WO2017209732A1 - A long acting pharmaceutical composition of protease inhibitor - Google Patents

A long acting pharmaceutical composition of protease inhibitor Download PDF

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Publication number
WO2017209732A1
WO2017209732A1 PCT/US2016/035029 US2016035029W WO2017209732A1 WO 2017209732 A1 WO2017209732 A1 WO 2017209732A1 US 2016035029 W US2016035029 W US 2016035029W WO 2017209732 A1 WO2017209732 A1 WO 2017209732A1
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Prior art keywords
group
carbon atoms
formula
protease inhibitor
lysine
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PCT/US2016/035029
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French (fr)
Inventor
James Nienyuan CHANG
Hsiang-Fa Liang
Meng-Hsin Chen
Kuei-Ling Kuo
An-Chieh Li
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Taimed Biologics, Inc.
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Priority to EP16904195.1A priority Critical patent/EP3463374A4/en
Priority to JP2018544210A priority patent/JP6704058B2/en
Priority to PCT/US2016/035029 priority patent/WO2017209732A1/en
Priority to CN201680085468.2A priority patent/CN109475563A/en
Publication of WO2017209732A1 publication Critical patent/WO2017209732A1/en

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    • 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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Abstract

Disclosed herein is a long acting pharmaceutical composition for treating or preventing human immunodeficiency virus (HIV) infection. The pharmaceutical composition 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. A method for treating or preventing HIV infection with the pharmaceutical composition is also disclosed.

