Clofazimine composition and method for treating or preventing viral infections

Abstract

Disclosed herein are methods for treating and / or preventing viral infections, particularly those methods for administering by inhalation a pharmaceutically effective dose of clofazimine provided in a formulation suitable for inhalation, in the form of a solution, suspension, or as a dry powder.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 018,677, filed on May 1, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] This specification discloses compositions and methods for treating and preventing viral infections, including coronavirus infections such as COVID - 19. In particular, the compositions include clofazimine in an inhalation suspension or dry powder for administration by spraying or oral inhalation.

Background Art

[0003] A viral disease (or viral infection or infectious disease) occurs when a pathogenic virus invades an organism's body and infectious virus particles (virions) attach to and invade susceptible cells. Viruses replicate using the cell's own machinery within the infected cell and release new viruses from this cell. The virus infects other cells of the organism and continues to replicate until the immune system cannot overcome the viral load / content or suppress the viral infection, and the disease condition persists.

[0004] Coronavirus disease 2019 (COVID - 19) is an infectious disease caused by SARS - CoV - 2, a virus closely related to the SARS virus. This disease caused the 2019 - 2020 coronavirus pandemic, which spreads mainly from person to person through fine droplets suspended in the air when an infected person breathes or coughs. The period from exposure to symptom onset is usually 2 - 14 days. To prevent this disease, it is recommended to wash hands, keep a distance from coughing people, and avoid touching one's own face. If there has been close contact with a person determined to be positive in a virus test, they are isolated for 10 - 14 days. Also, it is recommended to cover one's nose and mouth with the bent elbow when coughing.

[0005] Some people show few or no symptoms, while others experience fever, cough, and shortness of breath. Some cases progress to pneumonia and multiple organ failure. Currently, there is no approved vaccine or specific antiviral drug treatment, and responses include symptomatic treatment, supportive care, and experimental methods. The mortality rate is estimated to be between 1% and 3%. The World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) recommend that individuals suspected of carrying the virus wear a medical mask and seek medical advice by telephone rather than visiting a clinic in person. It is also recommended that those caring for someone suspected of being infected wear masks. It is also recommended that the general public wear masks when engaging in indoor and outdoor activities.

[0006] The WHO declared the 2019-2020 coronavirus pandemic a Public Health Emergency of International Concern (PHEIC). As of February 19, 2020, mainland China was the only region where community transmission of the disease had been confirmed. Now, with almost every country in the world, including Europe and the United States, significantly affected, the disease has been classified as a global pandemic. A vaccine has now been developed and administered to millions of people worldwide, but regulatory authorities have only approved its use in emergencies. Several treatments, such as remdesivir, have been approved to shorten the time from infection to recovery, but there is no clearly defined therapy approved to inhibit the virus and treat human COVID-19. [Overview of the project] [Problems that the invention aims to solve]

[0007] Therefore, there is a need for novel methods and compositions for treating viral infections, and in particular for use in treating and inhibiting coronavirus infections, improved alternative methods and compositions. [Means for solving the problem]

[0008] This specification discloses methods and compositions for treating viral infections, comprising an antibiotic such as clofazimine delivered to the lungs via oral inhalation. The method involves delivering a certain dose of the composition to a patient having a viral infection, the dose being lower than the corresponding intravenous or oral dose currently administered, and thus reducing the occurrence of side effects caused by standard treatment with clofazimine. This method is advantageous because it can accelerate the treatment of a patient with a lower dose than oral tablets, and can reach the site of action quickly, while potentially resulting in smaller amounts and fewer toxic side effects.

[0009] In one embodiment, the method involves administering a clofazimine composition to a patient in need of treatment in a therapeutically effective dose, which is delivered to the patient's lungs. The clofazimine composition may be provided to the patient in the form of a neat drug, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt thereof. In some embodiments, the clofazimine composition includes a pharmaceutically acceptable carrier or pharmaceutical additive. In certain embodiments, the clofazimine composition may include a solution, suspension, or dry powder for inhalation, which can be used with a nebulizer, metered-dose inhaler, or dry powder inhaler.

[0010] In other embodiments, a method is provided for preventing a viral infection of the lungs, comprising administering to a subject a composition containing clofazimine that is sustainably released in the lungs, thereby increasing the lung residence time of clofazimine and protecting the lungs from viral infection.

[0011] In one embodiment, an improved method for treating a viral infection of the lungs is provided, the method comprising delivering a therapeutically effective amount of a composition comprising clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine to the lungs of a patient by aerosol, wherein the effective amount of clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine delivered to the lungs is lower than a therapeutically effective oral dose.

[0012] In some embodiments, a therapeutic method is disclosed comprising administering to a subject requiring such treatment a therapeutic dose of a composition comprising clofazimine and a pharmaceutically acceptable carrier and / or pharmaceutical additive, wherein the viral infection is coronavirus, influenza, Ebola hemorrhagic fever, or another viral infection affecting the lungs, or a combination thereof.

