Classifications

• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
  • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

• the present invention relates to long acting parenteral (LAP) formulations of betulin derivatives as well as methods of treating Human Immunodeficiency Virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) using the same.
• LAP long acting parenteral
• HAART highly active antiretroviral therapy
• salvage therapy includes at least two, and preferably three, fully active drugs.
• first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase (RT) and protease (PR).
• RT reverse transcriptase
• PR protease
• One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.
• the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.
• Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase (IN) inhibitors.
• resistance to all three new drug classes has already been reported both in vitro and in vivo.
• Such betulin derivatives include 4-(((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-Chlorobenzyl)(2- (dimethylamino) ethyl)amino)-1 -hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b, 6, 7, 7a, 8, 9, 10, 1 1 , 1 1 a, 1 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid which is the
• the present invention addresses the issue of non-compliance as well as treatment of resistant strains of HIV by formulating betulin derivatives, including the compound of Formula I , as a LAP composition suitable for administration, for example, once per month, once every 2 months, once every 3 months, once every 6 months or once every 12 months.
• composition including at least one betulin derivative or a pharmaceutically acceptable salt thereof.
• a method for the treatment of an HIV infection in a human having an HIV infection including administering to the human a LAP pharmaceutical composition including at least one betulin derivative or a
• a method for the treatment of an HIV infection in a human having an HIV infection including administering to the h mpound of Formula I
• a LAP pharmaceutical composition including at least one betulin derivative or a pharmaceutically acceptable salt thereof in medical therapy.
• a seventh aspect of the present invention there is provided the use of at least one betulin derivative or a pharmaceutically acceptable salt thereof in the preparation of a long acting parenteral medicament for use in the treatment of HIV infection in a human.
• a compound of Formula I there is provided the use of a compound of Formula I
• Figure 1 depicts a plot of LAP Mean Concentration of a compound of Formula
• Figure 2 depicts a plot of LAP Mean Concentration of a compound of Formula
• Figure 3 depicts a plot of LAP Mean Concentration of a compound of Formula
• the HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains - matrix (MA), capsid (CA), nucleocapsid (NC) and p6 - and two spacer peptides, SP1 and SP2, represents a new therapeutic target.
• Pr55Gag The HIV Gag polyprotein precursor
• MA protein domains - matrix
• CA capsid
• NC nucleocapsid
• SP1 and SP2 two spacer peptides
• Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.
• Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles.
• Bevirimat has activity against ART-resistant and wild- type HIV, and has shown synergy with antiretrovirals from all classes.
• Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.
• PCT/US2012/024288 "Novel Anti-H IV Compounds and Methods of Use Thereof ;
• Chinese PCT Application No. PCT/CN201 1/001303 "Methylene Derivatives of Betulin”;
• With each iteration of maturation inhibitor a need exists to optimize the polymorphism isolate coverage and achieve maximum potency while minimizing the protein shift. To date, no maturation inhibitor has achieved an optimal balance of these three properties.
• a suitable compound other than the compound of Formula I may also be selected from any compound described in Table 1 below.
• HIV-1 HIV-1
• HAART or highly active antiretroviral therapy consisting of at least three antiretroviral drugs, may fail following the development of viral resistance.
• Factors contributing to the incomplete suppression of HIV and to the development of resistance include insufficient drug potency, non-compliance, restricted tissue penetration, drug resistance and several host factors, such as host genetics.
• compliance during a life-long treatment is crucial, as establishing minimal inhibitory drug concentrations in the blood inhibits viral growth and the development of resistant strains.
• HIV by formulating a betulin derivative, including -(((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)- 3a-((R)-2-((4-Chlorobenzyl)(2-(dimethylamino) ethyl)amino)-1 -hydroxyethyl)-1 -isopropyl- 5a,5b,8,8, 1 1 a-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9, 10, 1 1 , 1 1 a, 1 1 1 b, 12, 13, 13a- octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (the compound of Formula I) as a long-acting parenteral (LAP) composition or depot formulation suitable for administration, for example,
• compositions comprising an active ingredient which is the compound of Formula I, or a pharmaceutically acceptable salt thereof, suitable for administration once monthly or longer.
