the invention include, but are not limited to, mannitol (about 3 to about 5 weight%), trehalose (about 7 to about 10 weight%), sucrose (about 7 to about 10 weight%), glucose (about 3 to about 5 weight%), dextrose (about 3 to about 5 weight%), and the like.
• the invention provides a composition which is a lyophilized micro-suspension.
• the invention provides a pharmaceutical composition wherein the amount of polyethylene glycol present in the composition, expressed as weight%, is between about 10-55%. In one embodiment of the invention, the amount of polyethylene glycol present in the composition is between about 15-50%. In a second embodiment of the invention, the amount of polyethylene glycol present in the composition is between about 20- 50%. In one embodiment of the invention, the amount of polyethylene glycol present in the composition is between about 20-40%. In one embodiment of the invention, the amount of polyethylene glycol present in the composition is between about 30-50%. In one embodiment of the invention, the amount of polyethylene glycol present in the composition is between about 40-50%.
• the invention provides a pharmaceutical composition wherein the amount of ethanol present in the composition, expressed as weight%, is between about 1- 35%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 5-30%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 5-25%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 10-30%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 10-25%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 15-30%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 15-20%.
• the amount of ethanol present in the composition is between about 15-25%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 20-25%. In one embodiment of the invention, the amount of ethanol present in the composition is between about 25-35%.
• the pharmaceutical composition comprises mannitol.
• the invention provides a pharmaceutical composition wherein the amount of mannitol is present in the composition expressed as weight% is between 1-5%. In one embodiment of the invention, the amount of mannitol present in the composition is between about 2-4%.
• the pharmaceutical composition comprises lecithin.
• the invention provides a pharmaceutical composition wherein the amount of lecithin present in the composition expressed as weight% is between about 1-25%. In one embodiment of the invention, the amount of lecithin in the composition is between about 5-25%. In one embodiment of the invention, the amount of lecithin in the composition is between about 10- 20%. In one embodiment of the invention, the amount of lecithin in the composition is between about 1-5%. In another embodiment of the invention, the amount of lecithin present in the composition is about 1%, 2%, 3%, 4%, or 5%.
• the lecithin is egg-based. In another embodiment of the invention, the lecithin is soy-based. In one embodiment, if soy-based, the lecithin is about 80 weight% phosphatidylcholine. In one embodiment, if soy-based, the lecithin is 100 weight% phosphatidylcholine.
• the invention provides a composition which is a homogeneous solution.
• the invention provides a composition which is a heterogeneous suspension.
• the invention provides a pharmaceutical composition wherein the amount of water present in the composition, as measured by Karl Fischer titration, is about 1%, 2%, 3%, 4%, or 5%. In one embodiment of the invention, the amount of water present in the composition is less than about 3%. In one embodiment of the invention, the amount of water present in the composition is less than about 2.5%. In one embodiment of the invention, the amount of water present in the composition is less than about 2%. In one embodiment of the invention, the amount of water present in the composition is less than about 1.5%. In one embodiment of the invention, the amount of water in the composition is less than about 1%.
• compositions of the invention comprising Formula la, or a pharmaceutically acceptable salt thereof. It will be understood that all the above embodiments apply to compositions of the invention comprising Formula lb, or a pharmaceutically acceptable salt thereof. It will be understood that the above embodiments apply to compositions of the invention comprising a compound of Formula la as a free base. It will be understood that the above embodiments apply to compositions of the invention comprising a compound of Formula la as a free base. It will be understood that the above embodiments apply to compositions of the invention comprising a compound of Formula la as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base. It will be understood that the above embodiments apply to compositions of the invention comprising a compound of Formula lb as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base.
• the invention provides a pharmaceutical composition comprising about 20% by weight of a compound of Formula la or a compound of Formula lb, about 45% by weight of PEG200, about 20% by weight of ethanol, and about 15% by weight of lecithin.
• the invention provides a pharmaceutical composition comprising about 30% by weight of a compound of Formula la or a compound of Formula lb, about 45% by weight of PEG200, and about 25% by weight of ethanol.
• the invention provides a composition comprising about 30% by weight of a compound of Formula la or a compound of Formula lb, about 50% by weight of PEG200, and about 20% by weight of ethanol.
