Pharmaceutical compositions for treating infections with neurotropic viruses

Abstract

The present invention relates to a pharmaceutical composition comprising as an active agent at least one antiviral agent for use in the prevention or treatment of infection by a neurotropic virus, in particular a virus of the Coronaviridae family or a virus of the Retroviridae family, wherein the pharmaceutical composition is administered by the nasal route, in particular via the olfactory pathway.

Description

[Technical Field]

[0001] The present invention relates to compositions and methods for treating infections caused by neurotropic viruses, particularly viruses of the Coronaviridae family or Retroviridae family, and more particularly by SARS-CoV-2 virus or human immunodeficiency virus (HIV). [Background technology]

[0002] In December 2019, cases of pneumonia of unknown cause emerged in Wuhan, China, and rapidly spread throughout the country. On January 7, 2020, the causative pathogen was identified as the novel coronavirus, which was named 2019-nCoV, and later SARS-CoV-2.

[0003] This novel virus is very closely related to both SARS-CoV (82% nucleotide identity) and MERS-CoV (50% nucleotide identity), but is distinctly different from both.

[0004] COVID-19 is the name of the disease caused by SARS-CoV-2, but its initial mortality rate suggested it was less severe than SARS and MERS. However, the rapid increase in the number of people developing the disease quickly suggested that SARS-CoV-2 was more infectious than both SARS-CoV and MERS-CoV. As of May 11, 2020, there have been 4,063,525 reported cases of COVID-19 (according to the case definitions and testing strategies applied in the affected countries), including 282,244 deaths.

[0005] Several scientific papers have reported neurological disorders in patients infected with SARS-CoV-2. The mechanism remains unclear, but it is thought to be either caused by the virus entering the brain via the olfactory nerves or by an inflammatory process that reaches the brain. However, other viruses can reach the brain and remain there for months, years, or even decades.

[0006] Significant efforts are being made to find a drug effective against SARS-CoV-2. Among the various compounds tested, remdesivir, a drug previously developed for the treatment of Ebola virus infection, was reported in a news release from the U.S. National Institutes of Health (NIH) dated April 29, 2020, to show promising efficacy and acceptable safety in the treatment of COVID-19. Preliminary results show that patients treated with remdesivir had a 31% faster recovery time than those treated with placebo (p<0.001). More specifically, the median time to recovery was 11 days for patients treated with remdesivir compared to 15 days for patients treated with placebo. The results also suggested a benefit to survival, with a mortality rate of 8.0% in the remdesivir group compared to 11.6% in the placebo group (p=0.059).

[0007] However, the efficacy of remdesivir is not yet fully established, as Wang et al. (2020) Lancet doi.org / 10.1016 / S0140-6736(20)31022-9 reported that in their clinical trial, the use of remdesivir was not associated with a time lag to clinical improvement.

[0008] Therefore, there is still a need for alternative therapies to prevent or treat infection with SARS-CoV-2, particularly its neurological effects.

[0009] More generally, many viruses, particularly those belonging to the retroviridae family, can infect the central nervous system (CNS), especially the brain, and cause neurological disorders ranging in severity from mild to dementia, such as HIV-associated neurocognitive disorder (HAND).

[0010] Neurological disorders caused by these viruses also require alternative treatments. [Overview of the project]

[0011] This invention stems from the inventors' unexpected discovery that administering antiviral agents via the olfactory nerve pathway can improve their effectiveness against neurotropic viruses, particularly coronaviruses or retrovirals, and especially against SARS-CoV-2 or human immunodeficiency virus (HIV).

[0012] While we do not wish to be bound by any particular theory, the inventors believe that one reason why antiviral drugs used against SARS-CoV-2 or HIV are ineffective is that the virus can evade these drugs by circulating through the nervous system, particularly through infection of the olfactory nerve, where the drugs cannot reach the virus.

[0013] Accordingly, the present invention relates to a pharmaceutical composition comprising at least one antiviral agent as an active agent for use in the prevention or treatment of infection in individuals by neurotropic viruses, particularly viruses of the Coronaviridae family or retroviridae family, wherein the pharmaceutical composition is administered via the nasal route, particularly via the olfactory nerve route.

