EA046313B1 - DOSAGE FORMS OF THERAPEUTIC DRUGS FOR FLU - Google Patents

Description

State of the art

Influenza spreads throughout the world in seasonal epidemics, killing hundreds of thousands of people every year and millions during pandemic years. For example, the 20th century saw three influenza pandemics that killed tens of millions of people, each of which was caused by the emergence of a new strain of the virus in humans. Often these new strains arise from transmission from other animal species and the spread of an existing influenza virus to humans.

Influenza is primarily spread from person to person through large virus-laden droplets produced when infected people cough or sneeze; these large droplets can then settle on the mucous membranes of the upper respiratory tract of susceptible people who are close (for example, within about 6 feet (1.8 m)) of infected people. Transmission can also occur through direct or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose, or mouth. Adults can infect others with the flu from 1 day before symptoms appear until about 5 days after symptoms appear. Young children and people with weakened immune systems may be contagious for 10 days or more after symptoms appear.

Influenza viruses are RNA viruses of the Orthomyxoviridae family, which includes five genera: influenza A virus, influenza B virus, influenza C virus, Isavirus, and Thogotovirus.

The influenza A virus genus is responsible for seasonal influenza and pandemic influenza epidemics. It includes one species, the influenza A virus, and wild waterfowl are the natural hosts for a wide variety of influenza A viruses. Sometimes viruses are transmitted to other species and can then cause devastating outbreaks in poultry or cause an influenza pandemic in humans. Type A viruses are the most dangerous pathogens for humans among the three types of influenza and cause the most severe illness. Influenza A virus can be classified into different serotypes based on the antibody response to these viruses. The serotypes confirmed in humans, ordered by number of known human deaths in the pandemic, are: H1N1 (caused the Spanish flu in 1918), H2N2 (caused the Asian flu in 1957), H3N2 (caused the Hong Kong flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which is a potential pandemic threat), H1N2 (endemic to humans and swine), H9N2, H7N2, H7N3 and H10N7.

The influenza B virus genus is responsible for seasonal influenza and includes one species, the influenza B virus. Influenza B almost exclusively affects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates 2-3 times slower than type A and is therefore less genetically diverse, having only one serotype of influenza B. As a result of the lack of antigenic diversity, immunity to influenza B is usually acquired at an early age. However, influenza B mutates sufficiently that durable immunity is not possible. The reduced rate of antigen change combined with a limited host range (suppression of interspecies antigenic shift) ensures that influenza B pandemics will not occur.

The influenza C virus genus includes one species, influenza C virus, which infects humans and pigs and can cause severe disease and local epidemics. However, influenza C is less common than other types and usually causes mild illness in children.

Influenza viruses of different serotypes and genera are very similar in structure. The influenza virus genome consists of eight single-stranded RNAs packaged into rod-shaped structures of varying sizes known as the ribonucleoprotein complex (RNP). Each RNP contains a unique viral RNA, multiple copies of the scaffold nucleoprotein, and a heterotrimeric viral polymerase composed of PA, PB1, and PB2 subunits, which catalyzes transcription and replication of the viral genome. Recent biochemical and structural studies of the influenza polymerase complex provide mechanistic insights into cap uptake and RNA synthesis by influenza polymerase. Briefly, the PB2 cap binding domain first sequesters host pre-mRNA by binding to its 5′ cap. PA, a subunit of the endonuclease, then cleaves the captured pre-mRNA 10–13 nucleotides after the cap. The PB2 subunit then rotates approximately 70° to direct the capped primer to the active site of the PB1 polymerase. The PB1 subunit directly interacts with both the PB2 and PA subunits. These subunits contain highly conserved domains across different influenza strains and have attracted attention as potential targets for influenza drugs. In addition to the polymerase complex, the influenza genome encodes its own neuraminidase (NA), hemagglutinin (HA), nucleoprotein (NP), matrix proteins, M1 and M2, and nonstructural proteins, NS1 and NS2. NA is the target of the antiviral drugs oseltamivir (Tamiflu®) and zanamivir (Relenza®). These drugs are sialic acid analogs that inhibit the enzymatic activity of NA, slowing the release of progeny virus from infected cells.

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Influenza incurs direct costs due to disability and associated treatment, as well as indirect costs of preventive measures. In the United States, total costs associated with influenza exceed $10 billion annually, while it has been estimated that a future pandemic could result in hundreds of billions of dollars in direct and indirect costs. Prevention costs are also high. Governments across the globe have spent billions of US dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with procuring drugs and vaccines and developing exercises and strategies to improve border controls.

Current treatment options for influenza include vaccination and chemotherapy or chemoprophylaxis with antiviral drugs. Influenza vaccination with the influenza vaccine is often recommended for high-risk groups such as children and older adults, or people with asthma, diabetes, or heart disease. However, it is possible to get the flu vaccine and still get the flu. The vaccine is reviewed each season for a few specific flu strains, but may not include all of the strains actively infecting people in a given season. It takes manufacturers about six months to formulate and produce the millions of doses needed to combat seasonal epidemics; sometimes during this time a new or under-recognized strain emerges and infects people even though they have been vaccinated (for example, Fujian H3N2 influenza in the 2003-2004 influenza season). It is also possible to become infected just before vaccination and become ill with the very strain the vaccine is supposed to prevent, since the vaccine takes two weeks to become effective.

In addition, the effectiveness of these influenza vaccines varies. As a result of the virus's high rate of mutation, a given flu vaccine usually provides protection for no more than a few years. A vaccine designed for one year may not be effective the next year because the flu virus changes rapidly over time and other strains become dominant.

Due to the absence of RNA proofreading enzymes, RNA-dependent influenza vRNA RNA polymerase makes a single nucleotide insertion error approximately every 10 thousand nucleotides, which is the approximate length of influenza vRNA. Consequently, almost every newly created influenza virus represents mutant-antigenic drift. The division of the genome into eight distinct vRNA segments allows for mixing or reassortment of vRNAs if a single cell is infected with more than one viral lineage. The resulting rapid change in viral genetics causes antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with NA inhibitors being particularly effective, but viruses can develop resistance to approved NA inhibitor antiviral drugs. The emergence of multidrug-resistant pandemic influenza A viruses is also described in detail. Drug-resistant pandemic influenza A is becoming a serious threat to human health. In addition to drug-resistant influenza A viruses, NA inhibitors are approved for the treatment of early influenza infection (within 48 hours of onset of influenza symptoms).