• the invention provides a composition comprising about 20% by weight of a compound of Formula la or a compound of Formula lb, about 55% by weight of PEG200, and about 20% by weight of ethanol. In yet another aspect, the invention provides a composition comprising about 19% by weight of a compound of Formula la, about 61% by weight of PEG200 and about 20% by weight of ethanol.
• the composition of the invention comprises water and contains less than 1% by weight of polyethylene glycol. In another aspect, the composition of the invention is a heterogeneous suspension.
• the invention provides a composition in which the suspended solids comprise a compound of Formula la, or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a composition in which the suspended solids comprise a compound of Formula lb, or a pharmaceutically acceptable salt thereof. In one aspect, the invention provides a composition in which the suspended solids comprise a compound of Formula la, as the free base. In one aspect, the invention provides a composition in which the suspended solids comprise a compound of Formula lb, as the free base. It will be understood that the above embodiments apply to compositions of the invention in which the suspended solids comprise a compound of Formula la as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base. It will be understood that the above embodiments apply to compositions of the invention in which the suspended solids comprise a compound of Formula lb as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base.
• the composition of the solids which are suspended is about 20% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 25% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 30% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 35% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 40% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 45% by weight of a compound of Formula la.
• composition of the solids which are suspended is about 50% by weight of a compound of Formula la. It will be understood that these embodiments apply to compositions of the invention in which the suspended solids comprise a compound of Formula la as a pharmaceutically acceptable salt or as a free base, or as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base.
• the composition of the solids which are suspended is about 20% by weight of a compound of Formula lb. In another embodiment of the invention, the composition of the solids which are suspended is about 25% by weight of a compound of Formula lb. In another embodiment of the invention, the composition of the solids which are suspended is about 30% by weight of a compound of Formula lb. In another embodiment of the invention, the composition of the solids which are suspended is about 35% by weight of a compound of Formula la. In another embodiment of the invention, the composition of the solids which are suspended is about 40% by weight of a compound of Formula lb. In another embodiment of the invention, the composition of the solids which are suspended is about 45% by weight of a compound of Formula lb.
• the composition of the solids which are suspended is about 50% by weight of a compound of Formula lb. It will be understood that these embodiments apply to compositions of the invention in which the suspended solids comprise a compound of Formula lb as a pharmaceutically acceptable salt or as a free base, or as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base.
• the invention provides a composition further comprising one or more of the following excipients, sodium acetate, acetic acid, mannitol, sodium chloride, Poloxamer 338, or Poloxamer 188.
• the invention provides a pharmaceutical composition comprising Poloxamer 338 or Poloxamer 188.
• the invention provides a pharmaceutical composition comprising Poloxamer 338 and Poloxamer 188.
• the invention provides a pharmaceutical composition comprising mannitol or sodium chloride.
• the invention provides a pharmaceutical composition comprising mannitol and sodium chloride.
• the invention provides a pharmaceutical composition comprising sodium acetate or acetic acid.
• the invention provides a pharmaceutical composition comprising sodium acetate and acetic acid.
• the mass of a compound of Formula la or a compound of Formula lb is expressed relative to the total volume of the formulation.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 50-500 mg/mL.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 150-300 mg/mL.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 200- 300 mg/mL.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 250-350 mg/mL.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 300-400 mg/mL. In a further embodiment, the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 350-450 mg/mL. In another embodiment, the composition comprises a compound of Formula la or a compound of Formula lb at a concentration between about 400-500 mg/mL.
• the composition comprises a compound of Formula la or a compound of Formula lb at a concentration of about 200 mg/mL, about 225 mg/mL, about 250 mg/mL, about 275 mg/mL, about 300 mg/mL, about 325 mg/mL, about 350 mg/mL, about 375 mg/mL, about 400 mg/mL, about 450 mg/mL or about 500 mg/mL.
• the invention provides a pharmaceutical composition comprising a compound of Formula la or a compound of Formula lb at a concentration of about
• the invention provides a composition comprising about 300 mg/mL of a compound of Formula la or a compound of Formula lb, about 5.4% by weight of P338, about 3.5% by weight of mannitol, and the remainder of the formulation as water or aqueous acetate buffer.
• compositions of this invention further comprise one or more of glycerol, polyvinylpyrrolidone K19, polyvinylpyrrolidone K12, Span, urea, NMP, ethyl lactate, polysorbate 80, or Polysorbate 20.
