EP3463374A1 - Composition pharmaceutique à action prolongée à base d'un inhibiteur de protéase - Google Patents

Composition pharmaceutique à action prolongée à base d'un inhibiteur de protéase

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Publication number
EP3463374A1
EP3463374A1 EP16904195.1A EP16904195A EP3463374A1 EP 3463374 A1 EP3463374 A1 EP 3463374A1 EP 16904195 A EP16904195 A EP 16904195A EP 3463374 A1 EP3463374 A1 EP 3463374A1
Authority
EP
European Patent Office
Prior art keywords
group
carbon atoms
formula
protease inhibitor
lysine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16904195.1A
Other languages
German (de)
English (en)
Other versions
EP3463374A4 (fr
Inventor
James Nienyuan CHANG
Hsiang-Fa Liang
Meng-Hsin Chen
Kuei-Ling Kuo
An-Chieh Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taimed Biologics Inc
Original Assignee
Taimed Biologics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taimed Biologics Inc filed Critical Taimed Biologics Inc
Publication of EP3463374A1 publication Critical patent/EP3463374A1/fr
Publication of EP3463374A4 publication Critical patent/EP3463374A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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

Definitions

  • This invention concerns a new pharmaceutical composition of a protease inhibitor providing a long acting effect in inhibition of the activity of HIV aspartyl protease, which is advantageously used to develop a new approach in treatment of HIV.
  • This invention also generally relates to a method for treating HIV.
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • the HIV retrovirus reproduces in these cells, especially the so-called T-helper cells, and kills them in the process.
  • T-helper cells While the body has the ability to re-generate T-helper cells to some extent, after years of continuous cell destruction by HIV and fighting back by the immune system, the virus eventually emerges as the battle's winner.
  • the progressive destruction of T- helper cells leads to weakening of the immune system which in turn, opens the door to opportunistic pathogens. When this happens, HIV-infected people start to show clinical symptoms. If left unchecked, HIV infection leads to death in a matter of years.
  • HIV In order to reproduce in infected cells, HIV needs three major enzymes that are carried inside the viral particle. These three enzymes, reverse transcriptase, protease and integrase, thus represent ideal targets for antiviral therapy. Of these, reverse transcriptase has been the first enzyme targeted by the pharmaceutical industry. Inhibitors of the viral protease have been developed more recently and their use as drugs for AIDS treatment began only in 1996. Although the development of reverse transcriptase and protease inhibitors has improved significantly the survival time and quality of life of HIV-infected patients, their use leads to unwanted side effects, such as anemia, neurotoxicity, bone marrow suppression and lipodystrophy.
  • the present invention provides a new approach for treatment or prevention of HIV infection.
  • a new long acting pharmaceutical composition of a protease inhibitor and a method for treating HIV infection with the long acting pharmaceutical composition are provided.
  • the present invention provides a long acting pharmaceutical
  • composition for treating or preventing HIV infection which comprises a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a
  • lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.
  • the average effective particle size of the lysine-based aspartyl protease inhibitor or salt thereof is preferably less than about 300 nm, more preferably about 200 nm and most preferably between about 100 nm and about 200 nm.
  • the present invention provides a pharmaceutical composition for administration by intramuscular or subcutaneous injection, which comprises a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a
  • lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.
  • the present invention provides a method for treating or preventing HIV infection for long term.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of the invention by intramuscular or subcutaneous injection one a week to a month.
  • the dose of the suspension is about 5 to about 65 mg/kg of the subject's body weight.
  • the present invention provides a use of a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment or prevention of HIV infection by intramuscular or subcutaneous injection once a week to a month; wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.
  • the medicament is administered once a month.
  • Figure 1 shows the PK profiles of TMB-607 in humans administrated with TMB-657 in the oral form.
  • Figure 2 shows the PK profiles of TMB-607 in rats administrated with TMB-607 in the forms of micro-particles (2470 nm) and nano-suspension (240 nm) respectively.
  • FIG 3 shows the plasma levels of TMB-607 in beagle dogs after subcutaneous (SC) and intramuscular (IM) injections respectively.
  • Figure 4 shows the plasma levels of TMB-607 in monkeys administrated with the TMB-607 in the form of nano-suspension in different particle sizes (240 nm and 113 nm).
  • the present invention has demonstrated for the first time that a new approach for preventing or treating HIV infection by a long acting pharmaceutical composition for administration by intramuscular or subcutaneous injection.
  • the present invention provides a long acting pharmaceutical composition for treating or preventing HIV infection, which comprises a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier; wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm, preferably less than about 300 nm, more preferably about 200 nm and most preferably between about 100 nm and about 200 nm.
  • Ambrilia Biopharma Inc. has developed lysine-based aspartyl protease inhibitor having the activity of HIV-1 protease inhibitor, as described in U.S. Patent No. 6,632,816, which is entirely incorporated herein by reference.