[0014] The present invention also relates to a method for preventing or treating infection in an individual by a neurotropic virus, particularly a virus of the Coronaviridae or Retroviridae family, comprising administering to the individual a pharmaceutical composition comprising at least one antiviral agent as an active agent, wherein the pharmaceutical composition is administered via the nasal route, particularly via the olfactory nerve route. [Modes for carrying out the invention]

[0015] Detailed description of the invention As intended herein, the word "comprising" is synonymous with "include" or "contain." When a subject is said to "comprising" one or more features, it means that features other than those mentioned may also be included in that subject. Conversely, the expression "composed of" is synonymous with "consisting of." When a subject is said to consist of one or more features, it means that features other than those mentioned are not included in that subject.

[0016] virus Where intended herein, the infections to be prevented or treated are those caused by neurotropic viruses. Neurotropic viruses, as well as those well known to those skilled in the art, can infect nerve cells. The neurotropic viruses according to the present invention may be neuroinvasive and / or neurotoxic. The neurotropic viruses according to the present invention can infect the central nervous system, particularly the brain, and / or the peripheral nervous system.

[0017] The neurotropic virus according to the present invention is preferably selected from the group consisting of Japanese encephalitis virus, Venezuelan encephalitis virus, California encephalitis virus; poliovirus, coxsackievirus, echovirus, mumps virus, measles virus, influenza virus, rabies virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, HHV-6 virus, rubella virus, JC virus, retroviridae viruses, herpesviridae family viruses, coronaviruses, and their mutants and variants.

[0018] Preferred neurotropic viruses of the retroviridae family according to the present invention are human immunodeficiency virus (HIV), particularly HIV-1 or HIV-2, human T lymphotropic virus 1, or mutants or variants thereof.

[0019] A preferred neurotropic virus of the Herpesviridae family according to the present invention is a herpes simplex virus (HSV), particularly HSV-1 or HSV-2, or a mutant or variant thereof.

[0020] Preferably, the infection to be prevented or treated is caused by a virus of the Coronaviridae family.

[0021] Preferably, the virus defined above belongs to the genus Alphacoronavirus, Betacoronavirus, Deltacoronavirus, or Gammacoronavirus, more preferably to the genus Betacoronavirus, and most preferably to the subgenus Sarbecovirus or Merbecovirus.

[0022] Preferably, the virus defined above is also a human virus, i.e., a virus capable of infecting humans.

[0023] Preferably, the virus defined above is selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV, and mutants or variants thereof.

[0024] Preferably, the virus defined above is SARS-CoV-2, or a mutant or variant thereof.

[0025] SARS-CoV-2 is particularly described in Fuk-Woo Chan et al. (2020) Emerging Microbes & Infections 9:221-236, which is incorporated herein by reference, and is also referred to as 2019-nCoV, HCoV-19, SARS2, COVID-19 virus, Wuhan coronavirus, Wuhan seafood market pneumonia virus, human coronavirus 2019.

[0026] Preferably, the virus defined above is SARS-CoV-2, having the genomic sequence defined by the NCBI reference sequence NC_045512.2 (SEQ ID NO: 1), or its complementary sequence, or a mutant or variant thereof. Mutants or variants of SEQ ID NO: 1 can be found, in particular, by searching for SARS-CoV-2 taxid:2697049 on the "NCBI virus" website. Preferred variants of SARS-CoV-2 according to the present invention are selected from the group consisting of K417N, K417T, L452R, T478K, E484K, E484Q, N501Y, and D614G, and in particular have at least one mutation in the spike protein. The preferred variant of SARS-CoV-2 according to the present invention is a variant of interest, more preferably selected from the group located in B.1.1.7 (alpha), B.1.1.7+E484K, B.1.351 (beta), P.1 (gamma), B.1.617.1 (kappa), B.1.617.2 (delta), and B.1.617.3.

[0027] Where intended herein, a “mutant or variant” of the virus or the genome sequence of the virus defined above is a genome sequence or nucleotide sequence having at least 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity with the genome sequence of the virus defined above.

[0028] Where intended herein, a first nucleotide sequence having "at least X% identity" with a second nucleotide sequence differs from the second sequence, in particular, by at least one nucleotide insertion, repression, or substitution. Furthermore, the percentage of identity between two nucleotide sequences is defined herein as the number of positions where bases are identical when the two sequences are optimally aligned, divided by the total number of bases in the longer of the two sequences. Two sequences are said to be optimally aligned when the percentage of identity is maximized. Furthermore, as will be apparent to those skilled in the art, it may be necessary to add gaps to obtain optimal alignment between two sequences. Furthermore, when calculating the percentage of identity between an RNA nucleotide sequence and a DNA nucleotide sequence, uracil (U) bases and thymine (T) bases at the same position are considered identical.