Thus, there is a need for dosage forms of antiviral agents against influenza virus that can be administered by pulmonary delivery.

The essence of the invention

Proposed herein are dosage forms of Compound 1 and excipient. In some cases, the dosage form contains: (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) filler. In various cases, the dosage form consists essentially of: (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) filler. In various cases, the dosage form is a powder dosage form for administration by inhalation containing: (a) compound 1 or a pharmaceutically acceptable salt thereof; and (b) an excipient consisting essentially of lactose monohydrate, said dosage form having a particle size distribution characterized by a volume mean diameter (VMD) of 1 to 2 μm, with a D ₁₀ value of 0.5 μm to 0.7 μm, D ₅₀ from 1 µm to 1.4 µm and D ₉₀ from 2.5 µm to 2.8 µm. In some cases the VMD is 1.5 µm, with D ₁₀ 0.6 µm, D ₅₀ 1.3 µm and D ₉₀ 2.8 µm.

In various embodiments, the filler contains lactose or, more specifically, contains lactose monohydrate. In some cases, the filler is micronized. The filler may have a volume mean diameter (VMD) from 0.5 µm to 10 µm. In some cases, the filler has a VMD of 1.5 to 5 µm.

In various embodiments, compound 1 or a salt thereof is micronized. Compound 1 may be crystalline (in crystalline form), and in some cases it is presented in the form of a micronized crystal. In some cases, the crystalline form of Compound 1 is Form B and has an X-ray powder diffraction (XPD) pattern showing 2θ values of 5.6, 6.8, 8.4, 10.1, 10.6, 11.3, 15. 1, 15.8, 18.0, 18.5, 19.1, 20.4 and 20.9

- 2 046313 ± 0.2°. In various cases, compound 1 (eg in Form B) has a melting point between 280°C and 283°C. In various cases, compound 1 may be presented as Form A or Form C.

Compound 1 or a salt thereof may have a volume mean diameter (VMD) of 0.5 μm to 10 μm. In some cases, the VMD of compound 1 is between 1.5 and 5 µm. The dosage forms described herein may have a weight ratio of Compound 1 or a salt thereof to excipient from 1:3 to 1:5. In some cases the specified mass ratio is 1:4.

The dosage forms described herein may be formulated to be administered by inhalation. They are provided as dosage forms for delivering Compound 1 or a salt thereof to a subject by inhalation. The dosage forms described herein, when administered by inhalation, can provide a lung concentration of the drug compound that is at least 50 times higher than the plasma concentration of the drug compound 1 hour after inhalation. In various cases, the concentration of the drug compound in the lungs is at least 100 times higher than the concentration of the drug compound in the plasma 1 hour after inhalation. In various cases, the concentration of the drug compound in the lungs is at least 50 times higher than the concentration of the drug compound in the plasma 24 hours after inhalation. In various cases, the concentration of the drug compound in the lungs is at least 100 times higher than the concentration of the drug compound in the plasma 24 hours after inhalation. In various cases, the concentration of the drug compound in the lungs is at least 50 times higher than the concentration of the drug compound in the plasma 48 hours after inhalation. In various cases, the concentration of the drug compound in the lungs is at least 100 times higher than the concentration of the drug compound in the plasma 48 hours after inhalation.

Further provided herein are methods of treating or preventing influenza virus infection or replication in a subject in need thereof, comprising administering to the subject a dosage form described herein.

Also provided are methods for preparing the dosage form described herein by: (a) micronizing Compound 1 or a salt thereof to produce particles of Compound 1; (b) optionally micronizing the excipient to produce excipient particles; and (c) mixing the micronized Compound 1 or a salt thereof and the optionally micronized excipient to obtain a dosage form. In various cases, micronization of Compound 1 or its salt or excipient is accomplished by manual or jet milling.

In various cases, the proposed method may further include crystallization of compound 1 or a salt thereof prior to micronization. In some cases, crystallization involves mixing Compound 1 or a salt thereof and ethanol at a temperature of at least 50° C., cooling to room temperature to allow Compound 1 or a salt thereof to crystallize, and collecting the crystals by filtration, and optionally drying the crystals before micronization. The mixing temperature can be 75°C. In some cases, mixing is carried out for 4 to 10 hours.

Herein, crystalline forms of Compound 1 are further provided. In some cases, Compound 1 is represented as Form B, and said crystal may exhibit an X-ray powder diffraction (XPD) pattern having 2θ values of 5.6, 6.8, 8.4, 10. 1, 10.6, 11.3, 15.1, 15.8, 18.0, 18.5, 19.1, 20.4 and 20.9 ± 0.2°. In some cases, Form B has a DPR substantially as shown in FIG. 1. In various cases, Form B has a melting point from 280°C to 283°C. In some cases, Compound 1 is represented as Form C, and said crystal may exhibit substantially the same RPD pattern as shown in FIG. 3 (mid spectrum).

Brief description of graphic materials

In fig. Figure 1 shows an X-ray powder diffraction (X-ray powder diffraction) pattern of crystalline compound 1 in Form B.

In fig. Figure 2 shows a DSC (differential scanning calorimetry) thermogram of crystalline compound 1 in form B.

In fig. Figure 3 shows the RPD pattern of crystalline compound 1 in form C (middle spectrum).

In fig. Figure 4 shows a comparison of the XRD patterns of crystalline compound 1 obtained by the suspension method for (from top to bottom) Form C, Form C, Form B, Form B and Form A.

In fig. Figure 5 compares the XRD patterns of crystalline compound 1 prepared by the antisolvent method for (from top to bottom) Form C, Form E, and Form A.

