JP2009538822A5 - - Google Patents

Description

Treatment of viruses in veins

(Related application)
This patent document claims the benefit of priority of US Provisional Patent Application No. 60 / 772,748, filed February 13, 2006, and International Application No. PCT / US2006 / 013535, filed April 12, 2006. These applications are hereby incorporated by reference.

Peramivir, a neuraminidase inhibitor used against influenza viruses, has significant activity against influenza viruses in in vitro and experimentally infected mice (Govorkova et al., Non-Patent Document 1, Smeet et al. al., Non-Patent Document 2). In clinical trials using this drug, the therapeutic effect on influenza infection shown after oral administration to humans for several days was unfortunately not optimal. Currently, there is a need for methods and formulations useful for the treatment of human viral infections (eg, influenza infection).
Antimicrobial Agents and Chemotherapy, 45 (10), 2723-2732 (2001) Antimicrobial Agents and Chemotherapy, 45 (3), 743-748 (2001)

It has unexpectedly been found that a single intravenous administration of peramivir to mice is effective in treating influenza. That these findings was that unexpected, in addition to the fact that a single dose of the compound was very effective, that effective treatment by using a low dose of the compound is Ru are provided This is because it became clear. The ability to achieve a therapeutically useful effect with a single dose is particularly important, as patient compliance issues that arise when multiple doses are required are minimized with a single dose. In addition, low dose administration is important because doing so greatly reduces the cost and potential for side effects. Peramivir the By injecting intravenous injection and intramuscular against human plasma peramivir concentration becomes high, were unexpectedly discovery that half-life is prolonged.

  Accordingly, one embodiment of the invention provides a method of treating a human viral infection (eg, influenza infection), wherein the method comprises an amount of Formula I, II, III, or IV having effective antiviral activity. A compound of

またはこれらの医薬的に許容可能な塩を静脈内経路によってヒトに投与するステップを含む。

Or administering these pharmaceutically acceptable salts to a human by the intravenous route.

  The invention also provides a method of inhibiting neuraminidase in the human body, wherein the method comprises an amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable amount thereof, with effective inhibitory activity. Administering salt to the human by an intravenous route.

  The invention also provides unit dosage forms suitable for intravenous administration to humans, comprising up to about 400 mg of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.

  The present invention relates to compounds of formula I, II, III, or IV, or pharmaceuticals thereof, up to about 1,000 mg (eg, up to about 800, 600, 500, 400, 300, 200, 150, 100, or 75 mg). Also provided are unit dosage forms suitable for intravenous administration to humans, comprising pharmaceutically acceptable salts.

The present invention provides a packaging material, a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a protocol for administering the compound to a human by an intravenous route. A kit containing the same is also provided.

The present invention extends the life expectancy or mortality of a group of mammals exposed to a source of influenza virus by intravenously administering the drug to each member of the group presenting clinical symptoms of infection. There is also provided the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for intravenous injection intended to reduce

The present invention is aimed at extending the life expectancy of a group of mammals exposed to a source of influenza virus or reducing the mortality rate by administering the drug intravenously to each member of the group. Also provided is the use of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in intravenous injection.

  Peramivir, a neuraminidase inhibitor used against influenza viruses, has previously been shown to have significant activity against influenza viruses in in vitro and experimentally infected mice. (Govorkova et al., (2001), Smee et al., (2001)). Unfortunately, the inhibitory effect on human influenza shown in clinical trials with this drug was not sufficient. These inadequate effects are due to insufficient drug absorption by once daily oral administration to patients.

  Peramivir has been shown to be well absorbed when administered intravenously (iv) to mice and the plasma concentration of the compound remains at a relatively high level for at least 6 hours. Yes. A series of experiments presented herein show that a single treatment with intravenous administration of peramivir protects mice infected with influenza virus.

  Thus, certain embodiments of the invention provide a method of treating a human viral infection, wherein the method comprises an amount of a compound of formula I, II, III, or IV having effective antiviral activity,

またはこれらの医薬的に許容可能な塩を静脈内経路によってヒトに投与するステップを含む。

Or administering these pharmaceutically acceptable salts to a human by the intravenous route.