[0029] As intended herein, preventing or treating an individual infection with a neurotropic virus includes preventing or treating symptoms, disorders, syndromes, conditions, or diseases associated with an infection with a neurotropic virus.

[0030] As intended herein, preventing or treating infection in an individual with a coronavirus is encompassed by preventing or treating symptoms, disorders, syndromes, conditions, or diseases associated with infection by a coronavirus, and more particularly by SARS-CoV-2, such as pneumonia or COVID-19.

[0031] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating loss of smell associated with viral infection.

[0032] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating taste disorders associated with viral infections.

[0033] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating encephalopathy associated with viral infections.

[0034] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating neuroinflammation associated with viral infections.

[0035] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating neurological disorders associated with viral infections.

[0036] Preferably, the pharmaceutical compositions defined above are for use in preventing or treating neurocognitive disorders associated with viral infections, and in particular for preventing or treating HIV-associated neurocognitive disorders (HAND).

[0037] individual Preferably, the individual is a bird, such as a chicken, or a mammal, such as a human, a dog, especially a cat, a cat, especially a horse, a cow, a pig, a sheep, or a goat, or a camelid, and more preferably, the individual is a human.

[0038] The individuals defined above may be of any age. Preferably, the individuals defined above are humans who are 20 years of age or older, 30 years of age or older, 40 years of age or older, or 50 years of age or older, more preferably 60 years of age or older, even more preferably 70 years of age or older, and most preferably 80 years of age or older. Preferably, the individuals defined above are humans who are 80, 70, 60, 50, 40, 30, or under 20 years of age.

[0039] The individual defined above may be male or female. Preferably, the individual defined above is a male individual.

[0040] Preferably, the individual defined above suffers from at least one other disease or condition, particularly selected from hypertension, diabetes mellitus, especially type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease, especially ischemic myopathy, chronic respiratory disease, or cancer.

[0041] Preferably, the individual defined above is overweight or obese.

[0042] According to the usual definition, a human individual is considered overweight if their BMI (Body Mass Index: weight in kg divided by the square of height in meters) is 25 kg / m 2 or more and less than 30 kg / m 2 ; and is considered obese if their BMI is 30 kg / m 2 or more. An individual according to the present invention can significantly exhibit severe obesity particularly characterized by a BMI of 35 kg / m 2 or more in humans.

[0043] More generally, the individual defined above is human and has a BMI of 25 kg / m 2 , 26 kg / m 2 , 27 kg / m 2 , 28 kg / m 2 , 29 kg / m 2 , 30 kg / m 2 , 31 kg / m 2 , 32 kg / m 2 , 33 kg / m 2 , 34 kg / m 2 , 35 kg / m 2 or 40 kg / m 2 or more is preferred.

[0044] Furthermore, the individual defined above may also have abdominal obesity, particularly corresponding to excessive visceral adipose tissue. According to the usual definition, a male human individual has abdominal obesity if the abdominal circumference is 94 cm or more, particularly more than 102 cm, and a female human individual has abdominal obesity if the abdominal circumference is 80 cm or more, particularly more than 88 cm. The measurement of the abdominal circumference is well known to those skilled in the art: Therefore, the abdominal circumference is preferably measured in an individual in a standing position with gentle exhalation at the midpoint between the last floating rib and the upper end of the iliac crest.

[0045] The individuals defined above are male and preferably have an abdominal circumference of 90cm, 91cm, 92cm, 93cm, 94cm, 95cm, 96cm, 97cm, 98cm, 99cm, 100cm, 101cm, or 102cm or more. Furthermore, the individuals according to the present invention are female and preferably have an abdominal circumference of 75cm, 76cm, 77cm, 78cm, 79cm, 80cm, 81cm, 82cm, 83cm, 84cm, 85cm, 86cm, 87cm, or 88cm or more.

[0046] Preferably, the individual according to the present invention has acquired immunodeficiency syndrome (AIDS) or is at risk of developing AIDS.

