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WO2024227037A1 - Compositions pharmaceutiques colloïdales à action prolongée d'inhibiteurs de transfert de brin de l'intégrase et méthodes associées - Google Patents

Compositions pharmaceutiques colloïdales à action prolongée d'inhibiteurs de transfert de brin de l'intégrase et méthodes associées Download PDF

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Publication number
WO2024227037A1
WO2024227037A1 PCT/US2024/026590 US2024026590W WO2024227037A1 WO 2024227037 A1 WO2024227037 A1 WO 2024227037A1 US 2024026590 W US2024026590 W US 2024026590W WO 2024227037 A1 WO2024227037 A1 WO 2024227037A1
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dtg
strand transfer
transfer inhibitor
integrase strand
particle
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Rodney J.Y. Ho
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University of Washington
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University of Washington
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    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • HIV daily pills are referred to as highly active antiretroviral therapies (or HAART) are composed of combinations anti-retroviral therapeutics, which is often referred to as cART.
  • the cART’s are intended to prevent HIV replication with drug substances intended to inhibit multiple replication checkpoints and maximally suppress virus replication.
  • HAART or cART typically compose of two to three drug substances intended to inhibit viral reverse transcriptase (RT), protease, and/or integrase (often referred to as integrase strand transfer inhibitor or INSTI).
  • RT reverse transcriptase
  • protease protease
  • INSTI integrase strand transfer inhibitor
  • HIV drugs with long-acting (LA) pharmacokinetic properties are developed to increase dosing intervals with intent to increase treatment adherence and reduce pill burden.
  • Typical approach is to produce long-acting HIV medicinal product involves selecting water insoluble derivatives that exhibit longer terminal half-life in the blood to produce injectable dosage form that will sustain drug levels for weeks-to-months.
  • LA-CAB an INSTI
  • LA-RPV LA rilpivirine
  • Both LA-CAB and LA-RPV are manufactured with excipients such as, PEG400, and poloxamer (polymeric compounds) to form small drug crystals amenable for injection. These products retain native crystalline states. Nanocrystalline or nanocrystals are indented to improve solubility of water insoluble drugs. As a result, nano-drug crystal platforms, by reduction the size of natural state of large particulate drug crystalline, are typically used to increase drug dissolution rate to enhance oral absorption. However, nanocrystalline are metastable state and tend to reverse to more stable larger structure of drug in polymorphic crystalline form. Metastable nanocrystalline drugs are known to be unstable to enhance water solubility.
  • approaches and technologies have been described to produce long- acting drug products.
  • Some of the technologies include (1) conjugation of drug molecule to erodible bio-polymers that release drug molecules as it detached from polymer over time; (2) encapsulation into polymeric particles that are biodegradable (e.g. PLGA or PLA); or hydrogel for slowly releasing encapsulates drug molecules; (3) encapsulating into lipid vesicles, silica, clay and other carriers; and (4) grinding of large drug crystals in insoluble suspension with polymeric excipients to form small, nano-crystalline drug product that slowly dissolve upon injection
  • the disclosure described herein provides a novel composition and simple process that enable production of colloidal drug product that are stable and appropriate for making injectable, pharmaceutical suspension product for achieving long-acting drug presence in the body.
  • the present disclosure provides a colloidal integrase strand transfer inhibitor particle comprising an integrase strand transfer inhibitor and an amino acid.
  • Representative integrase strand transfer inhibitors useful in the particle include dolutegravir, bictegravir, cabotegravir, raltegravir, and elvitegravir.
  • Representative amino acids useful in the particle include glutamine and tryptophan.
  • the present disclosure provides an injectable pharmaceutical composition, comprising a suspension of the colloidal integrase strand transfer inhibitor particles described herein and an aqueous carrier.
  • the present disclosure provides a method for treating or preventing HIV in a subject, comprising administering to subject in need thereof a therapeutically effective amount of the integrase strand transfer inhibitor particles described herein or the injectable pharmaceutical composition described herein.