  In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

In certain embodiments, the viral infection is an influenza infection. In certain embodiments, the viral infection is an influenza A infection or an influenza B infection. In certain embodiments, the viral infection is caused by a virus strain of the formula H _x N _y, wherein, X is 1 to 16 integer, Y is 1-9 integer. In certain embodiments, the influenza is H3N2, H1N1, H5N1, avian influenza, or seasonal influenza.

  In certain embodiments, the amount having effective antiviral activity is up to about 800 mg. In certain embodiments, the amount having effective antiviral activity is up to about 400 mg. In certain embodiments, the amount having effective antiviral activity is up to about 300 mg. In certain embodiments, the amount having effective antiviral activity is up to about 200 mg.

  In certain embodiments, the entire effective dose is administered in a single intravenous administration. In certain embodiments, a total effective dose is administered in multiple intravenous administrations.

  In certain embodiments, a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

In certain embodiments, the plasma concentration of the compound 12 hours after administration of the compound is higher than the IC _{50 of the} virus responsible for the viral infection.

  Certain embodiments of the invention provide a method of inhibiting neuraminidase in the human body, the method comprising an amount of a compound of formula I, II, III, or IV having effective inhibitory activity,

またはこれらの医薬的に許容可能な塩を静脈内経路によってヒトに投与するステップを含む。

Or administering these pharmaceutically acceptable salts to a human by the intravenous route.

  In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the amount having effective inhibitory activity is up to about 800 mg. In certain embodiments, the amount having effective inhibitory activity is up to about 400 mg. In certain embodiments, the amount having effective inhibitory activity is up to about 300 mg. In certain embodiments, the amount having effective inhibitory activity is up to about 200 mg.

  In certain embodiments, a total dose is administered that has effective inhibitory activity in a single intravenous administration. In certain embodiments, a total dose is administered that has effective inhibitory activity in multiple intravenous administrations.

  In certain embodiments, a compound of formula Ia, or a pharmaceutically acceptable salt thereof, is administered.

  In certain embodiments, the method may further comprise the step of orally administering the neuraminidase inhibitor to the human.

  In certain embodiments, the orally administered neuraminidase inhibitor is oseltamivir carboxylate.

  In certain embodiments, the neuraminidase inhibitor administered orally is a compound of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the neuraminidase inhibitor administered orally is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the orally administered neuraminidase inhibitor is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the orally administered neuraminidase inhibitor is administered for up to 20 days. In certain embodiments, the orally administered neuraminidase inhibitor is administered for up to 10 days. In certain embodiments, the orally administered neuraminidase inhibitor is administered for up to 5 days.

  Certain embodiments of the present invention provide unit dosage forms suitable for intravenous administration to humans, wherein the unit dosage form comprises up to about 800 mg of a compound of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩を含む。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the unit dosage form contains up to about 400 mg of compound or salt. In certain embodiments, the unit dosage form contains up to about 300 mg of compound or salt. In certain embodiments, the unit dosage form contains up to about 200 mg of compound or salt.

  Certain embodiments of the present invention include packaging materials, compounds of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩、ならびに静脈内経路によって化合物をヒトへ投与するための手順書を含むキットを提供する。

Alternatively, a kit is provided that includes a pharmaceutically acceptable salt thereof and a protocol for administering the compound to a human by the intravenous route.

  In certain embodiments, the compound is provided in a formulation suitable for intravenous administration.

  In certain embodiments, the kit contains up to about 800 mg of compound or salt. In certain embodiments, the kit contains up to about 400 mg of compound or salt. In certain embodiments, the kit comprises up to about 300 mg of compound or salt. In certain embodiments, the kit comprises up to about 200 mg of compound or salt.

Certain embodiments of the present invention provide kits comprising packaging material, the unit dosage forms described herein, and instructions for administering the compound to a human by the intravenous route.