Detailed Description of the Invention

Described herein are compositions of anti-influenza compounds and the use of said compositions to inhibit the activity of influenza virus. In some aspects, the present invention relates generally to the use of the compositions described herein to inhibit the replication of influenza viruses in a biological sample or in a patient, to reduce the number of influenza viruses (reduce viral titer) in a biological sample or in a patient, and to treat or prevent influenza in a patient. Compositions described in

- 3 046313 herein, may be intended for pulmonary administration to a subject, patient or host, for example, by inhalation.

The compositions described herein are useful as therapy against influenza virus infection. Thus, in some aspects, the use of a therapeutically effective amount of a composition described herein is provided for the treatment or prevention of influenza virus infection or replication in a human patient. For example, the influenza virus may be a pandemic or drug-resistant pandemic/seasonal influenza virus.

In various cases, a method of inhibiting the endonuclease activity of influenza polymerase in an influenza A or B virus has been provided, comprising contacting the virus with a composition described herein. In some cases, a method of treating or preventing influenza A or influenza B infection in a host is provided, comprising administering to the host a therapeutic amount of a composition described herein. In various cases, a method of reducing the endonuclease activity of influenza polymerase in an influenza A or influenza B virus in a host has been provided, comprising administering to the host a therapeutic amount of a composition described herein. In some cases, a method of reducing influenza virus replication in a host is provided, comprising administering to the host a therapeutic amount of a composition described herein.

Connection 1.

The compositions described herein contain, among other things, 3-(2-(5-chloro-Spyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-7H-pyrrolo[2,3-d ]pyrimidin-7-yl)bicyclo[2.2.2]octane-2-carboxylic acid, alternatively referred to herein as Compound 1. The active moiety of Compound 1 is predicted to be an inhibitor of the CAP binding domain of PB2.

Compound 1 may exist in free form or, as appropriate, in salt form. Salts that are pharmaceutically acceptable are of particular interest because they are suitable for administering those compounds that are components of the described combinations for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some cases for use in separating stereoisomeric forms of the compounds described herein or intermediates thereof.

As used herein, the term pharmaceutically acceptable salt refers to those salts of a compound which are medically suitable for use in contact with human and lower animal tissues without undue side effects such as toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, scientists S. M. Berge et al. pharmaceutical salts are described in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. These salts can be obtained in situ during the final isolation and purification of the compounds.

If a compound described herein contains a basic group or sufficiently basic bioisostere, then acid addition salts can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the resulting salt. In practice, acid addition salts may be a more convenient form of application, and the use of the salts is equivalent to the use of the free base form.

Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid, or using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycero phosphate, glycolate, gluconate, glycolate , hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxa lat, palmitate, pamoate, pectinate, persulfate , 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc.

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If the compound described herein contains a carboxylic acid group or a sufficiently acidic bioisostere, then base addition salts can be prepared by: 1) reacting the purified compound in its acid form with a suitable organic or inorganic base, and 2) isolating the resulting salt. In practice, the use of a base addition salt may be more convenient, and the use of the salt form is essentially equivalent to the use of the free acid form. Salts derived from suitable bases include alkali metal (eg sodium, lithium and potassium), alkaline earth metal (eg magnesium and calcium), ammonium and K+^^alkyl salts. Quaternization of any basic nitrogen-containing groups is also contemplated herein. connections described in this document. Products that are soluble or dispersible in water or oil can be obtained by quaternization.

Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Sodium and potassium salts are generally preferred. Additional pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine salts formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are derived from metal bases, which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines, which are often used in medicinal chemistry due to their low toxicity and suitability for medical use. Ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, Nbenzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine , dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

Other acids and bases, although not themselves pharmaceutically acceptable, can be used to prepare salts useful as intermediates for the preparation of the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

The components of the combinations can be presented in the form of a solvate. The term solvate refers to a molecular complex of a compound (including its salt) with one or more solvent molecules. Said solvent molecules are those commonly used in the pharmaceutical field which are known to be harmless to the recipient, such as water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term hydrate refers to a molecular complex containing a specific compound and water.

Compound 1 or a salt or solvate thereof may be micronized for use in the compositions described herein. Micronized refers to the solid form containing particles smaller than 15 microns. In various cases, compound 1 or a salt or solvate thereof may be present in the form of particles ranging in size from 0.5 μm to 10 μm, for example, from 1 μm to 10 μm, from 2 μm to 10 μm, from 3 μm to 10 μm , from 4 µm to 10 µm, from 5 µm to 10 µm, from 6 µm to 10 µm, from 1 µm to 7 µm, from 2 µm to 7 µm, from 3 µm to 7 µm, from 2 µm to 6 µm, from 2 µm to 5 µm, from 3 µm to 7 µm or from 3 µm to 6 µm.

Compound 1 or a salt or solvate thereof can be micronized by any known technology. In some cases, micronization is carried out in a jet mill or by hand grinding.

Compound 1 may be present in the described compositions in crystalline form.

Form B. In various cases, the crystalline form can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, which has peaks at about 5.6, 6.8, 8.4, 10.1, 10.6, 11 ,3, 15.1, 15.8, 18.0, 18.5, 19.1, 20.4 and 20.9 ± 0.2° 2θ, using Cu Κα radiation, referred to as Form B. In some embodiments implementation, crystalline compound 1 can be characterized by essentially the same X-ray powder diffraction pattern as in FIG. 1, which essentially means that said peaks may vary by about ±0.2°. It is well known in the RPD field that while the relative heights of peaks in a spectrum depend on a number of factors, such as sample preparation and instrument geometry, peak positions are relatively insensitive to experimental details.

In some cases, crystalline compound 1 may be characterized by a differential scanning calorimetry (DSC) thermogram, for example substantially as in FIG. 2. In some cases, crystalline compound 1 has a melting point of from 280°C to 283°C, or about 282°C.

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Form A. In various cases, the crystalline form may be characterized by an x-ray powder diffraction pattern obtained as described in the Examples having 2θ peaks substantially similar to those in FIG. 4, referred to as Form A. Essentially means that the described peaks can vary by about ±0.2°. It is well known in the RPD field that while the relative heights of peaks in a spectrum depend on a number of factors, such as sample preparation and instrument geometry, peak positions are relatively insensitive to experimental details.