  • the present disclosure provides a method for treating a disease or condition preventable or treatable by administering an integrase strand transfer inhibitor, comprising administering to a subject in need thereof a therapeutically effective amount of the integrase strand transfer inhibitor particles described herein or the injectable pharmaceutical composition described herein.
  • FIG. 1 is a schematic illustration of the binding of an integrase strand transfer inhibitor (INSTI) to the integrase catalytic site (e.g., E152, D64, and DI 16) of HIV integrase enzyme by a representative triad of coplanar oxygen atoms in the inhibitor via bridging Mg 2+ ions.
  • INSTI integrase strand transfer inhibitor
  • FIG. 2 compares the chemical structures of representative integrase strand transfer inhibitors, each with a triad of coplanar oxygen atoms (circled). Halogenated phenyl ring substituents also circled.
  • FIG. 3A is an image of representative colloidal integrase strand transfer inhibitor particles comprising dolutegravir (DTG) and glutamine (Gin).
  • This product is referred to as DTG-CS product and has a final molar ratio of glutamine (Gln)-to-dolutcgravir (DTG) of 9:2.
  • the particles are spherical in shape and have a diameter of about 354 nm. The size of particles can be tuned to produce a range of size based by the ratio of Gin to DTG and to rate of Gin addition.
  • FIG. 3B is an image of dolutegravir nanocrystals having a diameter of about 10 pm.
  • FIGS. 4A and 4B are images comparing representative colloidal integrase strand transfer inhibitor particles: dolutegravir (DTG) and glutamine (Gin) (FIG. 4A); and dolutegravir (DTG) and tryptophan (Trp) (FIG. 4B).
  • the single-dose injection of DTG in CS formulated product produced long-acting plasma drug concentrations time-course of dolutegravir.
  • Data presented were obtained with 2 non-human primates M. Nemestrina. No notable untoward effects in NHP observed over 15 weeks. For comparison plasma time-course of 5mg/kg soluble DTG in NHP after a single subcutaneous dosing is presented.
  • FIG. 6 is an image of representative colloidal integrase strand transfer inhibitor particles: bictegravir (BIC) and glutamine (Gin).
  • the BIC-CS particles have diameters from about 2 to about 300 nm.
  • FIG. 7 compares DTG-CS particle size (nm) as a function of glutamine concentration (% wt/v). Varying the ratio of DTG:Gln showed a direct relationship between Gin concentration (% wt/v) and particle size. Increasing the Gin concentration, increased the DTG- Gln CS particle size over the range of Gin % tested.
  • FIG. 8 shows bictegravir particle (BIC-CS) formation as a function of glutamine concentration. Increasing concentrations of glutamine were added to a fixed concentration of 2.23 mM of bictegravir in solution. The increase in bictegravir particle formation was apparent immediately and completed within 1-2 min. The resulting particle in apparently turbid suspension was quantified with a spectrophotometer set to measure absorbance at 700 nm and expressed as A 700. The higher the absorbance means higher degree of bictegravir particle formed in suspension. The data were expressed as glutamine-to-bictegravir mole ratio.
  • compositions comprising stable colloids of HIV integrase inhibitors for making long-acting pharmaceutical injectable products for the treatment and prevention of HIV infection.
  • the compositions provide extended plasma timecourse of the HIV integrase inhibitors for 15 weeks or more when injected into a subject.
  • the present disclosure provides a colloidal integrase strand transfer inhibitor particle comprising an integrase strand transfer inhibitor and an amino acid.
  • the term “colloidal integrase strand transfer inhibitor particle” refers to a particle that includes a mixture of small particles of one substance (i.e., the INSTI inhibitor) distributed substantially uniformly throughout another substance (i.e., the amino acid).
  • the colloid particles are generally greater in size than those of a drug substance fully dissolved in a solution and lesser in size than those in a drug suspension.
  • integrase strand transfer inhibitor refers to a compound that inhibits the HIV integrase enzyme by binding to the integrase catalytic site (e.g., E152, D64, and/or DI 16) by a triad of coplanar oxygen atoms in the inhibitor via bridging Mg 2+ ions as shown schematically in FIG. 1.