  • X and Y are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF 3 ,— OCF 3 ,— CN,— N0 2 ,— NR4R5,— NHCOR 4 ,— OR 4 ,— SR 4 ,— COOR 4 ,— COR 4 , and— CH 2 OH or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula— OCH2O— and an ethylenedioxy group of formula— OCH2CH2O— , wherein Ri is selected from the group consisting of a straight alkyl group
  • a picolyl group selected from the group consisting of
  • a picolyloxy group selected from the group consisting of
  • a substituted pyridyl group selected from the group consisting of
  • X' and Y' are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF 3 ,— N0 2 ,— NR4R5,—
  • NHCOR 4 — OR 4 ,— SR 4 ,— COOR 4 ,— COR 4 and— CH 2 OH, wherein R 4 and R5, the same or different, are selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl group of 3 to 6 carbon atoms, wherein R 3 is selected from the group consisting of a diphenylmethyl group of formula IV
  • TMB-607 one compound called as PL- 100 (hereinafter called as TMB-607) was confirmed to have effective and selective at inhibiting the HIV-1 protease and a favorable cross-resistance profile having, which is of the structure of the formula lib: lib
  • TMB-607 was both effective and selective at inhibiting the HIV-1 protease. It was also confirmed in the cross-resistance studies against 63 Pi-resistant strains that TMB-607 showed lower levels of reduced susceptibility than any of approved Protease inhibitors (Pis), indicating the potential for good activity against existing Pi-resistant viruses in the treatment of experienced patients.
  • Pis Protease inhibitors
  • TMB-607 had a poor solubility, which is not appropriate for a medicament in humans. Accordingly, its phosphorylated pro-drug, called as TMB-657 (former coded PPL- 100) having an improved solubility and pharmacokinetic properties had been developed.
  • a new pharmaceutical composition of a lysine-based aspartyl protease inhibitor or salt thereof, particularly TMB-607 was developed to provide a long acting effect in the treatment or prevention of HIV infection, which can be administered once a week, and even once a month.
  • pharmaceutically effective amount refers to an amount effective in treating HIV infection in a patient. It is also to be understood herein that a “pharmaceutically effective amount” may be interpreted as an amount giving a desired therapeutic effect, either taken into one dose or in any dosage or route or taken alone or in combination with other therapeutic agents.
  • a "pharmaceutically effective amount” may be understood as an amount having an inhibitory effect on HIV (HIV-1 and HIV-2 as well as related viruses (e.g., HTLV-I and HTLV-II, and simian immunodeficiency virus)) infection cycle (e.g., inhibition of replication, reinfection, maturation, budding etc.) and on any organism depending on aspartyl proteases for their life cycle.
  • HIV HIV-1 and HIV-2
  • related viruses e.g., HTLV-I and HTLV-II, and simian immunodeficiency virus
  • infection cycle e.g., inhibition of replication, reinfection, maturation, budding etc.
  • this invention provides pharmaceutical compositions in which these novel compounds of formula I, as well as of formulae Ila, and lib, derived from L-lysine or L- lysine derivatives (as well as its lower homologue (i.e. L-ornithine)) are used to inhibit aspartyl proteases, including HIV aspaityl protease, thus providing protection against HIV infection.
  • HIV protease and “HIV aspartyl protease” are used interchangeably and refer to the aspartyl protease encoded by the human immunodeficiency virus type 1 or 2. In a preferred embodiment of this invention, these terms refer to the human immunodeficiency virus type 1 aspartyl protease.
  • therapeutically effective amount refers to an amount effective in treating or preventing HIV infection in a subject or a patient.
  • pharmaceutically acceptable carrier refers to a non-toxic carrier or adjuvant that may be administered to a patient, together with a compound of the present invention, and which does not destroy the pharmacological activity thereof.
  • the compounds of this invention include pharmaceutically acceptable derivatives of the compounds of formula I (as well as of formulae II, Ila, lib, and lie) and as applicable pharmaceut cally acceptable salts thereof.
  • the term "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an andvirally active metabolite or residue thereof.
  • the pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • acid salts include: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylhydrogensulfate, dodecylsulfate,
  • ethanesulfonate formate, fumarate, glucoheptanoate, glycerophosphate, glycollate, hernisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthylsulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, perchlorate, persulfate, 3 -phenyl propionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
  • the prepare the long acting pharmaceutical composition can be prepared by any commonly used and known methods by admixing the lysine-based aspartyl protease inhibitor or salt thereof in an appropriate particle size, with an appropriate surface modifier, and one or more appropriate pharmaceutically acceptable carriers.
  • the surface modifier is selected from the group consisting of poloxamers, alpha-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and phospholipids.
  • the surface modifier is selected from the group consisting of poloxamer 188, poloxamer 407, d-a-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS), Tween 80, and distearoylphosphatidylethanolamine- poly(ethylene glycol) (DSPE-PEG), which are supported by the examples shown in Table 1.
  • the long acting pharmaceutical composition disclosed herein are employed for the treatment and/or prevention of HIV infection in a subject, as well as prevention of HIV transmission.
  • treatment refers to effective inhibition of the HIV infection so as to delay the onset, slow down the progression, reduce viral load, and/or ameliorate the symptoms caused by HIV infection.
  • prevention means the onset of HIV infection is delayed, and/or the incidence or likelihood of HIV infection is reduced or eliminated.
  • prevention of HIV transmission means the incidence or likelihood of HIV being transmitted from one individual to another (e.g., from an HIV-positive woman to the child during pregnancy, labor or delivery, or breastfeeding; or from an HIV-positive subject to an HIV-negative partner) is reduced or eliminated.