• the pharmaceutical composition of this invention comprises a therapeutically effective amount of the compound of Formula la, or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition of this invention comprises a therapeutically effective amount of the compound of Formula lb, or a pharmaceutically acceptable salt thereof.
• the pharmaceutical composition of this invention comprises about 20%-30% by weight of a compound of Formula la, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 20%-30% by weight of a compound of Formula la as the free base. In another embodiment, the pharmaceutical composition of the invention comprises about 20%-30% by weight of a compound of Formula lb, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 20%-30% by weight of a compound of Formula lb as the free base.
• the pharmaceutical composition of this invention comprises about 20% by weight of a compound of Formula la, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 20% by weight of a compound of Formula la as the free base. In another embodiment, the pharmaceutical composition of the invention comprises about 20% by weight of a compound of Formula lb, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 20% by weight of a compound of Formula lb as the free base.
• the pharmaceutical composition of this invention comprises about 30% by weight of a compound of Formula la, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 30% by weight of a compound of Formula la as the free base. In another embodiment, the pharmaceutical composition of the invention comprises about 30% by weight of a compound of Formula lb, or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of this invention comprises about 30% by weight of a compound of Formula lb as the free base.
• compositions of the invention comprising a compound of Formula la as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base. It will be understood that the above embodiments apply to compositions of the invention comprising a compound of Formula lb as an amorphous compound, either as a pharmaceutically acceptable salt thereof, or as a free base.
• the particle diameter of a compound of Formula la or a compound of Formula lb is measured with a laser diffraction technique.
• This type of analysis is used in general practice for particle size characterization.
• An example of equipment capable of performing this analysis is a Malvern Mastersizer MS3000 instrument.
• Particle sizes are reported as percentiles of a distribution. Percentiles (e.g. X50) refer to the percent volume out of the total volume of the material tested which has an equivalent spherical diameter less than the reported value.
• the term "mean particle diameter" refers to X50 which is interchangeable with D50 or the 50 th percentile distribution.
• the mean particle diameter of a compound of Formula la or a compound of Formula lb is ⁇ about 0.2 pm. In another embodiment, the mean particle diameter of a compound of Formula la or a compound of Formula lb ranges between about 0.2 pm to about 0.5 pm. In another embodiment, the mean particle diameter of a compound of Formula la or a compound of Formula lb ranges between about 0.5 pm to about 3 pm. In another embodiment, the mean particle diameter of a compound of Formula la or a compound of Formula lb ranges between about 3 pm to about 5 pm. In another embodiment, the mean particle diameter of a compound of Formula la or a compound of Formula lb ranges between about 5 pm to about 10 pm.
• the DIO is ⁇ 0.9 pM, the D50 is ⁇ 2 pM and the D90 is ⁇ 4 pM. In one embodiment of the invention, for a compound of Formula lb, the DIO is ⁇ 0.9 pM, the D50 is ⁇ 2 pM and the D90 is ⁇ 4 pM.
• composition of the invention comprises any of the isomers of a compound of Formula la or a compound of Formula lb and they are included in the scope of this invention.
• the depicted stereoisomers in Formulas la and lb are >95% of all stereoisomers of the same chemical formula.
• the salts of the invention are pharmaceutically acceptable. Such salts may be acid addition salts or base addition salts.
• suitable pharmaceutically acceptable salts see, for example, Berge eta/, J. Pharm, Sci., 66, 1-19, 1977.
• Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-l,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate
• Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS, tromethamine), arginine, benethamine (/V-benzylphenethylamine), benzathine (/V,/V i dibenzylethylenediamine), /ws-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, demizole (1- chlorobenzyl-2-pyrrolildine-l'-ylmethylbenzimidazole), cydohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (/V-methylglucamine), piperazine
• the salt of a compound of Formula la is a sodium salt. In another embodiment, the salt of a compound of Formula lb is a sodium salt. In another embodiment, the salt of a compound of Formula la is a potassium salt. In another embodiment, the salt of a compound of Formula lb is a potassium salt.
• the present invention discloses methods of preventing HIV infection in a patient or reducing the risk of infection, comprising administering a pharmaceutical composition of the invention.