[0047] Preferably, the individual according to the present invention is infected with COVID-19 or is at risk of contracting COVID-19.

[0048] Preferably, the individual according to the present invention is suffering from or at risk of suffering from olfactory loss.

[0049] Preferably, the individual according to the present invention is suffering from or at risk of suffering from a taste disorder.

[0050] Preferably, the individual according to the present invention is suffering from or at risk of developing encephalopathy.

[0051] Preferably, the individual according to the present invention is suffering from or at risk of developing neuroinflammation.

[0052] Preferably, the individual according to the present invention is suffering from or at risk of suffering from a neurological disorder.

[0053] Preferably, the individual according to the present invention has a neurocognitive disorder, particularly HIV-related neurocognitive disorder (HAND), or is at risk of developing a neurocognitive disorder, particularly HIV-related neurocognitive disorder (HAND).

[0054] Antiviral drugs Where intended herein, any antiviral agent capable of preventing or treating infection by neurotropic viruses, particularly viruses of the Coronaviridae or Retroviridae families, may be used in accordance with the present invention. The antiviral agent may be, in particular, an inhibitor of viral polymerase (e.g., Nsp12 of SARS-CoV-2 or reverse transcriptase (RT) of HIV), viral helicase (e.g., Nsp13 or SARS-CoV-2), viral integrase (e.g., HIV integrase), or viral protease (e.g., HIV protease); an inhibitor of the binding of the virus to its target receptor (e.g., ACE-2 in the case of SARS-CoV-2, or CD4, CCR5, or CXCR4 in the case of HIV); a fusion inhibitor; or a general antiviral agent, such as interferon.

[0055] Preferably, the antiviral agent according to the present invention is a substrate of an individual's efflux transporter. Efflux transporters, also called efflux cell membrane transporters, are well known to those skilled in the art. Efflux transporters can be involved in drug resistance by transporting substrate drugs from inside the cell to the extracellular space. Examples of efflux transporters according to the present invention include P-glycoprotein (P-gp / ABCB1), multidrug resistance-associated protein 2 (MRP2 / ABCC2), and breast cancer resistance protein (BCRP / ABCG2).

[0056] However, antiviral drugs include hydroxychloroquine, chloroquine, atobakon, remdesivir, ribavirin, didanosine, penciclovir, favipiravir, nafamostat, cobicistat, nitazoxanide, azithromycin, carrimycin, recombinant human interferon α1β, pegylated interferon α-2a, oseltamivir, nicotine, tofacitinib, imatinib, acalabrutinib, losartan, valsartan, telmisartan, and tetrandine. Preferably, the following are selected from the group consisting of clevudine; tiliquinone; nitazoxanide; tilbroquinone; nifluzide; nifloxazide; minocycline; rovomycine; rocephine; HIV reverse transcriptase inhibitors, e.g., tenofovir; HIV protease inhibitors, e.g., lopinavir, ritonavir, lopinavir / ritonavir, darunavir, danoprevir, umifenovir; purine analogs; and pharmaceutically acceptable salts, derivatives, and prodrugs thereof.

[0057] The antiviral agent is more preferably selected from the group consisting of remdesivir, hydroxychloroquine, tenofovir, and lopinavir. The most preferred antiviral agent is mornupyravir.

[0058] Preferably, the antiviral agent is also an anti-HIV agent, and is selected from the following group: - Abacavir, - Abacavir / lamivudine, - Abacavir / Lamivudine / Zidovudine, - Atazanavir, - Atazanavir / cobicistat, - Bictegravir / tenofoviral afenamide - Cabotegravir / Rilpivirine, - Darunavir, - Darunavir / Cobicistat, - Darunavir / cobicistat / tenofovir alafenamide / emtricitabine - Delavirdine, - Didanosine, - Dolutegravir, - Dolutegravir / abacavir / lamivudine, - Dolutegravir / lamivudine, - Dolutegravir / Rilpivirine, - Drabilyn, - Doravirine / Tenofovir disoproxil fumarate / Lamivudine, - Efavirenz, - Efavirenz / Tenofovir disoproxil fumarate / Emtricitabine, - Elvitegravir, - Elvitegravir / cobicistat / tenofovir disoproxil fumarate / emtricitabine - Elvitegravir / tenofovir alafenamide / emtricitabine - Emtricitabine, - Emtricitabine / tenofovir alafenamide, - Emtricitabine / tenofovir disoproxil fumarate, - Enfvilchid, - Etravirine, - Fosamprenavir, - Hostemsavir, - Ibarizumab-uiyk, - Indinavir, - Lamivudine, - Lopinavir ritonavir, - Maraviroc, - Nelfinavir, - Nevirapine, - Raltegravir, - Lilpivirine, - Rilpivirine / tenofovir disoproxil fumarate / emtricitabine, - Rilpivirine / tenofovir alafenamide / emtricitabine - Ritonavir, - Saquinavir, - Stubzine, - Tenofovir alafenamide, - Tenofovir disoproxil fumarate, - Tenofovir disoproxil fumarate / lamivudine, - Tipranavir, - Zidovudine, and - Zidovudine / Lamivudine.