Certain embodiments of the present invention provide for the life expectancy of a group of mammals exposed to a source of influenza virus by intravenously administering the drug to each member of the group exhibiting clinical symptoms of infection. A compound of formula I, II, III, or IV in the manufacture of a medicament for use in intravenous injection intended to prolong or reduce mortality,

またはこれらの医薬的に許容可能な塩の使用を提供する。

Or the use of these pharmaceutically acceptable salts is provided.

  In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an avian influenza virus. In certain embodiments, the influenza virus is an influenza A virus or an influenza B virus. In certain embodiments, the influenza virus is H5N1 or a variant thereof. In certain embodiments, the influenza virus is a virus strain represented by the formula H _x N _y , where X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an H3N2 influenza virus, an H1N1 influenza virus, an H5N1 influenza virus, an avian influenza virus, or a seasonal influenza virus.

  In certain embodiments, each member of a group presenting with an infectious symptom is given only one intravenous dose of drug. In certain embodiments, multiple intravenous doses of drug are administered to each member of a group presenting with an infectious symptom.

  In certain embodiments, members of the group presenting with clinical symptoms of infection are treated with oral administration of a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In certain embodiments, the neuraminidase inhibitor is a compound of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩である。特定の実施形態においては、ノイラミニダーゼ阻害薬は式Ｉａ、ＩＩａ、ＩＩＩａ、またはＩＶａの化合物、

Or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。特定の実施形態においては、ノイラミニダーゼ阻害薬は式Ｉａの化合物、またはこれの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal that exhibits symptoms of infection.

  In certain embodiments, the use is aimed at reducing mortality.

Certain embodiments of the present invention provide for the extension of the average lifespan of a group of mammals exposed to a source of influenza virus, or mortality, by intravenous administration of the drug to each member of the group. A compound of formula I, II, III, or IV in the manufacture of a medicament for use in intravenous injection for reduction purposes,

またはこれらの医薬的に許容可能な塩の使用を提供する。

Or the use of these pharmaceutically acceptable salts is provided.

  In certain embodiments, the compound of formula I, II, III, or IV is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof.

In certain embodiments, the influenza virus is an avian influenza virus. In certain embodiments, the avian influenza virus is H5N1 or a variant thereof. In certain embodiments, the influenza virus is a virus strain represented by the formula H _x N _y , where X is an integer from 1 to 16 and Y is an integer from 1 to 9. In certain embodiments, the influenza virus is an influenza A virus or an influenza B virus. In certain embodiments, the influenza virus is an H3N2 influenza virus, an H1N1 influenza virus, an H5N1 influenza virus, an avian influenza virus, or a seasonal influenza virus.

  In certain embodiments, only one intravenous dose of drug is administered to each member of the group. In certain embodiments, multiple doses of drug are administered to each member of the group.

  In certain embodiments, the members of the group are treated by oral administration of a neuraminidase inhibitor. In certain embodiments, the neuraminidase inhibitor is oseltamivir carboxylate. In certain embodiments, the neuraminidase inhibitor is a compound of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩である。特定の実施形態においては、ノイラミニダーゼ阻害薬は式Ｉａ、ＩＩａ、ＩＩＩａ、またはＩＶａの化合物、

Or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。特定の実施形態においては、ノイラミニダーゼ阻害薬は式Ｉａの化合物、またはこれの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof. In certain embodiments, the neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the source of the virus is an infected bird. In certain embodiments, the source of the virus is a mammal that exhibits symptoms of infection.

  In certain embodiments, the use is aimed at reducing mortality.

  Certain embodiments of the present invention provide for intravenous injection aimed at achieving a plasma concentration of a compound effective in treating a virus in a human by administering the drug to the human by intravenous injection. A compound of formula I, II, III or IV in the manufacture of a medicament to be used;

またはこれらの医薬的に許容可能な塩の使用を提供する。

Or the use of these pharmaceutically acceptable salts is provided.