• the present invention features pharmaceutical compositions, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a surfactant system.
• the present invention features a pharmaceutical composition, comprising a therapeutically effective amount of hexadecyloxypropyl-9-R-[2- (phosphonomethoxy)propyl]-adenine, or a pharmaceutically acceptable salt thereof, and a surfactant system.
• compositions include, but are not limited to those described in PCT Published Application No. WO2013090664 deriving from US Provisional Application 61/576448, filed December 16, 201 1.
• terapéuticaally effective amount means a sufficient amount of a drug, compound, composition, product or pharmaceutical agent to abate or reverse or treat a malady in a human or other mammal.
• the present invention features parenteral pharmaceutical compositions for administration to a subject, for example a human.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system for weekly (once every week) administration.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system for bi-weekly (once every two weeks) administration.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system for once monthly administration.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system for bi-monthly (once every two months) administration.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system for tri-monthly (once every three months) administration.
• the present invention features long-acting parenteral pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a surfactant system administration once every six or twelve months, or any time point within this range.
• compositions of the present invention provide for the slow release of a compound of formula (I) over an extended period of time within the body of a subject.
• An embodiment of the present invention is a pharmaceutical composition suitable for parenteral administration comprising a compound of formula (I) and a surfactant system comprising a combination of polymers providing for the release of a compound of formula (I) over a period of one week to three months.
• a suitable combination of polymers is, for example, polysorbate 80 and polyvinylpyrrolidone (PVP).
• compositions of the present invention may be administered to the subject by various routes, including intramuscular (IM), intravenous (IV), or subcutaneous (SQ). Therefore, in one embodiment, the compositions of the present invention are administered to a subject by an intramuscular route. In another embodiment, the compositions of the present invention are administered to a subject by an intravenous route. In another embodiment, the compositions of the present invention are administered to a subject by a subcutaneous route.
• IM intramuscular
• IV intravenous
• SQ subcutaneous
• a surfactant system means any formulation suitable for pharmaceutical purposes that includes at least one surfactant.
• a surfactant system that can be used with the present invention may include, in addition to a surfactant, additional components such as buffers, polymers (for drug particles), wetting agents, stabilizers, tonicity modifiers, and solvents such as water.
• the surfactant system may include any surfactant as long as it is compatible with pharmaceutical applications.
• suitable surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates such as polysorbate 20 or 80), poloxamers (such as LUTROLTM F68, F108 and F127 which are block copolymers of ethylene oxide and propylene oxide, sodium dodecylsulfate and/or sodium lauryl sulphate), sorbitan esters of fatty acids (SPAN), polyethoxylated castor oil and its derivatives, tocopheryl polyethylene glycol succinate, and polyvinyl alcohols.
• polyoxyethylene sorbitan fatty acid esters polysorbates such as polysorbate 20 or 80
• poloxamers such as LUTROLTM F68, F108 and F127 which are block copolymers of ethylene oxide and propylene oxide, sodium dodecylsulfate and/or sodium lauryl sulphate
• the surfactant system comprises an amount of surfactant that ranges from about 0.01 % (w/v) to about 5% (w/v) surfactant. In other embodiments, the surfactant system comprises an amount of surfactant that ranges from about 0.1 % (w/v) to about 3% (w/v) surfactant. In still other embodiments, the surfactant system comprises about 0.2% (w/v) surfactant. In still other embodiments, the surfactant system comprises about 0.4% (w/v) surfactant. In other embodiments, the surfactant system comprises polysorbate-80 (e.g., Tween-80). In still other embodiments, the surfactant system comprises 0.4% (w/v) polysorbate-80.
• Representative stabilizers include, but are not limited to, polyethylene glycols, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylpropylcellulose,
• the surfactant system comprises an amount of stabilizer that ranges from about 0.01 % (w/v) to about 5% (w/v) stabilizer. In other embodiments, the surfactant system comprises an amount of stabilizer that ranges from about 1 % (w/v) to about 5% (w/v) stabilizer. In other embodiments, the surfactant system comprises an amount of stabilizer that ranges from about 1 % (w/v) to about 3% (w/v) stabilizer. In still other embodiments, the surfactant system comprises about 2% (w/v) stabilizer. In other embodiments, the surfactant system comprises polyethylene glycols. In other embodiments, the surfactant system comprises PEG-3350. In still other embodiments, the surfactant system comprises 2% (w/v) PEG-3350.