[0059] Preferably, the antiviral agents defined above have logP values ​​of at least -3;-2.5;-2;-1.5;-1;-0.5;0;0.5;1;1.5;2;2.5;3;3.5;4;4.5;5;5.5 or 6.

[0060] Preferably, the antiviral agents defined above have logP values ​​of 6;5.5;5;4.5;4;3.5;3;2.5;2;1.5;1;0.5;0;-0.5;-1;-1.5;-2;-2.5; or less than -3.

[0061] The logP value provides an indicator of the ability of an antiviral agent to diffuse across biological lipid membranes. A higher logP value indicates higher lipid solubility of the antiviral agent. Antiviral agents with a logP value of 1, 2, or greater than 3, preferably greater than 2, are generally considered to have the ability to diffuse across biological lipid membranes. 10 Determining the value of P is well known to those skilled in the art. P is K ow Also known as the n-octanol-water partition coefficient or ratio, P = (concentration of the substance in the octanol-rich phase) / (concentration of the substance in the water-rich phase). The octanol-rich phase contains essentially only octanol, and the water-rich phase contains essentially only water, such as distilled water. If a substance exists as several species, the concentration of the substance is the sum of the concentrations of those species.

[0062] Advantageously, the compositions according to the present invention can compensate for the transport of antiviral agents outside target cells by improving penetration into target cells, even for antiviral agents that have a good ability to diffuse across biological lipid membranes, i.e., antiviral agents having logP values ​​greater than 1, 2, or 3, when the antiviral agent according to the present invention is a substrate of an efflux transporter. Therefore, in one embodiment of the present invention, the antiviral agent is a substrate of an individual's efflux transporter and has a logP value greater than 1, 2, or 3, preferably greater than 2.

[0063] Preferably, the antiviral agent defined above has a water-soluble content of at least 0.001 mg / mL, 0.005 mg / mL, 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, or 0.5 mg / mL.

[0064] Preferably, the antiviral agents defined above have water solubility of 0.5 mg / mL, 0.1 mg / mL, 0.05 mg / mL, 0.01 mg / mL, 0.005 mg / mL, or less than 0.001 mg / mL.

[0065] Determining the water solubility of a substance is well known to those skilled in the art. This is the saturation concentration (m / v) of the substance in substantially pure water, for example, distilled water.

[0066] Preferably, the logP and water solubility values ​​referred to herein are measured at pH 7 under standard temperature (20°C) and pressure (1 atm).

[0067] For example: - Tenofovir disoproxil fumarate (TDF) has a logP value of approximately 1.25 and is water-soluble at approximately 13.4 mg / ml (in distilled water at 25°C); - Tenofovir alafenamide has a logP value of approximately 1.6 and a water solubility of approximately 4.86 mg / ml (at 20°C); - Emtricitabine has a logP value of approximately -0.43 and a water solubility of approximately 112 mg / ml; - Dolutegravir has a logP value of approximately 2.2 and is poorly soluble; - Abacavir has a logP value of approximately 1.2 and a water solubility of approximately 77 mg / ml (in the case of sulfate); - Lamivudine has a logP value of approximately -1.4 and a water solubility of approximately 70 mg / ml.

[0068] Preferably, the antiviral agent according to the present invention has a molecular weight of less than 10,000 g / mol, less than 5,000 g / mol, less than 2,500 g / mol, or less than 1,000 g / mol.