  Certain embodiments of the present invention are directed to intramuscular injections aimed at achieving plasma concentrations of compounds effective for the treatment of viruses in humans by administering drugs to humans by intramuscular injection. A compound of formula I, II, III or IV in the manufacture of a medicament to be used;

Or the use of these pharmaceutically acceptable salts is provided.

In certain embodiments, the plasma concentration of the compound 12 hours after injection of the compound is higher than the IC ₅₀ of the virus.

  Mice infected with influenza virus, A / Duck / MN / 1525/81 (type H5N1), were administered a single intravenous dose of peramivir at a dose of 20 mg, 10 mg, 3 mg / kg 1 hour prior to exposure to the virus. I was treated with. Two of the higher doses used showed significant protective effects of peramivir on mice, such as preventing death, reducing the occurrence of lung sclerosis, and reducing viral titers in the lungs. The inhibitory effect on the lung-related parameters at the 3 mg / kg dose was moderate. The compound was considered well tolerated in a concurrent toxicity control study. These data show that treatment with a single intravenous dose of peramivir is effective in mice infected with influenza virus.

Compound used in the present invention are publicly known in the art, as those skilled in the art it is also possible to synthesize (eg using available methods, see U.S. Pat. No. 6,562,861 ).

  Certain values mentioned herein with respect to radicals, substituents, and ranges are for illustrative purposes only and exclude other specified values or other values within specified ranges for radicals and substituents. is not.

  Certain compounds of formula I, II, III, or IV are compounds of formula Ia, IIa, IIIa, or IVa

またはこれらの医薬的に許容可能な化合物である。

Or a pharmaceutically acceptable compound thereof.

  Certain compounds of formula I, II, III, or IV are (1S, 2S, 3R, 4R) -3- (1-acetamido-2-ethylbutyl) -4-guanidino-2-hydroxycyclopentane-carboxylic acid, (1S, 2S, 3R, 4R) -3- (1-acetamido-2-propylpentyl) -4-guanidino-2-hydroxycyclopentanecarboxylic acid, (1R, 3R, 4R) -3- (1-acetamido- 2-propylpentyl) -4-guanidinocyclopentanecarboxylic acid, or (1R, 3R, 4R) -3- (1-acetamido-2-ethylbutyl) -4-guanidinocyclopentanecarboxylic acid, or a pharmaceutically acceptable salt thereof Possible salt.

  A particular compound of formula I is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

Those skilled in the art will appreciate that compounds having one or more chiral centers may exist in optically active and racemic forms and may be separated in optically active and racemic forms. Will. Some compounds may exhibit polymorphism. The use of all racemates, optically active forms, polymorphs, or stereoisomers of compounds of formula I, II, III, or IV, or mixtures thereof, having the beneficial properties described herein are within the scope of the present invention. And methods for formulating optically active forms using standard tests described herein, or other similar tests well known in the art (eg, Methods for measuring racemic resolution by crystal methods, synthesis from optically active starting materials , chiral synthesis, or chromatographic separation using a chiral stationary phase), and antiviral (eg, anti-influenza) activity are known in the art. Well known in the field.

If the compound has sufficient basicity or acidity to form a stable non-toxic acidic or basic salt, it may be appropriate to administer the compound as a salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate , Malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, phosphate, bicarbonate, and carbonate.

Step known standard in the art, for example, a compound having a sufficient basicity, such as amine, a pharmaceutically acceptable by reaction with a suitable acid to provide a physiologically acceptable anion A salt may be obtained. (Sodium examples, potassium or lithium) Alkali metal (examples calcium) or alkaline earth metal salts may also be made of work.