  • subject or “patient” refers to any primate subject, including human and non-human subjects (e.g., rhesus subjects).
  • a therapeutic amount of the pharmaceutical composition disclosed herein is administered to a subject in need.
  • the term "therapeutically effective amount” means the dose required to effect an inhibition of ⁇ infection so as to treat and/or prevent HIV infection.
  • the dosage of an antibody depends on the disease state and other clinical factors, such as weight and condition of the subject, the subject's response to the therapy. The precise dosage to be therapeutically effective and non-detrimental can be determined by those skilled in the art.
  • a suitable dose of the long acting pharmaceutical composition for intramuscular or subcutaneous administration to adult humans is in the range of about 5 to about 65 mg/kg of subject's body weight once a week, or even once a month.
  • the suspension of TMB-607 one example of the ly sine-based aspartyl protease inhibitor, a surface modifier, and a pharmaceutically acceptable carrier, provide a long acting effect, wherein the lysine- based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm.
  • Example 4 It was also confirmed in Example 4 that the animals after treated with a single intramuscular or subcutaneous injection of the TMB-607 in the form of nano-suspension had prolonged plasma levels of TMB-607, see Figure 3. Furthermore, it was demonstrated in
  • Example 5 that both the particle size of 214 nm and that of 113 nm could prolong the plasma levels, and the smaller size of TMB-607 (113 nm) possessed the higher plasma level and longer effective duration.
  • TMB-607 was added into a aqueous polymer solution with a 1: 1 to 7: 1 drug to polymer ratio (D/P ratio, by w/w).
  • the suspension mixture was then poured into Delta Vita 15-300 (DV-15, Netzsch Premier Technologies, USA-Exton, PA), which was partially filled with 0.1-3 mm Zr0 2 grinding beads in the grinding chamber.
  • the suspension mixture was ground at various speeds and for approximately 6 hours to 7 days until the mean particle size reached submicron range.
  • the drug concentration of the nanonized suspension mixture was adjusted by WFI.
  • TMB-607 for injectable suspension DP was in the range 20 mg/ml - 400 mg/ml.
  • Table 1 Composition, concentration and particle size of the nano-suspensions of TMB-607
  • TMB-607 in the forms of microparticle (2470 nm) and nano-suspension (240 nm) were subcutaneously administrated at a dose of 16.7 and 23.5 mg/kg, respectively.
  • the results were shown in Figure 2, indicating that nanosized TMB-607 could prolong the plasma level above the protein binding adjusted EC50 for 14 days, but TMB-607 microparticles did not.
  • a dramatic high Cmax observed in the group treated with the TMB-607 in the form of microparticles in the initial time period which would cause significant side effects to human body.
  • TMB-607 in the form of nanosuspension presented a sustained release profile in the study period.
  • Example 3 Comparison between intramuscular and subcutaneous injections
  • a dog study was conducted to compare the pharmacokinetics of TMB-607 after a single intramuscular or subcutaneous injection of the nano-suspension.
  • Each treatment group consisted of 3 male Beagle dogs at a dose of 60 mg/kg.
  • the particle size used in this study was around 150 nm, and the plasma levels of TMB-607 were monitored for 6 weeks.
  • no significant difference was observed in the AUCO-t values between the dogs treated with TMB-607 at 60 mg/kg via two dosing routes: a subcutaneous and intramuscular administration, while the Cmax values for the intramuscular dosing route were higher than those for the subcutaneous dosing route.
  • Example 5 Plasma levels of TMB-607 in monkeys administrated with the nano- suspensions in different particle sizes
  • the nano-suspension of TMB-607 at the different particle sizes of 214 nm and 113 nm were injected into monkeys respectively.
  • Each treatment group consisted of 3 monkeys at a dose of 60 mg/kg.
  • Figure 5 shows the plasma levels of TMB-607 monitored for 4 weeks. Comparing the different particle size of administration of TMB-607 at 60 mg/kg, both AUCO-t and tm generally increased while decreasing the particle size of TMB-607 nano-suspensions. The results were shown in Figure 4, indicating that the smaller size of TMB-607 particle possesses the higher plasma level and longer effective duration.
  • the present invention provides a suspension of a lysine-based aspartyl protease inhibitor or salt thereof, a surface modifier, and a pharmaceutically acceptable carrier; wherein the lysine-based aspartyl protease inhibitor or salt thereof has an average effective particle size of less than about 500 nm, which can be developed to a long acting pharmaceutical composition for treatment or prevention of HIV infection.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • AIDS & HIV (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physics & Mathematics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique à action prolongée pour le traitement ou la prévention de l'infection par le virus de l'immunodéficience humaine (VIH). La composition pharmaceutique comprend une suspension d'un inhibiteur de la protéase aspartique à base de lysine ou d'un sel de celui-ci, un modificateur de surface et un support de qualité pharmaceutique ; l'inhibiteur de la protéase aspartique à base de lysine ou son sel présentant une taille de particule moyenne effective inférieure à environ 500 nm. L'invention concerne également une méthode de traitement ou de prévention d'une infection par le VIH à l'aide de la composition pharmaceutique.
EP16904195.1A 2016-05-31 2016-05-31 Composition pharmaceutique à action prolongée à base d'un inhibiteur de protéase Withdrawn EP3463374A4 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2016/035029 WO2017209732A1 (fr) 2016-05-31 2016-05-31 Composition pharmaceutique à action prolongée à base d'un inhibiteur de protéase