  • the integrase strand transfer inhibitors described herein have a triad of coplanar oxygen atoms as shown in FIGS. 1 and 2.
  • FIG. 2 illustrates the chemical structures of representative integrase strand transfer inhibitors with the triad of coplanar oxygen atoms, circled in each.
  • Representative triads of coplanar oxygen atoms include the following moieties of Formulae (I), (IA), (IB), and (II):
  • Representative integrase strand transfer inhibitors described herein include dolutegravir, bictegravir, cabotegravir, raltegravir, and elvitegravir.
  • Dolutegravir, bictegravir, and cabotegravir include the moiety of Formulae (I) and (IA)
  • raltegravir includes the moiety of Formula (IB)
  • elvitegravir includes the moiety of Formula (II).
  • the colloidal integrase strand transfer inhibitor particles described herein include an amino acid. The amino acid stabilizes the colloidal particle.
  • the halogenated phenyl ring of the INSTIs may also interacts with phenyl ring of tryptophan potentially through pi-pi electron interactions.
  • the colloidal integrase strand transfer inhibitor particles described herein advantageously carry, transport, and ultimately deliver the integrase strand transfer inhibitor contained therein, have advantageous pharmacokinetic properties and profiles compared to their respective integrase strand transfer inhibitors alone, and are effective for the prolonged delivery of the integrase strand transfer inhibitor, which are releasable over time from the particles.
  • the integrase strand transfer inhibitor particles described herein are long-acting particles for the delivery of their integrase strand transfer inhibitor contained therein.
  • the integrase strand transfer inhibitor is selected from the group consisting of dolutegravir, bictegravir, cabotegravir, raltegravir, and elvitegravir. In other embodiments, the integrase strand transfer inhibitor is selected from the group consisting of dolutegravir, bictegravir, and cabotegravir. In further embodiments, the integrase strand transfer inhibitor is selected from the group consisting of raltegravir and elvitegravir. In one embodiment, the integrase strand transfer inhibitor is dolutegravir.
  • the colloidal integrase strand transfer inhibitor particles described herein include an amino acid.
  • the amino acid is glutamine.
  • the amino acid is tryptophan.
  • Suitable amino acids include L-isomers, D-isomers, and racemic amino acids.
  • the integrase strand transfer inhibitor is dolutegravir (DTG) and the stabilizing amino acid is glutamine (Gin).
  • the molar ratio of dolutegravir to glutamine is 1: 0.5-12 m/m. In other of these embodiments, the molar ratio of dolutegravir to glutamine (DTG:Gln) is 1:4.9 m/m.
  • the integrase strand transfer inhibitor is dolutegravir (DTG) and the stabilizing amino acid is tryptophan (Tip).
  • the molar ratio of dolutegravir to tryptophan (DTG:Trp) is 1: 0.5-12 m/m.
  • the molar ratio of dolutegravir to glutamine (DTG:Trp) is 1:4.9 m/m.
  • the integrase strand transfer inhibitor is bictegravir (BIC) and the stabilizing amino acid is glutamine (Gin).
  • the molar ratio of bictegravir to glutamine (BIC:Gln) is 1 : 0.5-12 m/m. In other of these embodiments, the molar ratio of bictegravir to glutamine (BIC:Gln) is 1:5 m/m.
  • the integrase strand transfer inhibitor is bictegravir (BIC) and the stabilizing amino acid is tryptophan (Trp).
  • the molar ratio of bictegravir to tryptophan is 1 : 0.5-12 m/m.
  • Example 1 The preparation of representative integrase strand transfer inhibitor particles (DTG:Gln) and corresponding injectable composition is described in Example 1.
  • Other representative integrase strand transfer inhibitor particles e.g., DTG:Trp and BIC:Gln
  • Integrase strand transfer inhibitor particles that include cabotegravir, raltegravir, and elvitegravir and corresponding injectable composition are prepared according to the procedure described in Example 1.
  • the present disclosure provides an injectable pharmaceutical composition, comprising a suspension of the colloidal integrase strand transfer inhibitor particles described herein in an aqueous solvent.