A compound of formula I, II, III, or IV can be formulated as a pharmaceutical composition and administered by intravenous route to a mammalian host, eg, a human patient. Solutions of the active compound or its salts can be formulated in water, optionally mixed with a nontoxic surfactant. Dispersions can similarly be formulated with glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, as well as oils. Under normal storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection or infusion include the active ingredient (s) suitable for the immediate preparation of sterile injectables or infusions or dispersions and optionally encapsulated in liposomes sterile aqueous solutions or dispersions, or that obtained contains sterile powders. In all cases, the ultimate dosage form must be a sterile liquid and must be stable under the conditions of manufacture and storage. Liquid carriers or excipients are, for example, water, ethanol, polyols (glycerol examples, propylene glycol, liquid polyethylene glycidyl co Lumpur), vegetable oils, nontoxic glyceryl esters, and or solvents containing them suitable mixtures A liquid dispersion medium may be used. For example, proper fluidity can be maintained by forming liposomes, maintaining the required particle size in the case of a dispersion, or using a surfactant. By using various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like, the action of microorganisms can be suppressed. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions is achieved by using substances that delay absorption, such as aluminum monostearate or gelatin, in the composition.

A sterile injection can be prepared by adding the active ingredient (one or more) together with any other ingredients described above to a suitable solvent, followed by optional filter sterilization. In the case of sterilized powders used for the preparation of sterile injections, the preferred method of preparation is vacuum drying or freeze-drying technology. in addition it is possible to obtain a desired Ingredient additional arbitrary and.

  As used herein, the terms “treat”, “treatment of”, and “treatment” include only the step of administering a compound prior to the onset of clinical symptoms of a disease state / condition for the purpose of preventing the progression of any symptom. Rather, after the occurrence of one or more clinical symptoms of the disease state / condition, administering the compound for the purpose of reducing or eliminating any such symptoms, properties, or characteristics of the disease state / condition . Such treatment need not be absolutely useful. As described herein below, the active compound can be administered prior to exposure to the virus. The agent can also be administered after exposure to the virus (eg, within 1, 2, 3, 4, or 5 days).

  The phrase “unit dosage form” as used herein relates to an intravenous dosage formulation containing a specific amount of drug and is intended to be administered in its entirety in a single dose. This is in contrast to the supply of non-constant quantities of drugs, such as bottled drugs, that require metered doses.

  In one embodiment, the invention provides a method of treating a human viral infection, wherein the method comprises an effective amount of a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. Administering a salt to a human by intravenous administration. In general, an effective amount is administered in a single intravenous administration. In some embodiments, an effective amount is administered in multiple doses. Thus, the use of the method of the present invention ensures that patient compliance is properly followed and that the required effective drug dose is small.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV having effective inhibitory activity is up to about 1000 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 800 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 600 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV having effective inhibitory activity is up to about 500 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 400 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 300 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 200 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV having effective inhibitory activity is up to about 150 mg.

  In one embodiment of the invention, the amount of a compound of formula I, II, III, or IV that has effective inhibitory activity is up to about 75 mg.

  According to the methods of the invention, a compound of formula I, II, III, or IV is administered to a human by the intravenous route. In one embodiment of the invention, the compound of formula I, II, III, or IV is administered once to a human by the intravenous route. In another embodiment of the invention, the neuraminidase inhibitor is also orally administered to the human. In one embodiment of the invention, the orally administered neuraminidase inhibitor is oseltamivir carboxylate. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula I, II, III, or IV,

またはこれらの医薬的に許容可能な塩である。本発明の一実施形態においては、経口投与されるノイラミニダーゼ阻害薬は式Ｉａ、ＩＩａ、ＩＩＩａ、またはＩＶａの化合物、

Or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, IIa, IIIa, or IVa,

またはこれらの医薬的に許容可能な塩である。本発明の一実施形態においては、経口投与されるノイラミニダーゼ阻害薬は、式Ｉａの化合物、またはこれの医薬的に許容可能な塩である。

Or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the orally administered neuraminidase inhibitor is a compound of formula Ia, or a pharmaceutically acceptable salt thereof.

  According to the methods of the present invention, a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, such as an antiviral agent (eg, an agent having activity against influenza) or an antibiotic It can be administered with one or more additional therapeutic agents.

Intravenous formulations of the invention can also include one or more additional therapeutic agents such as antiviral agents (eg, agents having activity against influenza) and antibiotics.