[0069] Preferably, the antiviral agent according to the present invention is selected from the group consisting of tenofovir disoproxil, particularly tenofovir disoproxil fumarate (TDF), tenofovir alafenamide, particularly tenofovir alafenamide fumarate (TAF), emtricitabine, dolutegravir, abacavir, particularly abacavir sulfate, lamivudine, and combinations thereof.

[0070] In one embodiment of the present invention, the antiviral agent is not interferon. In another embodiment of the present invention, the antiviral agent is not ribavirin.

[0071] Pharmaceutical composition Preferably, the pharmaceutical composition defined above further comprises at least one pharmaceutically acceptable vehicle, carrier, or additive suitable for administration via the nasal pathway, particularly the olfactory nerve pathway.

[0072] Vehicles, carriers, or additives suitable for administration via the nasal route are well known to those skilled in the art and may be particularly selected from the group consisting of fatty or lipophilic solvents or phases and aqueous or hydrophilic solvents or phases.

[0073] The fatty or lipophilic solvent or phase may contain or consist of at least one fatty acid, monoglyceride, diglyceride, triglyceride, fatty alcohol, fatty ester, or a combination thereof.

[0074] For example, the fatty acid may be docosahexaenoic acid or isopropyl palmitate.

[0075] For example, the monoglyceride may be a mixture of monoacylglycerols obtained by directly esterifying glycerol with carpylic acid (octanoic acid) and capric acid (decanoic acid), such as CAPMUL® MCM NF (Abitec).

[0076] For example, triglycerides may also be caprylic / capric triglyceride.

[0077] Maisine(registered trademark) CC (Gattefosse), also known as glycerol / glyceryl monolinoleate, is an example of a combination of mono, di, and triglycerides.

[0078] For example, the fatty alcohol may be myristate isopropyl alcohol or stearyl alcohol.

[0079] For example, the fatty ester may be isopropyl lauroyl sarcosinate in particular.

[0080] The aqueous or hydrophilic solvent or phase may include or consist of water, glycols, such as glycerol, carboxymethylcellulose, benzyl alcohol, or a combination thereof.

[0081] The fatty or lipophilic solvent phase may also include, or consist of, 2-(2-ethoxyethoxy)ethanol, for example, TRANSCUTOL® (Gattefosse).

[0082] The aqueous or hydrophilic solvent or phase may contain a pH adjuster, such as citric acid or hydrochloric acid.

[0083] The pH of the aqueous solvent or phase is preferably 5 to 7, more preferably 5 to 6.

[0084] The aqueous or hydrophilic solvent or phase may also include at least one salt, such as citrate, monosodium phosphate anhydrous, disodium phosphate, or sodium chloride.

[0085] Preferably, the pharmaceutical composition defined above further comprises at least one tension-active emulsifier or auxiliary surfactant particularly selected from the group consisting of polysorbate 80, cocoglycosides, sugar esters, polyol esters, e.g., sorbitan esters (e.g., Span 80), lecithin, cholesterol, glycols, polyethylene glycol and its derivatives, polyglycerols, and creatine dodecyl esters.

[0086] As is well known to those skilled in the art, glycol refers to alkyl diols. Preferred glycols according to the present invention are ethylene glycol, i.e., ethane-1,2-diol; propylene glycol, i.e., propane-1,2-diol; propane-1,3-diol; butane-2,3-diol; or 2-methylpropane-1,3-diol.

[0087] Preferably, the tension-activated emulsifier or auxiliary surfactant is present in an amount of 15% (w / w) or less of the pharmaceutical composition.

[0088] At least one preservative, such as benzalkonium chloride, may also be included in the pharmaceutical composition defined above. The preservative, such as benzalkonium chloride, is preferably at a concentration of less than 0.1% (m / m). The preservative, such as benzalkonium chloride, is preferably at a concentration greater than 0.001% (m / m).

[0089] Preferably, the pharmaceutical composition defined above is in the form of a formulation selected from the group consisting of lipid solutions, oil-in-water microemulsions, aqueous solutions, glycol aqueous solutions, water-in-oil microemulsions, micelle solutions, and reverse micelle solutions.