  • the injectable pharmaceutical composition includes from about 1 to about 2 mg integrase strand transfer inhibitor/mL.
  • the injectable pharmaceutical composition includes from about 10 to about 15 mg amino acid /mL.
  • the injectable pharmaceutical composition (or formulation) further includes a biocompatible pharmaceutical excipient. Suitable excipients include histidine, parabens, sucrose, lactose, Tween 20, and Tween 80.
  • the injectable pharmaceutical composition (or formulation) further includes a pegylated modifier. Suitable pegylated modifiers include lipid-conjugated PEGs with varying PEG MW (range: 500-5000) and acylated PEGs with varying PEG MW (range: 500-5000).
  • the present disclosure provides methods for using the colloidal particles and injectable pharmaceutical compositions.
  • the present disclosure provides a method for treating or preventing HIV in a subject.
  • the method comprises administering a therapeutically effective amount of the integrase strand transfer inhibitor particles described herein or the injectable composition described herein to subject in need thereof.
  • the present disclosure provides a method for treating or preventing a disease or condition treatable by administering an integrase strand transfer inhibitor in a subject.
  • the method comprises administering a therapeutically effective amount of the integrase strand transfer inhibitor particles described herein or the injectable composition described herein to subject in need thereof.
  • Other conditions or diseases known to be treatable by integrase strand transfer inhibitor include certain leukemias and cancers related to retroviral induced oncogene activation.
  • the integrase strand transfer inhibitor particles or the injectable compositions are administered by injection.
  • 0.5 - 6 mL of the injectable compositions (formulations) described herein are administered in one to four injections subcutaneously or intramuscularly.
  • the administration may be at any interval between 7 and 365 days.
  • Subjects that benefit from the above methods include subjects at risk of HIV exposure, those living with HIV, those recently exposed to HIV, and individual living with HIV that cannot swallow pills.
  • the present disclosure provides a long-acting HIV therapeutic product comprising an HIV integrase (INSTI) inhibitor (e.g., dolutegravir or DTG, a current HIV drug substance).
  • INSTI HIV integrase
  • the therapeutic product described herein is a colloidal pharmaceutical injectable product (e.g., colloidal DTG product).
  • the colloidal pharmaceutical product includes a colloid (e.g., DTG colloid), which is distinct from current drug delivery technologies, including liposome, nano-crystals, polymer conjugation or encapsulation, encasing in clay, carbon, silicon and other structure or materials used to produce a long-acting drug product.
  • the DTG colloid disclosed herein is stable in suspension and suitable for use as an injectable pharmaceutical product that exhibit long-acting pharmacokinetics in mammals.
  • Dolutegravir is a current first-line HIV drug that effectively inhibits HIV viral sequences to integrate into host human genomic DNA to product HIV progeny.
  • the DTG colloid disclosed herein includes an amino acid that stabilizes the colloid.
  • glutamine one of the essential amino acids for protein building block for animals and humans, was effective for stabilizing the colloid
  • dolutegravir sodium (DTG) was dissolved in water at 20 g/L at 25°C.
  • Glutamine (Gin) is also dissolved in water 15 g/L at 25°C.
  • To 8 pails of DTG [20g/L], 2 parts of Gin (15g/L) were added in a glass container and mixed at 25 °C. Immediately after mixing, the mixture form colloid exhibiting cloudy appearance. These spherical particles, detectable and observable under a high- resolution polarized microscope (see FIG. 3A and 4A).
  • the particles exhibited a diameter of 354 nm. These particles are stable at room temperature or 4°C storage and not subject to destabilization upon dilution (after DTG-CS is formed).
  • the resulting DTG-Gln particle is also referred to herein as DTG-CS as they are verified to be colloid and stable product.
  • the mole ratio of DTG to Gin is 2:9 (m/m).
  • the DTG-Gln product or DTG- CS composed of 2:9 m/m DTG-to-Gln was used as representative as described, unless otherwise noted.