Thus, intravenous administration of peramivir for the purpose of treating viral infection is described herein. Intramuscular administration of peramivir for the treatment of viral infection is also described herein (see Example 2), which is international application PCT / US2006 / 013535 filed on April 12, 2006. Further examples of intramuscular administration of peramivir for the treatment of viral infections as described in are given further, the disclosure of which is incorporated herein by reference. Furthermore, as described herein, by administering peramivir intravenous injection and intramuscular injection into humans, plasma peramivir concentration indicates a high, look unexpectedly that blood 漿内 half-life is prolonged It was issued.

As described herein, the compounds described herein can be used to treat viruses such as influenza viruses. For example, the compounds can be used in the treatment of any one of the following strains, or combinations thereof. In the table below, “H” represents the type of hemagglutinin and “N” represents the type of neuraminidase. The formula H _x N _y where X is an integer from 1 to 16 and Y is an integer from 1 to 9 can also be used to describe the combinations shown in the table.

  Table 1

ウイルスは、例えば鳥ウイルスまたはヒト化鳥ウイルスであってもよい。従って、語句「鳥ウイルス」には、鳥型のウイルスおよびヒト化型の鳥ウイルスの両方が含まれる。

The virus may be, for example, an avian virus or a humanized avian virus. Thus, the phrase “bird virus” includes both avian and humanized avian viruses.

  Certain embodiments of the present invention provide for intravenous injection aimed at achieving a plasma concentration of a compound effective in treating a virus in a human by administering the drug to the human by intravenous injection. A compound of formula I, II, III or IV in the manufacture of a medicament to be used;

またはこれらの医薬的に許容可能な塩の使用を提供する。

Or the use of these pharmaceutically acceptable salts is provided.

  Certain embodiments of the present invention are directed to intramuscular injections aimed at achieving plasma concentrations of compounds effective for the treatment of viruses in humans by administering drugs to humans by intramuscular injection. A compound of formula I, II, III or IV in the manufacture of a medicament to be used;

またはこれらの医薬的に許容可能な塩の使用も提供する。

Or the use of these pharmaceutically acceptable salts is also provided.

  Certain embodiments of the invention also provide a composition comprising peramivir formulated for intravenous administration to humans. Certain embodiments of the present invention also provide a composition comprising peramivir formulated for intravenous administration used in the treatment of viruses by achieving a plasma concentration of peramivir effective in treating the virus in humans. .

  Certain embodiments of the present invention also provide compositions comprising peramivir formulated for intramuscular administration to humans. Certain embodiments of the invention also provide a composition comprising peramivir formulated for intramuscular use for the treatment of viruses by achieving a plasma concentration of peramivir effective for the treatment of viruses in humans. .

In certain embodiments of the invention, the plasma concentration of the compound at least about 12 hours after injection is higher than the IC ₅₀ of the virus.

In certain embodiments of the invention, the plasma concentration of the compound at least about 24 hours after injection is higher than the IC ₅₀ of the virus.

In certain embodiments of the invention, the plasma concentration of the compound at least about 36 hours after injection is higher than the IC ₅₀ of the virus.

In certain embodiments of the invention, the plasma concentration of the compound at least about 48 hours after injection is higher than the IC ₅₀ of the virus.

In certain embodiments of the invention, the plasma concentration of the compound at least about 60 hours after injection is higher than the IC ₅₀ of the virus.

In certain embodiments of the invention, the plasma concentration of the compound at least about 72 hours after injection is higher than the IC ₅₀ of the virus.

  In certain embodiments of the invention, the virus is an influenza virus. In certain embodiments of the invention, the virus is an avian influenza virus. In certain embodiments of the invention, the virus is H5N1 type, or a variant thereof.

  Examples of the present invention will now be illustrated using the following non-limiting examples.