[0090] Emulsions, particularly nano or microemulsions, are well known to those skilled in the art and are described in particular in Ullio-Gamboa et al. (2019) Nanomedicine 14:1579-1593, which are incorporated herein by reference. For example, with respect to lipophilic antiviral agents such as hydroxychloroquine or lopinavir, i.e., those having low water solubility and / or logP > 3, pharmaceutical compositions can be formulated as any of the following: Lipid solution, or An oil-in-water microemulsion having an aqueous (i.e., hydrophilic) phase and a fatty (i.e., lipophilic) phase into which an antiviral agent is solubilized.

[0091] At least one tension-activated emulsifier or auxiliary surfactant can be added to the microemulsion.

[0092] For example, with respect to hydrophilic antiviral agents such as remdesivir or tenofovir, i.e., those with high water solubility and / or logP < 3, the pharmaceutical compositions defined above can be formulated as any of the following: An aqueous solution optionally containing at least one pH adjuster, at least one salt, or at least one glycol, A water-in-oil microemulsion having an aqueous (i.e., hydrophilic) phase and a fatty (i.e., lipophilic) phase in which an antiviral agent is solubilized.

[0093] At least one tension-activated emulsifier or auxiliary surfactant can be added to the microemulsion.

[0094] Preferably, the pharmaceutical composition according to the present invention comprises at least one antiviral agent having a logP value of 3, 2, or less than 1, more preferably less than 2, and is formulated as a water-in-oil microemulsion.

[0095] Preferably, the water-in-oil microemulsion according to the present invention comprises 60-80% oil (i.e., fatty) phase (mass of oil phase / mass of water-in-oil microemulsion) and 20-40% water (i.e., aqueous) phase (mass of aqueous phase / mass of water-in-oil microemulsion).

[0096] More preferably, the water-in-oil microemulsion according to the present invention comprises 60-80% (m / m) of an oil (i.e. fatty) phase and 20-40% (m / m) of a water (i.e. aqueous) phase, comprising (i) 50-60% (m / m) of a mixture of monoglycerides and glycols, particularly propylene glycol, and (ii) 10-20% (m / m) of at least one tension-active emulsifier or auxiliary surfactant.

[0097] A mixture of monoglycerides and glycols, particularly propylene glycol, may contain, in particular, 25-35% (m / m) of monoglycerides and 25-35% (m / m) of glycols, especially propylene glycol.

[0098] At least one tension-active emulsifier or auxiliary surfactant may be a mixture of Span 80, polysorbate 80, and propylene glycol.

[0099] Optionally, the water-in-oil microemulsion according to the present invention may further contain a preservative, such as benzalkonium chloride.

[0100] Administration Pharmaceutical compositions are administered via the nasal route, particularly via or targeting the olfactory nerve pathway. For this purpose, administration of the composition via the intranasal route, i.e., intranasal administration, is preferred.

[0101] Where intended herein, nasal administration, particularly intranasal administration, is carried out so as to bring the nasal mucosa of the nasal cavity into contact with the pharmaceutical composition as defined above. More specifically, nasal administration, particularly intranasal administration, is carried out so as to bring the nasal mucosa of the olfactory region of the nasal cavity into contact with the pharmaceutical composition as defined above.

[0102] Numerous methods and apparatuses for nasal administration, particularly intranasal administration, are known to those skilled in the art. In particular, the pharmaceutical compositions defined above may be administered as nasal lavage solutions or nasal drops using a spray system or atomizer.

[0103] The device for nasal administration may be a single-dose, double-dose, or multi-dose device. Single-dose or double-dose devices are particularly suitable for administering pharmaceutical compositions that do not contain preservatives. [Examples]

[0104] Examples of pharmaceutical compositions according to the present invention are shown below for the following compounds, according to their octanol-water ratio (LogP) and water solubility. TIFF2023538475000001.tif56170

[0105] Example 1: Pharmaceutical composition containing tenofovir disoproxil fumarate The composition comprises a high-temperature water-in-oil microemulsion incorporating tenofovir disoproxil fumarate at a concentration of 1 to 100 mg / ml, with the oil phase containing 21 / 5 / 1 / 6 volumes (by weight) of soybean oil / Span80 / Tween80 / propylene glycol, to which benzalkonium chloride (less than 0.1 w%) is added.

[0106] Example 2: Pharmaceutical composition containing hydroxychloroquine The composition contains a microemulsion incorporating hydroxychloroquine at a concentration of 1-20 mg / ml, with the microemulsions prepared from 75-96 w% / 2-15 w% / 2-10 w% of MAISINE® / Span80 / water, to which benzalkonium chloride (less than 0.1 w%) is added.