• Suitable buffer salts include, but are not limited to, buffer salts selected from phosphate salts, citrate salts, acetate salts, and tartrate salts, etc.
• the surfactant system comprises an amount of buffer salts that ranges from about 1 mM to about 10OmM buffer salt. In other embodiments, the surfactant system comprises an amount of buffer salts that ranges from about 2mM to about 50mM buffer salt. In other embodiments, the surfactant system comprises an amount of buffer salts that ranges from about 3mM to about 25mM buffer salt. In other embodiments, the surfactant system comprises an amount of buffer salts that ranges from about 5mM to about 15mM buffer salt.
• the surfactant system comprises about 10mM buffer salt.
• the pH of the buffer salt is adjusted to range from about pH 6.0 to about pH 8.0. In other embodiments, the pH of the buffer salt is adjusted to range from about pH 6.5 to about pH 7.5. In other embodiments, the pH of the buffer salt is adjusted to range from about pH 6.7 to about pH 7.3.
• the buffer salt comprises phosphate buffered saline (PBS). In another embodiment, the buffer salt comprises phosphate buffered saline at a concentration of about 10mM. In another embodiment, the buffer salt comprises phosphate buffered saline at a concentration of about 10 mM and a pH of about 6.9.
• Suitable tonicity modifiers include, but are not limited to, sodium chloride, mannitol, sucrose, maltose, and dextrose, etc.
• the tonicity modifier comprises sodium chloride.
• the tonicity modifier is sodium chloride.
• the surfactant system comprises a concentration of tonicity modifier that ranges from about 0 to about 350 mM.
• the surfactant system comprises a concentration of tonicity modifier that ranges from about 0 to about 175 mM.
• the surfactant system has a tonicity that ranges from about 250 to about 350 mOsmol/kg.
• the compound of Formula I (or any compound in Table 1 ) can be suspended as microparticles in a surfactant system and aqueous buffer.
• the compound of Formula I can be in an amorphous form or in a crystalline form.
• the drug particle size (D 50 ) will range from about 0.05 ⁇ to about 100 ⁇ . In other embodiments, the drug particle size will range from about 0.1 ⁇ to about 50 ⁇ . In other embodiments, the drug particle size will range from about 0.1 ⁇ to about 20 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 0.1 ⁇ to about 10 ⁇ .
• the drug particle size (D 50 ) will range from about 0.1 ⁇ to about 5 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 1 ⁇ to about 5 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 0.05 ⁇ to about 0.05 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 0.5 ⁇ to about 5 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 5 ⁇ to about 25 ⁇ . In other embodiments, the drug particle size (D 50 ) will range from about 25 ⁇ to about 100 ⁇ .
• the drug particle size in the surfactant system can be mixed sizes.
• having substantially different particle sizes from relatively large to relatively small can achieve acceptable pharmacokinetic parameters for the formulation because the small particles are absorbed and metabolized quicker than the larger particles.
• This type of mixed particle size formulation could enhance the long acting nature of the present invention by providing a quicker release of drug to the subject early after
• the present LAP invention could comprise two or more substantially different particle sizes that would allow for earlier and later release of the compound of Formula I (or compound of Table 1 ) and such differing absorption kinetics would be a means of enhancing a durable long acting drug exposure.
• the compound of Formula I is in a microparticle form, wherein the microparticles of the compound of Formula I range in size from about 0.05 ⁇ to about 100 ⁇ , wherein said microparticles comprise two or more substantially different particle sizes.
• the drug particles of the compound of Formula I are encapsulated into polymer based microparticles that can, optionally, be subsequently freeze dried for extended storage.