Publications (2)

Publication Number Publication Date
EP3463374A1 true EP3463374A1 (fr) 2019-04-10
EP3463374A4 EP3463374A4 (fr) 2020-01-22

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP16904195.1A Withdrawn EP3463374A4 (fr) 2016-05-31 2016-05-31 Composition pharmaceutique à action prolongée à base d'un inhibiteur de protéase

Country Status (4)

Country Link
EP (1) EP3463374A4 (fr)
JP (1) JP6704058B2 (fr)
CN (1) CN109475563A (fr)
WO (1) WO2017209732A1 (fr)

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998035666A1 (fr) * 1997-02-13 1998-08-20 Nanosystems Llc Preparation de pastilles de naproxene nanoparticulaire
WO1998057648A1 (fr) * 1997-06-16 1998-12-23 Vertex Pharmaceuticals Incorporated Procede d'amelioration de la biodisponibilite des polymorphes cristallins stables d'un compose
US7388008B2 (en) * 2004-08-02 2008-06-17 Ambrilia Biopharma Inc. Lysine based compounds
WO2006114001A1 (fr) * 2005-04-27 2006-11-02 Ambrilia Biopharma Inc. Procede d'amelioration de la pharmacocinetique d'inhibiteurs de protease et de leurs precurseurs
CA2632095A1 (fr) * 2005-11-30 2007-06-07 Ambrilia Biopharma Inc. Promedicaments d'inhibiteurs d'aspartyl protease a base de lysine et leurs procedes de fabrication
CA2651659C (fr) * 2006-05-30 2014-09-09 Tibotec Pharmaceuticals Ltd. Derives apparentes a la lysine en tant qu'inhibiteurs de l'aspartyl protease du vih
UA97641C2 (en) * 2006-06-23 2012-03-12 Тиботек Фармасьютикелз Лтд. Aqueous suspensions of tmc278
JP2010502569A (ja) * 2006-07-17 2010-01-28 アンブリリア バイオファーマ インコーポレイテッド 薬物動態学の改善方法

Also Published As

Publication number Publication date
CN109475563A (zh) 2019-03-15
JP2019510002A (ja) 2019-04-11
EP3463374A4 (fr) 2020-01-22
WO2017209732A1 (fr) 2017-12-07
JP6704058B2 (ja) 2020-06-03

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