[0107] Example 3: Pharmaceutical composition containing remdesivir The composition contains a microemulsion incorporating remdesivir at a concentration of 1 to 100 mg / ml, with each microemulsion being prepared from propylene glycol / glycerin / water in amounts of 2 to 8 w% / 2 to 8 w% / 84 to 96 w% respectively, to which benzalkonium chloride (less than 0.1 w%) is added.

[0108] Example 4: Pharmaceutical composition containing lopinavir The composition contains a microemulsion incorporating lopinavir at a concentration of 1-50 mg / ml, with each microemulsion prepared from 77-93 w% / 5-15 w% / 2-8 w% of triglycerides LABRAFAC® / Span80 / water, to which benzalkonium chloride (less than 0.1 w%) is added.

[0109] Example 5: Pharmaceutical composition containing tenofovir disoproxil fumarate The composition comprises a high-temperature water-in-oil microemulsion incorporating tenofovir disoproxil fumarate (TDF) at a concentration of 1 to 100 mg / ml, preferably 4 mg / ml, with the oil phase comprising 30 / 3 / 7 / 25 / 5 / 30 parts (by weight) of Capmul® MCM EP-NF / Span80 / Polysorbate 80 / Transcutol / Propylene Glycol and Water, to which benzalkonium chloride (less than 0.1 w%) is added.

[0110] The brain and plasma (TDF) concentrations were measured after administering the composition to mice orally (n=6) or via the nasal route (n=6) at a dose of 4 mg / kg over 5 days, and are shown in the table below: TIFF2023538475000002.tif54170

[0111] The brain concentration of TDF is significantly higher after nasal administration than after oral administration (more than 4 times). There is also an improvement in plasma bioavailability after nasal administration (+47%), but it is relatively lower than the brain concentration. This indicates that after nasal administration using the composition according to the present invention, TDF penetrates into the brain via the nasal pathway.

Claims

1. 1. A pharmaceutical composition comprising as an active agent at least one antiviral agent for use in the prevention or treatment of infection in an individual with a neurotropic virus, wherein the antiviral agent has a log P value of less than 2, wherein the pharmaceutical composition is administered by the nasal route, and wherein the composition is in the form of a water-in-oil microemulsion.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the pharmaceutical composition is administered by the nasal route via the olfactory nerve pathway.

3. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the antiviral agent has a molecular weight of less than 10,000 g / mol.

4. 4. The pharmaceutical composition for use according to any one of claims 1 to 3, wherein the antiviral agent is a substrate for an efflux transporter of an individual.

5. 5. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the neurotropic virus is selected from the group consisting of Japanese encephalitis virus, Venezuelan equine encephalitis virus, California encephalitis virus; poliovirus, coxsackievirus, echovirus, mumps virus, measles virus, influenza virus, rabies virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, HHV-6 virus, rubella virus, JC virus, viruses of the retroviridae family, viruses of the herpesviridae family, and viruses of the coronavirusidae family.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the virus is a human immunodeficiency virus (HIV), in particular HIV-1 or HIV-2.

7. 6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the virus is selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV and mutants or variants thereof.

8. 8. The pharmaceutical composition for use according to claim 7, wherein the virus is SARS-CoV-2, or a mutant or variant thereof.

9. 9. A pharmaceutical composition for use according to any one of claims 1 to 8 for use in preventing or treating anosmia and / or taste disorders associated with a viral infection.

10. 10. The pharmaceutical composition for use according to any one of claims 1 to 9, for use in preventing or treating encephalopathy associated with a viral infection, neuroinflammation associated with a viral infection, neurological disorders associated with a viral infection, or neurocognitive disorders associated with a viral infection.

11. 11. A pharmaceutical composition for use according to any one of claims 1 to 10 for use in preventing or treating HIV-associated neurocognitive disorder (HAND).

12. 12. A pharmaceutical composition for use according to any one of claims 1 to 11, further comprising at least one pharmaceutically acceptable vehicle, carrier or excipient suitable for administration via the nasal route.

13. 13. The pharmaceutical composition for use according to any one of claims 1 to 12, further comprising at least one surfactant, emulsifier or co-surfactant.