Description

A LONG ACTING PHARMACEUTICAL COMPOSITION OF PROTEASE
INHIBITOR
TECHNICAL FIELD OF THE INVENTION
[0001] 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.
BACKGROUND OF THE INVENTION
[0002] Human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS) through infection of specialized cells of the immune system carrying CD4 receptors. The HIV retrovirus reproduces in these cells, especially the so-called T-helper cells, and kills them in the process. 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.
[0003] 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. Most of the currently available anti-protease drugs are large molecules with limited abiiitv to cross the blood-brain harrier. [0004] Some new compounds devoid of these drawbacks have been developed to treat HIV infections, and to fight the resistant viral strains. PCX International Patent Application no. PCT/CA02/00190 (Stranix et al.) published under No. WO 02/064551 HIV disclosed protease inhibitors based on amino acid derivatives. This patent application includes, more particularly, N-amino acid substituted L-lysine derivatives (and analogs) possessing aspartyl protease inhibitory properties. It was also provided some alternate compounds with such properties. For example, US Patent No. 6,632,816 B l disclosed a novel class of aromatic derivatives possessing aspartyl protease inhibitory properties, and their biological
applications in Treatment of HIV infections. [0005] Long-acting antiretroviral agents are currently under development for the treatment of chronic HIV infection. Long-acting medications could offer an attractive option for people with HIV facing a lifetime of antiretroviral treatment. These agents have the advantage of being more convenient and potentially improving patient's adherence. However, none of previous studies provides a good long acting pharmaceutical composition of a protease inhibitor for treating HIV infection.
SUMMARY OF THE DISCLOSURE
[0006] The present invention provides a new approach for treatment or prevention of HIV infection. In various embodiments of the invention, 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.
[0007] In one aspect, 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.
[0008] In some preferred embodiments of the invention, 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. [0009] In another aspect, 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
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.
[0010] In a further aspect, 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. [0011] In one or more embodiment, the dose of the suspension is about 5 to about 65 mg/kg of the subject's body weight.
[0012] In a yet aspect, 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.
[0013] In one or more embodiment, the medicament is administered once a month.
BRIEF DESCRIPTION OF THE DRAWINGS [0014] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the embodiments. [0015] In the drawings:
[0016] Figure 1 shows the PK profiles of TMB-607 in humans administrated with TMB-657 in the oral form. [0017] 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.
[0018] Figure 3 shows the plasma levels of TMB-607 in beagle dogs after subcutaneous (SC) and intramuscular (IM) injections respectively.
[0019] 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).
DETAILED DESCRIPTION OF THE INVENTION
[0020] 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.
[0021] Accordingly, 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.
[0022] Lysine-based aspartyl protease inhibitor
[0023] 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.
[0024] As disclosed in U.S. Patent No. 6,632,816, the compound has the structure of formula I I
Figure imgf000007_0001
and when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein n is 3 or 4, wherein X and Y, 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, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF3,— OCF3,— CN,— N02,— NR4R5,— NHCOR4,— OR4,— SR4,— COOR4,— COR4, and— CH2OH 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 of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R2 is 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, and a group of formula R2A— CO— , R2A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy,— CH2OH,— CF3,— CH2CF3,— CH2CH2CF3, pyrrolidinyl, piperidinyl, 4-morpholinyl, CH302C— , CH302CCH2— , Acetyl-OCH2CH2— , HO2CCH2— , 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH3OC6H4CH2— , CH3NH— , (CH3)2N— ,
(CH3CH2)2N— , (CH3CH2CH2)2N— , HOCH2CH2NH— , CH3OCH20— , CH3OCH2CH20— , C6H5CH2O— , 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3- quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
Figure imgf000008_0001
a picolyl group selected from the group consisting of
Figure imgf000008_0002
a picolyloxy group selected from the group consisting of
Figure imgf000008_0003
a substituted pyridyl group selected from the group consisting of
Figure imgf000008_0004
a group selected from the group consisting -o
Figure imgf000009_0001
wherein X' and Y', 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, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF3,— N02,— NR4R5,—
NHCOR4,— OR4,— SR4,— COOR4,— COR4 and— CH2OH, wherein R4 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 R3 is selected from the group consisting of a diphenylmethyl group of formula IV
IV
Figure imgf000009_0002
a naphthyl-l-CEh— group of formula V
V
Figure imgf000009_0003
a naphthyl-2-CH2— group of formula VI VI
Figure imgf000010_0001
a biphenylmethyl group of formula VII
VII
Figure imgf000010_0002
and an anthryl-9-CH2— group of formula VIII
VIII
Figure imgf000010_0003
[0025] As stated in U.S. Patent No. 6,632,816, one particular embodiment of the compound is of the formula Ila:
Ila
Figure imgf000010_0004
[0026] Among the compounds of formula Ila, 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
Figure imgf000011_0001
[0027] It was confirmed in the antiviral studies that 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. A 48- week resistance selection study was performed by increasing the concentrations of TMB-607 against a laboratory-adapted virus in vitro. Four mutations in the protease open reading frame were selected. Site-directed mutagenesis studies indicate that single mutations did not result in significant resistance to TMB-607 in vitro.
[0028] However, 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.