  • X-ray diffraction techniques were employed. These techniques enable probing of new structural organizational distinction of DTG and Gin molecular’ arrangements. X-ray diffraction enables elucidation of structural distinction of native DTG crystalline, DTG and Gin admixture or either DTG or Gin alone. As shown in FIG. 3C, the DTG and Gin admixture (middle curve) was determined to be different from DTG-CS (top curve).
  • DTG-CS product made with either glutamine (Gin) or tryptophan (Trp) at the same ratio (2:9 (m/m)) was evaluated.
  • These DTG-CS products are stable in storage for extended periods.
  • These DTG-CS products cannot be destabilized when challenged with ionic amino acids, such as lysine or arginine in 10- to 100-fold excess relative to glutamine or tryptophan in solution.
  • ionic amino acids such as lysine or arginine in 10- to 100-fold excess relative to glutamine or tryptophan in solution.
  • positively charged lysine (in ionic form) or negatively charged glutamic acid (in ionic form) did not destabilize the DTG-CS product.
  • these data suggest that the interaction of DTG with Trp or with Gin are not ionic in nature.
  • chaotropic agent a well-understood H-bond breaker and generally referred to as chaotropic agent.
  • Urea has been known to protein scientist as chaotropic agent to denature the structure of protein composed of specific amino acid polymer sequence that folding and held together by hydrogen bonds and van der Waal’s forces to provide 3-dimentional structure for specific functions. Urea is able to break these bonds and unfold or denature proteins and break inter-amino acid H-bond (non-covalent) interactions as well as van der Waal’s interactions.
  • excipients to reduce self-aggregations or injectable colloid drug products could interfere with formation or ability of product to resuspend before use.
  • the DTG-CS suspensions were made at 2 mg/ml DTG with Gin stabilizer to determine ability to form a DTG-CS suspension.
  • 0.1% sucrose, 0.1% dextrose, or 0.014% pegylated lipid (mPEGiooo-DSPE) were added to determine formation of DTG-CS. After collecting DTG-CS particles by centrifugation at 500g x 10 min, they were resuspended in water at 1/10 of original volume.
  • Bictegravir particle (BIC-CS) formation as a function of glutamine concentration is shown in FIG. 8.
  • increasing concentrations of glutamine were added to a fixed concentration of 2.23 mM of bictegravir in solution.
  • the increase in bictegravir particle formation was apparent immediately and completed within 1-2 min.
  • the resulting particle in apparently turbid suspension was quantified with a spectrophotometer set to measure absorbance at 700 nm and expressed as A 700. The higher the absorbance means higher degree of bictegravir particle formed in suspension.
  • the data were expressed as glutamine-to- bictegravir mole ratio.
  • INSTI HIV integrase
  • the single-dose injection of DTG in CS formulated product produced long-acting plasma drug concentrations time-course of dolutegravir. Data presented were obtained with 2 non-human primates M. Nemestrina. No notable untoward effects in NHP were observed over 15 weeks. For comparison plasma time-course of 5mg/kg soluble DTG in NHP after a single subcutaneous dosing is presented.
  • the free drug (DTG) is prepared as a 1.6 mg/mL solution and given at equivalent dose 5mg/kg in NHP via subcutaneous route.
  • the plasma drug concentrations were measured with LC-MS/MS assay (the same as that for plasma NHP samples collected from NHP dose with equivalent 5 mg/kg DTG subcutaneous injection in DTG-CS dosage form. Data expressed were the mean value of 2 NHP.
  • the plasma drug level is below detection limit of the LC-MS/MS assay by day 2.
  • Reagents dolutegravir sodium salt (DTG) CAS # 1051375-19-9. MW: 419.38 (Cipla) glutamine (Gin): CAS #56-85-9, MW: 146.1 (Sigma) mPEG 2 ooo-DSPE Sodium Salt: CAS CAS #247925-28-6, MW: 2805.5 (Lipoid) sterile water for injection
  • 21 mg/mL stock solution of glutamine was prepared by adding 21 mg of glutamine powder into each mL of water.