Example 1 Effect of Peramivir Intravenous Treatment on Influenza A Virus Infection Experimental Design: Mice were infected from the nasal cavity with an amount of influenza virus thought to be LD100. A group of 10 mice was treated with a single intravenous dose of peramivir at doses of 20 mg, 10 mg, and 3 mg / kg one hour prior to exposure to the virus. In parallel with the above treatment, 20 infected mice were administered placebo (sterile saline) by intravenous route. Infected mice treated with drugs and control mice treated with placebo were observed daily for 21 days for death. As a toxicity control, 3 uninfected mice were treated with the highest dose of compound in parallel with the infected animals. All toxic control mice were observed for 21 days for death and weighed immediately before the first treatment and 18 hours after the last treatment. Five normal controls were weighed.

  Table 2. Effect of single intravenous treatment with peramivir on influenza A virus infection in mice

^ｂ第２１日目以前に死亡したマウスの死亡までの平均日数
生理食塩水で治療した対照と比較したとき、^＊＊Ｐ＜０．０１、^＊＊＊Ｐ＜０．００１。

^b Mean days to death of mice that died before day 21 ^** P <0.01, ^*** P <0.001 when compared to saline treated controls.

  In the infection induced in this experiment, 55% of mice died (Table 1), and the average number of days until death was 9.1 days. The protective effect on infected animals with single intravenous injections of 20 mg and 10 mg / kg peramivir was high, with 100% overcoming infection (P <0.01). All toxic controls tested in parallel survived and gained weight, indicating that the compounds in this experiment were well tolerated.

  These data indicate that peramivir is an effective influenza inhibitor when used in a single intravenous injection.

Example 2 Effect of Intravenous and Intramuscular Treatment with Peramivir in Humans To evaluate safety and pharmacokinetic parameters using intravenous and intramuscular administration, placebo control was performed by a healthy volunteer person. Peramivir was examined in a phase I clinical trial. In order to measure the concentration of drug in plasma, blood samples were collected from subjects at various time points after drug administration. The time course plots for intravenous and intramuscular administration are shown in FIGS. 1 and 2, respectively.

For intravenous administration study, peramivir concentration showed linear pharmacokinetics, blood 漿内 half-life is prolonged enough not normally found in, its length was over 12 hours.
At doses of 2 mg / kg and higher, the plasma peramivir concentration 48 hours after administration is higher than the IC ₅₀ of all influenza virus strains examined, including the H5 virus . At doses greater than 4 mg / kg, the drug concentration is higher than the IC ₅₀ even at the 72 hour time point.

Peramivir concentration intramuscular administration test showed linear pharmacokinetics, blood 漿内 half-life is usually had extended enough not observed. Even at 72 hours after administration, the concentration of peramivir is still higher than the IC ₅₀ values of all influenza virus strains examined.

In human volunteers, finding that extending or concentrations of blood 漿内 half-life of peramivir are conventional ones unexpected that not observed in, beneficial in the treatment intravenous and intramuscular administration of peramivir human influenza It shows that it is.

  All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference. In the preceding specification, the invention has been described in connection with specific embodiments thereof and described in detail for the purpose of illustration, but the invention is intended to allow further embodiments and provides a basis for the invention. It will be apparent to those skilled in the art that some of the details described herein may be changed significantly without departing from the principles.

  The terms “a” and “an” and “the” as used in the context of describing the present invention, and the use of similar referents, are clearly inconsistent unless otherwise indicated herein or by context. Unless otherwise, it should be construed as including both the singular and plural forms. The terms “including”, “having”, and “containing” unless otherwise noted are open ended terms (ie, “including but not limited to”). Meaning "). The description of range of values in this specification, unless otherwise indicated in this specification, merely serves as a simple way to individually reference each individual value within the range, and The values of are incorporated into the specification as if they were individually listed herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any and all examples, or exemplary phrases (e.g.,...) Given herein are for the purpose of clarifying the invention only, and unless otherwise stated. It is not intended to limit the scope of the invention.

FIG. 1 shows the plasma peramivir concentration time curve after 15 minutes intravenous infusion of peramivir in healthy volunteers. FIG. 2 shows the plasma peramivir concentration time curve after intramuscular injection of peramivir in healthy volunteers.

Claims (1)

A composition as described herein.