[0029] In the prevent invention, 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. [0030] Pharmaceutical Composition
[0031] The term "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. In the case of the present invention, 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.
[0032] In addition, 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.
[0033] The terms "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. [0034] The term "therapeutically effective amount" refers to an amount effective in treating or preventing HIV infection in a subject or a patient.
[0035] The terms "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. [0036] 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. [0037] As used herein, 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.
[0038] According to the invention, the pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of such 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.
[0039] With respect to the number of carbon atoms, the mention of the range of 1 to 6 carbon atoms is to be understood herein as incorporating each and every individual number of carbon atoms as well as sub-ranges such as, for example, 1 carbon atoms, 3 carbon atoms, 4 to 6 carbon atoms, etc.
[0040] According to the present invention, 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.
[0041] In the invention, the surface modifier is selected from the group consisting of poloxamers, alpha-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and phospholipids. Preferably, 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.
[0042] Methods of Treatment and Prevention
[0043] According to the invention, 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.
[0044] The term "treatment" of HIV infection 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. [0045] The term "prevention" of HIV infection means the onset of HIV infection is delayed, and/or the incidence or likelihood of HIV infection is reduced or eliminated.
[0046] The term "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.
[0047] The term "subject" or "patient" refers to any primate subject, including human and non-human subjects (e.g., rhesus subjects).
[0048] To treat and/or prevent HIV infection, a therapeutic amount of the pharmaceutical composition disclosed herein is administered to a subject in need. [0049] The term "therapeutically effective amount" means the dose required to effect an inhibition of ΗΓν 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. In one embodiment of the invention, 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. [0050] Long Acting Effect of the Pharmaceutical Composition according to the
Invention
[0051] According to the invention, it is confirmed in the examples that 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. As demonstrated in Example 3, the plasma levels of TMB-607 in the group treated with the TMB-607 in the form of nano-suspension (247 nm) by a subcutaneous administration maintained for more than 14 days, as compared with those in the group treated with the TMB-607 in the form of microparticle (2470 nm), see Figure 2. It was 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.
[0052] 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.
[0053] Examples [0054] Example 1 Preparation of nano-suspension of TMB-607
[0055] To prepare the nano-suspension by wet ball-milling process, 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 Zr02 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. When the wet ball-milling process was completed, the drug concentration of the nanonized suspension mixture was adjusted by WFI. Following the concentration adjustment, tonicity agent was added to adjust the osmolality of the suspension mixture to 300 mOsm/kg. The final concentration of TMB-607 for injectable suspension DP was in the range 20 mg/ml - 400 mg/ml. Their particle size of various formulation analyzed by a dynamic light scattering equipment (Zetasizer Nano S, Malvern) were around 100 nm - 500 nm. The formulations of the nano-suspension of TMB-607 as obtained was summarized in Table 1 below.
Table 1 Composition, concentration and particle size of the nano-suspensions of TMB-607
Figure imgf000016_0001
DSPE-PEG2000 1/1 3 20 276.0
Poloxamer 407 1/1 3 20 243.5
Poloxamer 407 4/1 3 20 233.8
Poloxamer 407 4/1 3 100 216.4
Poloxamer 407 4/1 3 240 210.4
Poloxamer 407 4/1 3 300 190.5
Poloxamer 188 4/1 3 300 350.5
Tween-80 4/1 3 300 187.3
Poloxamer 407 4/1 1 300 190.1
Poloxamer 407 4/1 0.5 200 146.8
Poloxamer 407 4/1 0.1 200 143.6
Poloxamer 407 5/1 0.1 200 113.0
Poloxamer 407 7/1 0.1 200 126.5
[0056] Example 2 Pharmacokinetic study of oral form TMB-657
[0057] A first-in-man single-dose escalation study of oral formulation TMB-657 was conducted at doses 300, 600 and 1200 mg. Six subjects received a single dose of TMB-657. The clinical pharmacokinetic profiles of TMB-607 was obtained in the patients with the single-dose escalation of TMB-657 in relation to its protein binding-adjusted antiviral activity (EC50 = 23 ng/ml). As shown in Figure 1, oral TMB-657 single dose could maintain the TMB-607 plasma level above the effect level (protein binding EC50, 23 ng/ml) for 24 hours. [Kazmierski, Antiviral drugs: from basic discovery through clinical trials, Chapter 2 Page 19, John Wiley & Sons, Inc, 2011.]
[0058] Example 3 Pharmacokinetic studies for TMB-607 in the forms of microparticles and nano-suspension
[0059] The studies demonstrated that an injectable formulation of nanonized TMB-607 results in stable blood plasma levels during a prolonged period of time (more than 1 month). In a rat study, 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. In addition, 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. In contrast, TMB-607 in the form of nanosuspension presented a sustained release profile in the study period.
[0060] Example 3 Comparison between intramuscular and subcutaneous injections [0061] 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. As shown in Figure 3, 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.
[0062] Example 5 Plasma levels of TMB-607 in monkeys administrated with the nano- suspensions in different particle sizes [0063] In a monkey pharmacokinetic study, 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.
[0064] Conclusion [0065] 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.