• encapsulated is used with regards to the present invention, it is meant that the compound of Formula I (or any compound in Table 1 ) is substantially surrounded by a polymer even though some compound may still be present on the surface of the encapsulated
• the dry microparticles can optionally suspended in an aqueous buffer solution.
• the polymers used to prepare such microparticles can be selected from a series of biodegradable polymers including poly (lactic-co-glycolic) acid (M w 5-200 kD) and its derivatives, such as polyethylene glycol based amphiphilic polymers, etc.
• the microparticle size (D 50 ) could range from about 1 ⁇ to about 100 ⁇ and the drug encapsulation could range from about 10% to about 70% (w/w). In one
• the drug particles of the compound of Formula I are encapsulated into polymer based microparticles such as those containing ResomerTM.
• the drug particles of the compound of Formula I are encapsulated into polymer based microparticles such as those containing ResomerTM 752S.
• in-situ gels could be used to encapsulate the compound of Formula I.
• This could be a water-miscible organic solvent-based solution that contains both the compound of Formula I and a gel-forming polymer that is water-insoluble.
• IM or SC the organic solvent dissipates away and the water-insoluble polymer precipitates out to form the gel containing the compound of Formula I.
• the the compound of Formula I would then slowly diffuse out as the polymer-based gel degrades in body.
• the polymers used to prepare in-situ gels are selected from a series biodegradable polymers including poly (lactic-co-glycolic) acid (M w 5-200 kD) and its derivatives, polyethylene glycol based amphiphilic polymers, etc.
• the organic solvents are selected from N-methyl pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamie (DMA), etc.
• NMP N-methyl pyrrolidone
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• DMA dimethylacetamie
• concentration of the polymer in the organic solvent could be between 1-50% (w/w) and the compound of Formula I concentration could be between 1- 50% (w/w).
• the microparticle formulation can be made through spray-drying process.
• the organic solution containing both the compound of Formula I and the selected polymer prepared as described herein is subjected to a spray-drying process where the organic solvent is rapidly evaporated under nitrogen gas flow to form the the compound of Formula I encapsulated microparticles.
• the drying temperature is no less than 35C and the solution spray rate is no less than 0.1 ml/min.
• the compound of Formula I and the selected polymer could be co-dissolved into the suitable organic solvent wherein the organic solvent must meet the following critieria: a) has a good solubility for the selected polymer; b) has a good miscibility with aqueous solution; and c) has a low toxicity and demonstrated safety when use in human; for example N-methyl pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamie (DMA), etc.
• NMP N-methyl pyrrolidone
• DMSO dimethylsulfoxide
• DMF dimethylformamide
• DMA dimethylacetamie
• the resulted solution containing both the compound of Formula I and selected polymer can be formulated by varying the polymer concentration, the polymer to the compound of Formula I ratio in the solvent so as to control the gel forming rate after administration and the subsequent drug diffusion rate.
• the solution finally is subjected to a terminal sterilization by ⁇ - irradiation on dry ice at a minimum dose of 25 kGy.
• An example of a combination of polymers includes a polysorbate, for example, polysorbate 80 as wetting agent and a polyvinylpyrrolidone (PVP), for example, Plasdone K29/32 as a stabilizer. Therefore, in one embodiment, the present invention features a parenteral pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and polysorbate 80 and the polyvinylpyrrolidone: Plasdone K29/32.
• PVP polyvinylpyrrolidone
• An embodiment of the present invention is a pharmaceutical composition for parenteral administration comprising a compound of formula (I) and a surfactant system suitable for commonly known sterilization technologies such as gamma irradiation, electron beam irradiation and autoclave sterilization.
• An embodiment of the present invention is a pharmaceutical composition for parenteral administration comprising a compound of formula (I) and a surfactant system that can be manufactured using aseptic technique.
• An embodiment of the present invention is a pharmaceutical composition for parenteral administration comprising a compound of formula (I) and a surfactant system suitable for gamma radiation sterilization.
• An embodiment of the present invention is a pharmaceutical composition for parenteral administration comprising a compound of formula (I) and a surfactant system suitable for sterilization technologies by electron beam irradiation or autoclave sterilization.