Form C. In various cases, the crystalline form may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples having 2θ peaks substantially similar to those in FIG. 3 (mid spectrum), referred to as Form C. Essentially means that the described peaks can vary by about ±0.2°. It is well known in the RPD field that while the relative heights of peaks in a spectrum depend on a number of factors, such as sample preparation and instrument geometry, peak positions are relatively insensitive to experimental details.

Compound 1 may also be presented as Form D or Form E, as described below in the Examples section.

Filler.

The compositions described herein contain an excipient. Fillers may include microcrystalline cellulose, dicalcium phosphate, lactose (including lactose monohydrate), trehalose, sucrose, mannose, mannitol, sorbitol, calcium carbonate, starches and magnesium or zinc stearates. In some cases, the filler is one or more of lactose, glucose and sodium starch glycolate. In some cases, the filler contains lactose, such as lactose monohydrate. In some cases, the filler is crystalline lactose monohydrate, such as Inhalac®, for example, Inhalac® 400.

The filler may be micronized for use in the compositions described herein. Micronized refers to the solid form containing particles smaller than 15 microns. In various cases, the filler may be in the form of particles ranging in size from 0.5 μm to 10 μm, for example, from 1 μm to 10 μm, from 2 μm to 10 μm, from 3 μm to 10 μm, from 4 μm to 10 μm, from 5 µm to 10 µm, from 6 µm to 10 µm, from 1 µm to 7 µm, from 2 µm to 7 µm, from 3 µm to 7 µm, from 2 µm to 6 µm, from 2 µm to 5 µm, from 3 µm to 7 µm or from 3 µm to 6 µm.

The filler can be micronized using any known technology. In some cases, micronization is carried out in a jet mill or by hand grinding.

In various cases, the compositions described herein contain compound 1 and excipient in a weight ratio of from 1:3 to 1:5. In various cases, the specified mass ratio is approximately 1:4.

Pulmonary administration and devices.

In some embodiments, the compositions described herein are configured to be administered to the lower respiratory tract (eg, lungs) directly through the respiratory tract via inhalation. Compositions for administration by inhalation may be an inhalable powder and may be administered via powder inhalation devices. Such devices are well known.

Inhalation compositions may be packaged to deliver a single dose or multiple doses. For example, the compositions may be packaged for multi-dose delivery similar to the methods described in GB 2242134, US Pat. Nos. 6,632,666, 5,860,419, 5,873,360, and 5,590,645 (which disclose the Diskus device), or GB2178965, GB2129691, GB2169265, US Pat. No. 4,778,054. 4811731 and 5035237 (in which the Diskhaler device is presented), or in EP 69715 (Turbuhaler device), or in GB 2064336 and US patent No. 4353656 (Rotahaler device). Multiple doses may be stored in a reservoir, or multiple doses packaged individually may be stored, for example, in blisters or capsules. Examples of suitable devices include, but are not limited to, TURBUHALER (Astra Zeneca), CLICKHALER (Innovata Biomed), EASYHALER (Orion), ACCUHALER, DISKUS, DISKHALER, ROTAHALER (GlaxoSmithKline), HANDIHALER, INHALATOR, AEROHALER (Boehringer Ingelheim), AEROLIZER ( Schering Plow) and NOVOLIZER (ASTA Medica).

When administered, for example, by inhalation, the compositions described herein demonstrate a high degree of exposure to the drug compound in the lungs compared to exposure in the plasma. A high degree of exposure to a drug compound is advantageous for several reasons. First, pulmonary administration provides rapid delivery of the therapeutic agent to the site of infection. Second, maintaining the concentration of the therapeutic agent in the lungs while minimizing plasma exposure provides the opportunity to reduce systemic adverse events because minimal amounts of the therapeutic agent are released from the site of infection. Third, the concentration of exposure in the lungs allows for the therapeutic effect to be maximized at the site of infection (eg, the lungs).

In some cases, administration of the composition described herein by inhalation provides pulmonary exposure of Compound 1 that is 50 times greater than the pulmonary exposure.

- 6 046313 plasma after 1 hour. In various cases, exposure in the lungs after 1 hour is 60 times higher than in plasma, or 70 times higher, or 80 times higher, or 90 times higher, or 100 times higher, or 125 times higher, or 150 times higher.

In some cases, administration of the composition described herein by inhalation provides pulmonary exposure of Compound 1 that is 50 times greater than plasma exposure at 24 hours. In various cases, pulmonary exposure at 24 hours is 60 times greater than plasma exposure. or 70 times higher, or 80 times higher, or 90 times higher, or 100 times higher, or 125 times higher, or 150 times higher.

In some cases, administration of the composition described herein by inhalation provides pulmonary exposure of Compound 1 that is 50 times greater than plasma exposure at 48 hours. In various cases, pulmonary exposure at 48 hours is 60 times greater than plasma exposure. or 70 times higher, or 80 times higher, or 90 times higher, or 100 times higher, or 125 times higher, or 150 times higher.

In various embodiments, even 4 days after administration via inhalation, exposure to Compound 1 in the lungs is at least 100 times greater than in plasma.

Methods of application.

The compositions described herein can be used to reduce the viral titer in a biological sample (eg, an infected cell culture) or in humans (eg, the viral titer in the lungs of a patient).

The terms influenza virus-mediated condition, influenza infection, or influenza are used interchangeably in this context to refer to a disease caused by infection with an influenza virus.

Influenza is an infectious disease that affects birds and mammals caused by influenza viruses. Influenza viruses are RNA viruses of the Orthomyxoviridae family, which includes five genera: influenza A virus, influenza B virus, influenza C virus, Isavirus, and Thogotovirus. The influenza A virus genus includes one species, influenza A virus, which can be classified into different serotypes based on the antibody response to these viruses. H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 H7N9 and H10N7. Influenza B virus genus includes one species, influenza B virus. Influenza B infects almost exclusively humans and is less common than influenza A. Influenza C virus genus includes one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C virus is less common than other types and usually causes mild illness in children.