• Pre-exposure prophylaxis or PrEP is when people at risk for HIV infection take HIV antiretroviral medicine to lower their chances of acquiring HIV infection. PrEP has been shown to be effective in reducing the risk of infection.
• HIV HIV or “Human Immunodeficiency Virus” refers to HIV-1 and/or HIV-2.
• patient refers to a human.
• the compounds, salts and compositions of this invention are believed to have as their biological target the HIV capsid and thus their mechanism of action is to modify in one or more ways the function of the HIV capsid.
• Combination therapies according to the present invention thus comprise the administration of at least one compound or a pharmaceutically acceptable salt thereof, of the invention, and the administration of at least one other agent which may be useful in the treatment of HIV infection.
• a compound or a pharmaceutically acceptable salt thereof, of the present invention, and the other agent may be formulated and administered together in a single pharmaceutical composition or may be formulated and administered separately. When formulated and administered separately, administration may occur simultaneously or sequentially in any order.
• Suitable other agents are selected from the group consisting of, abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate,
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la, or pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenof
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb, or pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir,
• the invention provides a therapeutically effective pharmaceutical composition
• a therapeutically effective pharmaceutical composition comprising a compound of Formula la, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofo
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenof
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofo
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK3739937/VH3739937, indinavir, islatravir, lamivudine, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, ten
• the other agent is selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil,
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoprox
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofo
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, ten
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenof
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, N6LS, GSK3739937/VH3739937, and S-365598.
• another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, maraviroc, rilpiverine, tenofovir disoproxil,
• the other agent is selected from the group consisting of, dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK3739937/VH3739937, GSK4000422/VH4000422, and S-365598.
• the other agent is selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.
• the other agent is selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S- 365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.
• the other agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent is dolutegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent is dolutegravir.
• the other agent is cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent is cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent is cabotegravir.
• the invention provides a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent is cabotegravir. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent is cabotegravir.
• the other agent is S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula la, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb, or a pharmaceutically acceptable salt thereof, and another therapeutic agent is S- 365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula la and another therapeutic agent is S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula lb and another therapeutic agent is S-365598.
• the invention provides a pharmaceutical composition comprising a compound of Formula la which is amorphous, and another therapeutic agent is S-365598. In another embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula lb which is amorphous, and another therapeutic agent is S-365598.
• GSK3640254 is a compound as described in Dicker I, Jeffrey JL, Protack T, et al.; GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile' Antimicrob Agents Chemother. 2022;66(l):e0187621.
• NCT04147715 is an HIV maturation inhibitor and the compound of clinical trial NCT04493684; N6LS: also known as VRC-HIVMAB091-00-AB, is a human monoclonal antibody and the compound of clinical trial NCT03538626; S-365598: is a third-generation HIV integrase strand-transfer inhibitor (INSTI) discovered by Shionogi; and S-648414 is the compound of clinical trial NCT04147715.
• INSTI HIV integrase strand-transfer inhibitor
• Formulation A (heterogeneous suspension) is found in Table A.
• the stirred suspension was maintained between 1-25 °C and was circulated at 45-145 mL/min through a wet bead mill (Netzsch Minicer) set at 5.5 m/s agitator tip speed, containing 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired mean particle diameter of about 0.3
• the concentration of the formulation was about 300 mg/mL of a suspended amorphous form of the compound of Formula la, with 5.4 w/vol% P338 and 3.5 w/vol% mannitol and the remainder of the composition comprised of the aqueous acetate buffer described above.
• Formulation B (heterogeneous suspension) is found in Table B.
• Sodium acetate (435.72 mg ) and glacial acetic acid (104 uL) were dissolved in water (500 mL) to afford a 10 mM acetate buffer solution.
• the acetate buffer solution (440.85 g) was combined with Poloxamer 338 (34.89 g) and mannitol (24.46 g) and the resulting solution was filtered through a 0.2 pm filter.
• the pH of the vehicle was measured as pH 5.02.
• the solution (278.25 g) was combined with the compound of Formula lb (110.25 g).
• the stirred suspension was maintained between 1-25 °C and was circulated at 45-145 mL/min through a wet bead mill (Netzsch Minicer) set at 5.8 m/s agitator tip speed, containing 0.3 mm YTZ grinding beads (Nikkato Corp) until the desired mean particle diameter of about 0.2 pm was achieved.