• An embodiment of the present invention is a pharmaceutical composition for parenteral administration that can be presented as a "ready to use” sterile suspension or lyophile for reconstitution.
• compositions of the present invention may be administered by subcutaneous or intramuscular injection.
• the compositions of the present invention may also be administered by intradermal or intravitreal injection or implant.
• the compositions of the present invention may also be administered by other parenteral routes of administration.
• compositions of the present invention may be performed by milling using a wet bead mill and sterilized by gamma irradiation.
• Another feature of the present invention is to simplify treatment regimens for
• HIV with the goal of enhancing patient compliance by providing a simplified dosage form containing therapeutically effective amounts of a compound of formula (I) or a
• the present invention also features a method for treating HIV infections in a human, which method comprises administering to said human a composition according to the invention.
• the present invention features the use of a pharmaceutical composition according to the invention in the treatment of HIV infections.
• the present invention features the manufacture of a medicament according to the invention for use in medical therapy.
• the present invention features the manufacture of a medicament according to the invention for use in the treatment of HIV infection.
• the present invention also features a method for treating HIV infections in a human which method comprises administering to said human a composition according to the invention before, during, or after therapy with a compound of formula (I) in tablet or solution form.
• treatment extends to treatment of an established malady, infection or symptoms thereof.
• the present invention also features a method for preventing HIV infections in a human, which method comprises administering to said human a composition according to the invention.
• the present invention features the use of a pharmaceutical composition according to the invention in the prevention of HIV infections.
• the present invention features the manufacture of a medicament according to the invention for use in prophylactic medical therapy.
• the present invention features the manufacture of a medicament according to the invention for use in preventing HIV infection.
• the present invention also features a method for treating or preventing HIV infections in a human which method comprises administering to said human a composition according to the invention before, during, or after therapy with a compound of formula (I) in tablet or solution form.
• a single treatment pharmaceutical composition comprising a therapeutically effective amount of a long acting formulation comprising a compound of formula (I):
• a parenteral pharmaceutical composition comprising a compound of formula (I):
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for subcutaneous administration.
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for intramuscular administration.
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration once weekly or longer.
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration once weekly.
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration once per month.
• a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration once every two months. In other embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration once every three months. In other embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) that is formulated for administration at any interval between 30 and 365 days.
• a pharmaceutical composition comprising a compound of formula (I), wherein the compound of formula (I) is present in the compostion in the form of crystalline nanoparticles.
• a pharmaceutical composition comprising a compound of formula (I), wherein the compound of formula (I) is present in the compostion in the form of matrix release particles.
• composition comprising a compound of formula (I), wherein the composition can be terminally sterilized by gamma irradiation.
• a method for the treatment of an HIV infection in a human having an HIV infection comprising administering to the human a single treatment pharmaceutical composition comprising a therapeutically effective amount of a acting formulation comprising a compound of formula (I):
• a method for the prevention of an HIV infection in a human comprising administering to a human at risk of acquiring an HIV infection, a single treatment pharmaceutical composition comprising a therapeutically effective amount of a long acting formulation comprising a compound of formula (I):
• a LAP pharmaceutical composition comprising: at least one betulin derivative or a pharmaceutically acceptable salt thereof.
• a LAP pharmaceutical composition comprising: the compound of Formula I
• a method for the treatment of an HIV infection in a human having an HIV infection comprising: administering to the human a LAP pharmaceutical composition including at least one betulin derivative or a pharmaceutically acceptable salt thereof.
• a method for the treatment of an HIV infection in a human having an HIV infection comprising: administering to the human a LAP pha la I
• a method for the prevention of an HIV infection in a human having an HIV infection comprising: administering to the human a LAP pharmaceutical composition including at least one betulin derivative or a pharmaceutically acceptable salt thereof.
• a method for the prevention of an HIV infection in a human having an HIV infection comprising: administering to the human a LAP pha la I
• a LAP pharmaceutical composition comprising: the compound of Formula I
• a LAP pharmaceutical composition comprising: the compound of Formula I
• surfactant system comprises a surfactant in an amount ranging from about 0.1 % (w/v) to about 3% (w/v) surfactant, or an amount ranging from 0.2% (w/v) to about 0.4% (w/v) surfactant, or the surfactant system comprises about 0.4% (w/v) surfactant.