In some embodiments, influenza or influenza viruses are associated with influenza A or B virus. In some embodiments, influenza or influenza viruses are associated with influenza A virus. In some specific embodiments, the influenza A virus is H1N1, H2N2, H3N2, H7N9, or H5N1. In some embodiments, the described combinations are effective in inhibiting the growth or replication of a pandemic or drug-resistant pandemic/seasonal influenza virus.

In humans, common symptoms of influenza are chills, fever, pharyngitis, muscle pain, severe headache, cough, weakness and general discomfort. In more severe cases, influenza causes pneumonia, which can be fatal, especially in young children and older adults. Although it is often confused with the common cold, the flu is a much more severe illness and is caused by a different type of virus. The flu can cause nausea and vomiting, especially in children, but these symptoms are more common with unrelated gastroenteritis, which is sometimes called the stomach flu or 24-hour flu.

Flu symptoms can appear quite suddenly one to two days after infection. Usually the first symptoms are chills or a feeling of chills, but fever with a body temperature of 38-39°C (about 100-103°F) is also common early in the disease. Many people are so sick that they are bedridden for days, with aches and pains throughout the body, worst in the back and legs. Flu symptoms may include: body pain, especially in the joints and throat, severe chills and fever, fatigue, headache, irritated, watery eyes, redness of the eyes, skin (especially the face), mouth, throat, and nose, stomach pain (in children with influenza B). Influenza symptoms are nonspecific, overlapping with many pathogens (influenza-like illnesses). Laboratory data are usually needed to confirm the diagnosis.

The terms disease, disorder, and pathological condition may be used interchangeably herein to refer to a medical or pathological condition mediated by an influenza virus.

In this context, the terms subject, host and patient are used interchangeably. The terms subject, host, and patient may refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), particularly a mammal such as a non-primate mammal (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat,

- 7 046313 cat, dog or mouse) or primate (for example, monkey, chimpanzee or human), and more specifically to humans. In some embodiments, the subject is a non-human animal, such as a farm animal (eg, a horse, cow, pig, or sheep) or a pet (eg, a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

The term biological sample as used herein includes, without limitation, cell cultures or extracts thereof; biopsy materials obtained from the body of a mammal, or their extracts; blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

As used herein, the term inhibition of influenza virus replication includes a reduction in the number of viral replications (eg, a reduction of at least 10%), up to and including complete arrest of viral replication (ie, a 100% reduction in the number of viral replications). In some embodiments, replication of influenza viruses is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

Influenza virus replication can be measured by any suitable method known in the art. For example, the influenza virus titer can be measured in a biological sample (eg, an infected cell culture) or in humans (eg, the virus titer in a patient's lungs). More specifically, for cell-based assays in which cells are grown in vitro in each case, virus is added to the culture in the presence or absence of an experimental agent and a virus-dependent breakpoint is measured after an appropriate time. For typical assays, Madin-Darby canine kidney (MDCK) cells and a standard tissue culture-adapted influenza strain, A/Puerto Rico/8/34, can be used. The first type of cellular assay that can be used depends on the death of infected target cells, a process called cytopathic effect (CPE), in which a viral infection causes depletion of cellular reserves and ultimately cell lysis. In the first type of cellular assay, a small proportion of cells in the wells of a microtiter plate are infected (usually 1/10 to 1/1000), the virus is allowed to undergo several rounds of replication over 48-72 hours, then the number of dead cells is measured by comparing the decrease in cellular ATP content with uninfected control samples. The second type of cell-based assay that can be used depends on the increase in virus-specific RNA molecules in infected cells, with RNA content measured directly using the branched DNA (bDNA) hybridization technique. In the second type of cellular assay, a small number of cells are first infected in the wells of a microtiter plate, the virus is allowed to replicate in the infected cells and proliferate in subsequent cell cycles, the cells are then lysed, and the viral RNA content is measured. The assay is stopped early, usually after 18-36 hours, when all target cells are still viable. Viral RNA is quantified by hybridization with specific olignucleotide probes attached to the walls of the assay plate, then amplified by hybridization with additional probes coupled to a reporter enzyme.

In this context, the viral titer or titer is a measure of the concentration of the virus. Serial dilution can be used to check the titer, providing approximate quantitative information based on an analytical procedure that inherently provides only positive or negative information. The titer corresponds to the highest dilution factor at which a positive result is still obtained; for example, a positive result in the first 8 serial twofold dilutions corresponds to a titer of 1:256. A specific example is the viral titer. To determine the titer, several dilutions are obtained, for example, 10 ^-1 , 10 ^-2 , 10 ^-3 , ..., 10 ^-8 . The lowest concentration of virus that still causes infection of cells is the viral titer.

As used herein, the terms treat, treat and provide treatment refer to therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or attenuating the progression, severity and/or duration of influenza virus-mediated conditions, or alleviating one or more symptoms (particularly, one or more noticeable symptoms) of influenza virus-mediated conditions due to the administration of one or more therapeutic agents (eg, one or more therapeutic agents, such as a compound or composition described herein). In specific embodiments, the therapeutic treatment includes attenuating at least one measurable physical parameter of the influenza virus-mediated condition. In other embodiments, the therapeutic treatment includes slowing the progression of the influenza virus-mediated condition, either physically, such as by stabilizing a noticeable symptom, or physiologically, such as by stabilizing a physical parameter, or both. In other embodiments, the therapeutic treatment includes weakening or stabilizing

- 8 046313 infections mediated by influenza viruses. Antiviral drugs can be used in outpatient settings to treat people already suffering from the flu, reducing the severity of symptoms and reducing the number of sick days.

The terms prophylaxis, prophylactic, prophylactic use, and prophylactic treatment in this context refer to any medical or health procedure intended to prevent, rather than treat or cure, a disease. As used herein, the terms prevent, warn, and preventive refer to reducing the risk of acquiring or developing a given condition, or reducing or inhibiting the recurrence of a given condition in a subject who is not sick but has been or may be around a person who has the disease. The term chemoprevention refers to the use of drugs, such as small molecule drugs, rather than vaccines, to prevent a disorder or disease.