• the concentration of the formulation was about 300 mg/mL of a suspended amorphous form of the compound of Formula lb, with 5.4% w/vol P338 and 3.5% w/vol mannitol and the remainder of the composition comprised of the aqueous acetate buffer described above.
• a glass bottle equipped with a lid was charged with PEG200 (67.5 g) and the solution was heated to 45 °C with stirring.
• the composition of the solution is 30 w/w% the compound of Formula lb, 45 w/w% PEG200, and 25 w/w% ethanol.
• a glass bottle equipped with a lid was charged with PEG200 (150 g) and the solution was heated to 45 °C with stirring.
• a glass bottle equipped with a lid was charged with PEG200 (1.75 mL), ethanol (0.35 mL), and sesame oil (1.40 mL), and the mixture was then vortexed.
• To the solution was slowly added the compound of Formula lb (628 mg), and the mixture was then vortexed.
• the solution was sonicated to afford a clear, homogeneous solution.
• the composition of the solution is PEG200 (47.3%), ethanol (6.6%), sesame oil (31%), compound of Formula lb (15.1%).
• Plasma samples were collected into K2EDTA tubes, placed on water ice immediately after collection, and centrifuged as soon as possible to obtain plasma. Plasma samples were stored at -70°C or colder until analysis by LC-MS/MS. All in vitro samples were injected on an MDS Sciex 5000 triple-quadrupole LC-MS/MS system.
• the analytical column used was a Waters Acquity 1.7 pm CSH Fluror Phenyl (2.1mm x 50 mm) maintained at 50°C.
• Mobile Phase A consisted of 0.1% (v/v) formic acid in MilliQ-purified water.
• Mobile Phase B consisted of 0.1% (v/v) formic acid in acetonitrile. The flow rate was 0.80 mL/min.
• the gradient was as follows: Mobile B was held for 0.2 minutes at 20% and then linearly increased from 20% to 75% over 0.4 min, followed by another linear increase from 75-95% over 0.55 min. It was then maintained at 95% for 0.35 min, and maintained at 20% for 0.49 min.
• Plasma samples were collected into K2EDTA tubes, placed on water ice immediately after collection, and centrifuged as soon as possible to obtain plasma. Plasma samples were stored at -70°C or colder until analysis by LC-MS/MS. All in vitro samples were injected on a MDS Sciex 6500+ triple-quadrupole LC-MS/MS system.
• the analytical column used was a Waters Acquity 1.7 pm BEH (C18, 2.1mm x 50 mm, 1.7 pm) maintained at 35 °C.
• Mobile Phase A consisted of 0.1% (v/v) formic acid in MilliQ-purified water.
• Mobile Phase B consisted of 0.1% (v/v) formic acid in acetonitrile. The flow rate was 0.80 mL/min.
• the gradient was as follows: Mobile B was held for 0.2 minutes at 2% and then linearly increased from 2% to 75% over 0.4 min, followed by another linear increase from 75-95% over 0.55 min. It was then maintained at 95% for 0.35 min, and maintained at 2% for 0.49 min.
• Formulation B was administered to Wistar Han Rats as a either a subcutaneous injection at a dose of 1.04 mL/kg; a subcutaneous injection at a dose of 3.46 mL/kg; or as an intramuscular injection at a dose of 0.52 mL/kg. Blood samples were collected at the times indicated in Tables 4-6 and were analyzed according to General Procedure B. Results of the PK experiments are described in Tables 4-6 and Figures 4-6.
• Formulation C was administered to Wistar Han Rats as either a subcutaneous injection at a dose of 1.5 mL/kg; a subcutaneous injection at a dose of 5 mL/kg; or as an intramuscular injection at a dose of 0.5 mL/kg. Blood samples were collected at the times indicated in Tables 7-9 and were analyzed according to General Procedure A. Results of the PK experiments are described in Tables 7-9 and Figures 7-9.
• Formulation J was administered to Wistar Han Rats as either a subcutaneous injection at a dose of 0.28 mL/kg or as an intramuscular injection at a dose of 0.28 mL/kg. Blood samples were collected at the times indicated in Tables 21-22 and were analyzed according to General Procedure A. Results of the PK experiments are described in Tables 21- 22 and Figures 21-22.

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