• a LAP pharmaceutical composition comprising: the compound of Formula I
• a method for the treatment of an HIV infection in a human having an HIV infection comprising: administering to the human a LAP pha la I
• a LAP pharmaceutical composition comprising: the compound of Formula I
• boosting agent such as, ritonavir.
• the boosting agent could be dosed simultanteously as the compound of Formula I in the same IV or SC syringe, or it could be dosed separately as an oral tablet or capsule.
• the LAP composition comprising the compound of
• Formula I is administered to the subject only after the subject has been administered treatment comprising a generally accepted antiretroviral (ARV) regimen.
• An initial ARV regimen generally consists of two NRTIs in combination with an NNRTI, a PI (preferably boosted with ritonavir [RTV]), an INSTI, or a CCR5 antagonist (namely maraviroc [MVC]).
• NNRTI-, PI-, INSTI-, or CCR5 antagonist-based regimens have all resulted in HIV RNA decreases and CD4 cell increases in a large majority of patients.
• one generally accepted ARV regimen comprises could be selected from any of the following for antiretroviral (ARV)-naive patients: efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC)
• raltegravir + tenofovir disoproxil fumarate/emtricitabine RAL + TDF/FTC
• betulin derivatives may be utilized in lieu of or with the compound of Formula I in the LAP formulations of the present invention.
• Such betulin derivatives may be chosen from those shown in Table 1 below:
• the betulin derivative is a compound of formula II:
• Example 86 Compound 155 -(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-(((4-chlorobenzyl)amino)methyl)-1- isopropyl-5a, 5b, 8, 8, 11a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9,10,11, 11a,11b,12,13, 13a-octadecahydro-2H- cyclopen tanoic acid.
• Example 88 Compound 157 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-(((4-chlorophenethyl)amino)methyl)-1- isopropyl-5a, 5b, 8, 8, 11a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 96 Compound 165 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((S)-2-((4-chlorobenzyl)((R)-pyrrolidin- 2-ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 109 Compound 178 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)(2-(pyrrolidin-1- yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 117 Compound 186 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((S)-2-(((S)-1-(5-chloropyridin-2- yl)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 121 Compound 190
• Example 128 Compound 197 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-(((R)-2-(dimethylamino)-1- phenylethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pentamethy
• Example 135 Compound 204
• Example 136 Compound 205 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((S)-2-((2- (dimethylamino)ethyl)(isopropyl)amino)-1-hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11a- pentamethyl-2-oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 144 Compound 213 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1-methoxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 155 Compound 224 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((cyclohexylmethyl)amino)-1- hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 163 Compound 232 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((S)-2-benzamido-1-hydroxyethyl)-1- isopropyl-5a, 5b, 8, 8, 11a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 171 Compound 240 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-(2-amino-N-benzylacetamido)-1- hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 201 Compound 270 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((1S)-2-(2, 6-dimethylmorpholino)-1 - hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 209 Compound 278 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-(((1H-pyrazol-4-yl)methyl)(2- (dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pentame oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 217 Compound 286 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((S)-2-(4-carbamoylpiperidin-1-yl)-1- hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 239 Compound 308 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((2-(5-chloropyridin-2-yl)propan- 2-yl)amino)-1-hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chr sen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 258 Compound 327 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-1-hydroxy-2-((2-(pyridin-3- yl)ethyl)amino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 269 Compound 338 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-1-hydroxy-2-((pyrimidin-2- ylmethyl)amino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 277 Compound 346 4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-(benzyl(2- (methylamino)ethyl)amino)- 1 -hydroxyethyl)- 1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2- oxo-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 296 Compound 365 4-(((3aR, 5aR, 5bR, laR, 9S, 11aR, 11bR, 13aS)-3a-((R)-1-hydroxy-2- (phenethylamino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.
• Example 307 Compound 376 4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((2-aminoethyl)(pyridin-2- ylmethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.

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