Prophylactic use includes use during outbreak detection to prevent infection or spread of infection in settings where many people who are at high risk of serious influenza complications live in close contact with each other (eg, hospital wards, day care centers, prisons, nursing homes etc.). It also includes use in populations that need protection from influenza but are not protected by vaccination (eg, due to a weakened immune system), those for whom the vaccine is not available, or those who cannot be vaccinated due to side effects. It also includes use for two weeks after vaccination or for any period after vaccination but before the vaccine takes effect. Prophylactic use may also include treating a person who does not already have influenza or is not considered to be at high risk for complications to reduce the likelihood of influenza infection and exposure to close contact with a high-risk person (eg, health care workers, nursing home staff, and etc.).

In this context, and as used by the US Centers for Disease Control and Prevention (US CDC), an influenza outbreak is defined as a sudden increase in acute fever respiratory illness (AFRI) occurring within 48 to 72 hours in a group of people in close proximity. with each other (eg, in the same area in nursing homes, in the same home, etc.), compared to normal background levels, or if any of the subjects in the group test positive for influenza.

In some embodiments, the present compositions are suitable as a preventative or prophylactic measure for a patient, particularly a person predisposed to complications associated with influenza virus infection. The proposed compositions may be useful in prophylactic methods in cases where the source of a disease or outbreak is confirmed, to prevent the spread of infection to the rest of the community or part of the population.

As used herein, an effective amount refers to an amount sufficient to provide the desired biological response. As used herein, the desired biological response is to inhibit the replication of influenza virus, to reduce the amount of influenza virus or to reduce or alleviate the severity, duration, progression or occurrence of influenza virus infection, to prevent the spread of influenza virus infection, to prevent recurrence, development, occurrence or progression symptom associated with influenza virus infection, or in enhancing or improving the prophylactic or therapeutic effect(s) of other therapy used against influenza infections. The exact amount of compound administered to a subject depends on the route of administration, the type and severity of the infection, and the characteristics of the subject, such as general health, age, sex, body weight, and drug tolerance. Those skilled in the art can determine appropriate dosages depending on these and other factors. For example, 3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyrigin-3-yl)-5-fluoro-7Hpyrrolo[2,3^]pyrimidin-7-yl)bicyclo[2.2. 2]octane-2-carboxylic acid or a pharmaceutically acceptable salt or solvate thereof can be administered to a subject in a dosage range of from about 0.01 to 100 mg/kg body weight per day for therapeutic or prophylactic treatment.

As used herein, a safe and effective amount of a compound or composition described herein is an effective amount of the compound or composition that does not cause unnecessary or harmful side effects in a patient.

In general, dosage regimens may be selected according to various factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition used; age, body weight, general health, gender and diet of the patient; timing of administration, route of administration, and rate of excretion of the particular compound used; the subject's renal and hepatic function; and the specific compound or salt thereof used, the duration of treatment; drugs used in combination or together with the particular compound used, and similar factors, well

- 9 046313 well-known in the field of medicine. An experienced practitioner can readily determine and prescribe the safe and effective amounts of the compounds described herein needed to treat, prevent, slow (either completely or partially) or stop the progression of a disease.

Doses of Compound 1 may range from about 0.01 to about 100 mg/kg body weight per day, from about 0.01 to about 50 mg/kg body weight per day, from about 0.1 to about 50 mg/kg body weight per day or from about 1 to about 25 mg/kg body weight per day. It should be understood that the total daily amount may be administered as a single dose or may be administered as multiple doses, such as twice daily (eg, every 12 hours), three times daily (eg, every 8 hours), or four times per day (for example, every 6 hours).

For therapeutic treatment, Compound 1 can be administered to a patient, for example, within 48 hours (or within 40 hours or less than 2 days, or less than 1.5 days or within 24 hours) after the onset of symptoms (for example, nasal congestion, sore throat , cough, aches, fatigue, headache and chills/sweating). The therapeutic treatment can be continued for any suitable period, for example, for 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during an outbreak, Compound 1 can be administered to a patient within, for example, 2 days after the onset of symptoms in the first case, and can be continued for any suitable period, for example, for 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Examples

Screening of polymorphs of compound 1 (suspension method). Approximately 10 mg of compound 1 was added to 200 μl of various solvents - methyl tert-butyl ether (MTBE), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), isopropyl alcohol and ethyl acetate in a 5/5 volume ratio (IPA /EtOAc), ethyl acetate (EtOAc), isopropyl alcohol and water in a volume ratio of 8/2, acetonitrile (ACN), acetone and tetrahydrofuran (THF). Each suspension was stirred at 700 rpm for 24 hours at 40°C. The remaining compound was separated in a centrifuge (10 min at 14,000 rpm) and then dried overnight in a vacuum oven at 30°C. If a clear solution remained, the resulting solution was dried under vacuum to obtain a dry solid. The dry solid was analyzed by RPD and the shape was determined. The results are presented in the following table._________________________________________________________

Solvent Characteristics according to RPD MTBE Pale yellow solid, Form A MeOH Pale yellow solid, Form B EtOH Pale yellow solid, Form B IPA Pale yellow solid, Form B IPA/EtOAc (5/5, v/v) Pale yellow solid, Form B EtOAc Pale yellow solid, Form B IPA/H2O (8/2, v/v) Pale yellow solid, form C ACN Pale yellow solid, form C Acetone Pale yellow solid, Form D THF Pale yellow amorphous substance

RPD patterns of crystals were recorded on a Bruker D8 Advance instrument with the following parameters. The results of the Form B RPD analysis are shown in FIG. 1. The results for Form C are shown in FIG. 3. The results for Forms A, B and C are shown in FIG. 4._______________________________________

Options Settings/values One step time 0.12 s X-ray tube settings Voltage: 40 kV; current: 40 mA Scan sector from 4 to 40 degrees Sample rotation speed 15 rpm

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Options Settings/values Scan speed 10 deg/min. Parameter 2 theta