Claims

WHAT IS CLAIMED IS:
1. A long acting pharmaceutical composition for treating or preventing human
immunodeficiency virus (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.
2. The composition of claim 1, wherein the average effective particle size of the lysine-based aspartyl protease inhibitor or salt thereof is less than about 300 nm
3. The composition of claim 1, wherein the average effective particle size of the lysine-based aspartyl protease inhibitor or salt thereof is less than about 200 nm.
4. The composition of claim 1, wherein the average effective particle size of the lysine-based aspartyl protease inhibitor or salt thereof is between about 100 nm and about 200 nm
5. The composition of claim 1, wherein the surface modifier is selected from the group consisting of poloxamers, alpha-tocopheryl polyethylene glycol succinates, polyoxyethylene sorbitan fatty acid esters, and phospholipids.
6. The composition of claim 1, wherein 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).
7. The composition of claim 1, wherein the lysine-based aspartyl protease inhibitor is of the structure of formula I
I
Figure imgf000019_0001
and when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein n is 3 or 4, wherein X and Y, 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, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF3,— OCF ,— CN,— N02,— NR4R5,—
NHCOR4,— OR4,— SR4,— COOR4,— COR4, and— CH2OH or X and Y together define an alkylenedioxy group selected from the group consisting of a methylenedioxy group of formula— OCH20— and an ethylenedioxy group of formula— OCH2CH20— , wherein Ri is selected from the group consisting of a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, wherein R2 is 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, and a group of formula R2A— CO— , R2A being selected from the group consisting of a straight or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3- furanyloxy,— CH2OH,— CF ,— CH2CF ,— CH2CH2CF , pyrrolidinyl, piperidinyl, 4- morpholinyl, CH302C— , CH302CCH2— , Acetyl-OCH2CH2— , H02CCH2— , 3-hydroxyphenyl, 4-hydroxyphenyl, 4-CH3OC6H4CH2— , CH3NH— , (CH3)2N— , (CH3CH2)2N— ,
(CH3CH2CH2)2N— , HOCH2CH2NH— , CH3OCH20— , CH3OCH2CH20— , C6H5CH20— , 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1- isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula
Figure imgf000020_0001
a picolyl group selected from the group consisting of
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
a group selected from the group consisting of
Figure imgf000021_0004
wherein X' and Y', 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, a cycloalkyl group of 3 to 6 carbon atoms, F, CI, Br, I,— CF3,— N02,— NR4R5,— NHCOR4,— OR4,— SR4,— COOR4,— COR4 and— CH2OH, wherein R4 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 R3 is selected from the group consisting of a diphenylmethyl group of formula IV
IV
Figure imgf000022_0001
a naphthyl-l-CH2— group of formula V
V
Figure imgf000022_0002
a naphthyl-2-CH2— group of formula VI
VI
Figure imgf000022_0003
a biphenylmethyl group of formula VII VII
Figure imgf000023_0001
and an anthryl-9-CH2— group of formula VIII
VIII
Figure imgf000023_0002
8. The composition of claim 7, wherein the lysine -based aspartyl protease inhibitor is of the structure of formula Ila:
Ila
Figure imgf000023_0003
9. The composition of claim 8, wherein the lysine -based aspartyl protease inhibitor is TMB-607 having the structure of formula lib: lib
Figure imgf000024_0001
10. The pharmaceutical composition of claim 1, which is used for administration by intramuscular or subcutaneous injection.
11. A method of treating or preventing HIV infection for a long term comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition any one of claims 1-10 by intramuscular or subcutaneous injection once a week to a month.
12. The method of claim 11, wherein the dose of the suspension is about 5 to about 65 mg/kg of the subject's body weight.
13. 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.
14. The use of claim 13, wherein the suspension is that set forth in any one of claims 2-10.
PCT/US2016/035029 2016-05-31 2016-05-31 A long acting pharmaceutical composition of protease inhibitor WO2017209732A1 (en)

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US20060287316A1 (en) * 2005-04-27 2006-12-21 Ambrilia Biopharma Inc. Method for improving pharmacokinetics of protease inhibitors and protease inhibitor precursors
US20090253926A1 (en) * 2005-11-30 2009-10-08 Ambrilla Biopharma Inc. Lysine-based prodrugs of aspartyl protease inhibitors and processes for their preparation
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