  • 7 mg/mL stock solution of mPEG 2 ooo-DSPE was prepared by adding 7 mg of mPEG 2 ooo-DSPE into each mL of water.
  • sterile injectable product For the sterile injectable product, all the 3 items were sterile filtered and the formulation process was carried out in a sterile hood.
  • the resultant mixture was allowed to mix for 5 min at low speed (about 60 rpm).
  • DTG-CS particle size and DTG concentration are adjustable with varying ratio of DTG: Gin in the preparation step.
  • DTG concentration the following steps were performed.
  • the final product is stable at 25 °C or 4°C with respect to particles size and drug concentration over the 6-8 months study period.
  • the method and formulation process are readily scalable and intentionally designed in simple and scalable steps for making injectable sterile drug product. No heating or cooling is required.
  • the size of the particles was determined by dynamic light scattering (DLS) (hydrodynamic size of particles determined by optically measuring particles undergoing Brownian motion in a small scattering volume). Depending on DTG:Gln ratio, the particles had an initial size of from about 200 to about 700 nm (preferred nanoparticle size) or a large size in the range of about 1 to about 2 microns.
  • DLS dynamic light scattering
  • DTG-CS diolutergravir:glutamine particles were prepared by controlled addition of glutamine to dolutegravir solution.
  • DSPE-mPEG2000 was included in the formation to avoid particle aggregation.
  • Varying the concentration of glutamine in the formulation step affects DTG-Gln CS particle size.
  • the ratio of DTG:Gln was adjusted.
  • a direct relationship between Gin concentration (% w/v) and particle size was observed.
  • Increasing the Gin concentration increased the DTG-Gln CS particle size.
  • FIG. 7 illustrates the effects of varying concentration of Gin on DTG-Gln CS particle size. DTG-Gln CS particle stability
  • DTG-Gln CS particles prepared as described herein are stable at 25°C or 4°C with respect to particles size and drug concentration over a period of at least 6-8 months and are not subject to reversal by magnesium ion (Mg 2+ ).
  • DTG-Gln CS particles can be reversed by addition of urea at high concentration.

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Abstract

L'invention concerne des compositions comprenant des colloïdes stables d'inhibiteurs de l'intégrase du VIH pour la production de produits pharmaceutiques injectables à action prolongée en vue de traiter et de prévenir des infections au VIH.
PCT/US2024/026590 2023-04-26 2024-04-26 Compositions pharmaceutiques colloïdales à action prolongée d'inhibiteurs de transfert de brin de l'intégrase et méthodes associées Pending WO2024227037A1 (fr)

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US63/498,461 2023-04-26

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WO2024227037A1 true WO2024227037A1 (fr) 2024-10-31

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040170699A1 (en) * 2001-04-27 2004-09-02 Jean-Yves Chane-Ching Hydroxyapatite dispersions comprising an amino acid as stabilizing agent and method for preparing same
WO2020086555A1 (fr) * 2018-10-22 2020-04-30 Board Of Regents Of The University Of Nebraska Promédicaments antiviraux et nanoformulations de ceux-ci
US20210230186A1 (en) * 2016-06-23 2021-07-29 Viiv Healthcare Company Compositions and methods for the delivery of therapeutics
WO2021236944A1 (fr) * 2020-05-21 2021-11-25 Gilead Sciences, Inc. Compositions pharmaceutiques contenant du bictégravir

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040170699A1 (en) * 2001-04-27 2004-09-02 Jean-Yves Chane-Ching Hydroxyapatite dispersions comprising an amino acid as stabilizing agent and method for preparing same
US20210230186A1 (en) * 2016-06-23 2021-07-29 Viiv Healthcare Company Compositions and methods for the delivery of therapeutics
WO2020086555A1 (fr) * 2018-10-22 2020-04-30 Board Of Regents Of The University Of Nebraska Promédicaments antiviraux et nanoformulations de ceux-ci
WO2021236944A1 (fr) * 2020-05-21 2021-11-25 Gilead Sciences, Inc. Compositions pharmaceutiques contenant du bictégravir

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