DSC of Form B crystals was recorded on a TA Q2000 instrument with the following parameters, and the DSC results are presented in FIG. 2.______________________________________________________________

Options DSK Method Linear change Temperature Range 30°C - 300°C Heating rate 10°C/min. Purge gas N2 Crucible type Aluminum, screw

Screening for Polymorphs of Compound 1 (Antisolvent Method): Approximately 25 mg of Compound 1 was weighed into a glass tube, then 0.5 ml of dimethylacetamide (DMA) was added to obtain a clear solution of 50 mg/ml. Antisolvents were then added dropwise to the resulting solution while stirring at 700 rpm at room temperature. The resulting crystals were then collected by centrifugation. The crystals were analyzed using XRD, the results are presented in Fig. 5, which shows Form E at the top, Form C at the middle, and Form A at the bottom.________________________________________________________________________________

Anti-solvent Volume of antisolvent added (ml) Observations RPD ACN 1.5 Homogeneous, opaque suspension Form E Ethanol 5 Clear solution IPA 5 Clear solution Acetone 5 Clear solution Water 0.5 Homogeneous, opaque suspension Form C

Polymorph formation at different temperatures - suspension. Approximately 25 mg of compound 1 was weighed into a glass tube, then 500 μl of various solvents was added. The solution was stirred at 700 rpm for 3 days at 55°C or 25°C. The remaining compound was separated in a centrifuge (10 min at 10,000 rpm) and then dried for 2 days in a vacuum oven at 30°C. The dry solid was analyzed by XRD. Summarized information for forms obtained under different conditions is presented below.________________________________________________

Solvent Way RPD Ethanol Suspension/25°C Form B Suspension/55°C Form B ACN Suspension/25°C Form A Suspension/55°C Form A Acetone Suspension/25°C Form A Suspension/55°C Form C

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MeOH Suspension/25°C Form B Suspension/55°C Form B MTBE Suspension/25°C Form A Suspension/55°C Form A IPA Suspension/25°C Form A Suspension/55°C Form A EtOAc Suspension/25°C Form A Suspension/55°C Form C IPA/ _H2O (8/2) Suspension/25°C Form C Suspension/55°C Form C EtOH/H2O (8/2) Suspension/25°C Form C Suspension/55°C Form C

Polymorph formation at different temperatures: Approximately 50 mg of compound 1 was weighed in a glass tube, then 500 μl of various solvents were added. The solution was then stirred at 700 rpm for 3 days at 55°C. The solid was separated by centrifuge (10 min at 10,000 rpm) and then dried for 2 days in a vacuum oven at 30°C. The solid was analyzed using RPD.

Approximately 25 mg of compound 1 was weighed into a glass vial, then stored at 25°C/60% RH or 40°C/75% RH for 1 week. The samples were then analyzed using RPD.

The results of the RPD are summarized below.

Solvent Water activity Way RPD 0% H2O/acetone 0 Suspension/55°C Amorphous+Form C 3% H2O/acetone (v/v) 0.32 Suspension/55°C Form C 11% H2O/acetone (v/v) 0.56 Suspension/55°C Form C 16% H ₂ O/acetone (v/v) 0.63 Suspension/55°C Form C 31% H ₂ O/acetone (v/v) 0.76 Suspension/55°C Form C 42% H ₂ O/acetone (v/v) 0.81 Suspension/55°C Form C

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79% H2O/acetone (v/v) 0.94 Suspension/55°C Form C Exposure to 25°C/60% RH 0.60 - Form A Exposure to 40°C/75% RH 0.75 - Form A

Polymorph formation at different temperatures (anti-solvent): Approximately 50 mg of compound 1 was weighed in a glass tube, then 1 ml of DMA was added, followed by sonication to obtain a clear solution. The solution was then stirred at 700 rpm at 55°C, then antisolvent was added for fast precipitation or slow precipitation. Fast precipitation: some antisolvent was quickly added and the solid was filtered within 1 hour. Slow sedimentation: some antisolvent was slowly added and the solid was filtered after being suspended for 3 days. The resulting solid was centrifuged (10 min at 10,000 rpm) and then dried for 2 days in a vacuum oven at 30°C. The solid was analyzed using RPD. The results of the RPD are presented below._____

Stock solution Anti-solvent Way Volume added antisolvent (ml) Observations RPD 50 mg API in DMA (50 mg/ml) ACN Fast deposition 3.0 Turbid suspension with sediment Form A Slow deposition 3.0 Homogeneous suspension Form F Water Fast deposition 1.0 Homogeneous suspension Form A Slow sedimentation 1.0 Homogeneous suspension Form A

Generalization of the results of the study of polymorphs.

Solvent Method and temperature Suspension 25 °C 40°C 55 °C 70°C MTBE Form A Form A Form A - MeOH Form B Form B Form B - EtOH Form B Form B Form B Form B IPA Form A Form B Form A - IPA/EtOAc (5/5, v/v) - Form B - - EtOAc Form A Form B Form C - IPA/H2O (8/2, v/v) Form C Form C Form C - EtOH/HO (8/2, v/v) Form C - Form C Form C ACN Form A Form C Form A - Acetone Form A Form D Form C - THF - Amorphous - - 0% H ₂ O acetone - - Amorphous+ form C - 3% _H2O /acetone (v/v) - - Form C - 11% H ₂ O/acetone (v/v) - - Form C - 16% H ₂ O/acetone (v/v) - - Form C -

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31% H ₂ O/acetone (v/v) - - Form C - 42% H ₂ O/acetone (v/v) - - Form C - 79% H ₂ O/acetone (v/v) - - Form C - Impact 25 °C/60% RH - - Form A - Impact 40 °C/75% RH - - Form A - Solution Solvent Method and temperature Anti-solvent Normal (25°C) Fast (55 °C) Slow (55°C) 50 mg connections 1 in DMA (50 mg/ml) ACN Form E Form A Form F water Form C Form A Form A IPA - - - EtOH - — acetone - - -

Micronization of Compound 1 Crystallized Compound 1 (Form B) was gradually added to the jet mill at an injector gas pressure of 4.5 bar, the grinding gas pressure was 4 bar. The micronized product exhibited the same characteristic peaks as the compound before micronization. In addition, the DSC results confirmed that the solid exothermic peak at 198.27°C and the single endothermic peak at 280.40°C before decomposition were identical to those observed in the sample before micronization. The particle size distribution (PSD) results of the dry dispersion showed that the particle size of the micronized compound was VMD=2.08 µm, Di ₀ =0.65 µm, D ₅₀ =1.44 µm and D ₉₀ =4.21 µm.

Micronization of lactose monohydrate. The characteristics of several lactose monohydrate materials were tested and the results are presented in the following table.

Sample Technological parameters PSD (µm) Gas pressure in injector/bar Grinding gas pressure/bar VMD D10 D50 D90 Inhalac 70 N/A n/a 211.43 128.70 212.61 294.71 Inhalac 70 micronized 4 3.5 3.77 1.09 3.43 7.03 Inhalac 230 n/a N/A 94.60 40.19 95.47 145.35 Inhalac 230 micronized 4 3.5 4.01 1.11 3.55 7.49 Inhalac 250 n/a N/A 52.25 14.95 49.74 90.85 Inhalac 250 micronized 4 3.5 6.24 1.08 2.99 11.31 Inhalac 250 micronized 4.5 4 3.91 0.96 2.56 6.66 Inhalac 250 micronized 5 4 3.15 1.19 2.78 5.55 Inhalac 250 micronized 5 4.5 3.51 1.06 2.64 6.05 Inhalac 400 n/a N/A 10.54 1.00 7.26 24.93 Inhalac 400 micronized 4 3.5 2.56 0.75 1.92 4.43 Inhalac 400 micronized 4.5 4 2.01 0.73 2.66 3.60 Inhalac 400 micronized 5 4 2.64 0.76 1.93 4.28 Inhalac 400 micronized 5 4.5 2.50 0.77 2.04 4.69

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Claims (12)

Obtaining a dosage form. Crystalline compound 1 (Form B) was crushed by hand, then mixed with lactose monohydrate (Inhalac 400) in a 1:4 ratio. The mixture was stirred, chopping by hand, for 10 minutes. The mixture was then ground in a jet mill under the following conditions: injector gas pressure 4.5 bar, grinding gas pressure 4 bar. The dry dispersion PSD data showed dosage form particle sizes VMD=1.52 µm, D ₁₀ =0.63 µm, D ₅₀ =1.26 µm and D _9j =2.77 µm. In vivo PK study in mice. To demonstrate pulmonary delivery of Compound 1 via inhalation, a pharmacokinetic study in mice (BALB/C) was performed. Mice were administered a single dose of ~1 mg of dry powder using an insufflator and samples were collected. Plasma and lung samples were collected at different time points, and concentrations of the drug compound in the lungs and plasma of the mice were determined. As shown in the following table, rapid accumulation of a high concentration of the drug compound in the lung tissue was observed when administered by inhalation. In contrast, drug concentrations in plasma were significantly lower than in the lungs. The data obtained indicate that delivery of Compound 1 can be effectively accomplished by inhalation administration using the dosage form described, allowing Compound 1 to be brought into contact with, for example, influenza-infected respiratory tracts. Interestingly, the concentration of the drug compound remained at least 100 times higher than the therapeutic dose on the fourth day (anti-influenza activity, EC ₅₀ 0.1-3 nM). The results obtained further support the potential clinical application of dry powder of compound 1 for the treatment of influenza infection.___________ Moment in time, hours Drug concentration compounds in the lungs, µM Drug concentration compounds in plasma, µM 1 984 5.6 24 218 0.081 48 8.6 0.052 72 0.63 0 96 0.35 0 CLAIM 1. Dosage form containing: (a) crystalline compound 1, which is 3-(2-(5-chloro-1H-pyrrolo[2,3b]pyridin-3-yl)-5-fluoro-7H-pyrrolo[2,3D]pyrimidin-7 -yl)bicyclo[2.2.2]octane-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, which has an X-ray powder diffraction (XPD) pattern exhibiting 2θ values of 5.6, 6.8, 8.4, 10.1 , 10.6, 11.3, 15.1, 15.8, 18.0, 18.5, 19.1, 20.4 and 20.9±0.2° (designated as form B), where crystalline compound 1 or a salt thereof is presented in micronized crystalline form; and (b) an excipient, wherein the dosage form is configured to be administered by inhalation. 2. The dosage form according to claim 1, wherein the dosage form is a powder dosage form for inhalation administration containing an excipient consisting essentially of lactose monohydrate, wherein said dosage form has a particle size distribution characterized by a volume mean diameter (VMD) of 1 to 2 µm, with D ₁₀ values from 0.5 to 0.7 µm, D ₅₀ from 1 to 1.4 µm and D ₉₀ from 2.5 to 2.8 µm. 3. Dosage form according to claim 1, characterized in that the filler contains lactose. 4. Dosage form according to claim 3, characterized in that the filler contains lactose monohydrate. 5. Dosage form according to any one of claims 1-4, characterized in that the filler is micronized. 6. Dosage form according to any one of claims 1-5, characterized in that the crystalline compound 1 or its salt has a melting point from 280 to 283°C. 7. Dosage form according to any one of claims 1-6, characterized in that compound 1 or its salt has a volume-average particle diameter from 0.5 to 10 μm. 8. Dosage form according to claim 7, characterized in that compound 1 or its salt has a volume-average particle diameter from 1.5 to 5 μm. 9. Dosage form according to any one of claims 1-8, characterized in that the filler has an average volume particle diameter from 0.5 to 10 microns. 10. Dosage form according to claim 9, characterized in that the filler has an average volume particle diameter from 1.5 to 5 microns. 11. Dosage form according to any one of claims 1 to 10, characterized in that the mass ratio of crystalline compound 1 or its salt to the filler is from 1:3 to 1:5. 12. A method of treating or preventing infection or replication of an influenza virus in a subject in need thereof, comprising administering to said subject a dosage form according to any one of claims 1 to 11 in an effective amount to treat an influenza infection. -