[0013] In certain embodiments, the method involves administering a therapeutically effective amount of clofazimine composition to a subject diagnosed with SARS-CoV-2 infection in order to inhibit viral replication. This composition comprises clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine such as clofazimine hydrochloride, clofazimine acetate, clofazimine citrate, clofazimine phosphate, clofazimine oxalate, clofazimine sulfate, or a combination thereof, along with a pharmaceutically acceptable pharmaceutical additive and / or carrier.

[0014] In another embodiment, a method for treating COVID-19 disease comprises administering to a patient in need a therapeutically effective amount of a clofazimine composition comprising clofazimine, a pharmaceutically acceptable derivative, or a salt thereof, or a combination thereof, and a pharmaceutically acceptable pharmaceutical additive and / or carrier, to inhibit viral replication and viral disease.

[0015] In one embodiment, the therapeutic method comprises administering a therapeutically effective amount of clofazimine composition to a subject, wherein the amount of clofazimine, a pharmaceutically acceptable derivative, or a salt thereof is such that the amount of clofazimine, a derivative, or a salt thereof per dose of the composition delivered to the lungs is approximately 1 mg to approximately 30 mg; approximately 1 mg to 20 mg; 1 mg to 10 mg; approximately 3 to 8 mg; or approximately 2 mg to approximately 6 mg. In one embodiment, the inhalation powder containing pharmaceutically acceptable pharmaceutical additives may contain 50 mg or less in total per dosage to be administered, which is delivered to the lungs by one or more inhalations using a dry powder inhaler, or by one or more breaths in a suspension sprayed with a nebulizer. In this embodiment and other embodiments, the dry powder clofazimine composition can be administered daily by being delivered in a unit dose in aerosol form from a cartridge or capsule using a metered-dose inhaler or dry powder inhaler.

[0016] In some embodiments, clofazimine is delivered by spraying from a nebulizer and may include a suspension or a suspension containing physiological saline. [Modes for carrying out the invention]

[0017] Embodiments disclosed herein provide a method for treating viral infections, comprising using clofazimine inhalation suspension (CIS) or inhalable dry powder as a countermeasure against coronaviruses, particularly SARS-CoV-2, which causes COVID-19 disease. The clofazimine in the composition inhibits viral infection and is administered directly to the lungs in the form of clofazimine suspension or dry powder. CIS is currently in preclinical development for the treatment of both pulmonary nontuberculous mycobacterial disease and tuberculosis, and is currently undergoing first-in-human GLP toxicity testing.

[0018] In an exemplary embodiment, a method for treating a viral infection is given by formula: [ka] The method involves administering a composition comprising an antibiotic compound having and a pharmaceutically acceptable carrier and / or pharmaceutical additive. In one embodiment, pharmaceutically acceptable derivatives or salts of this compound are also used alone or in combination with this compound in formulations, particularly in lung inhalation compositions for the treatment of viral lung diseases. In one embodiment, the compound is clofazimine, clofazimine, N,5-bis(4-chlorophenyl)-3-propane-2-yliminophenadine-2-amine, clofazimine, clofaziminum, 3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-(isopropylimino)phenadine, or a clofazimine crystalline polymorph or polymorph such as a triclinic (FI) polymorph, a monoclinic (FI) polymorph, an orthorhombic polymorph (FI) polymorph, and a high-temperature polymorph (FI IV). Examples of clofazimine salts include clofazimine hydrochloride, clofazimine acetate, clofazimine citrate, clofazimine forate, clofazimine phosphate, clofazimine oxalate, and clofazimine sulfate. In the embodiments thereof, when clofazimine is used alone or in combination with others in the composition, it may refer to any form of clofazimine unless a derivative, salt, or polymorph is specifically mentioned.

[0019] In other exemplary embodiments, a dry powder for oral inhalation is formed by combining the above-described antibiotic compound composition with a pharmaceutically acceptable carrier or pharmaceutical additive such as diketopiperazine, and this diketopiperazine is provided in particulate form. In this embodiment, the diketopiperazine forms crystalline composite particles having a median mass of <10 μm.

[0020] In one embodiment, the clofazimine compound in the composition has antiviral activity against SARS-CoV-2 and may inhibit viral replication, thereby resolving viral disease or alleviating the symptoms of viral disease. In in vitro studies, clofazimine can reduce or eliminate viral replication by 40% at a concentration of 2.5 μM (or approximately 1.2 μg / ml). Clafazimine has been used in the treatment of bacterial infections, for example, in the treatment of leprosy and bacterial infections of the lung disclosed in International Publication No. 2020 / 040818, provided as an oral capsule. The relevant parts of this disclosure are incorporated by reference.

[0021] In exemplary embodiments, clofazimine compositions, such as CIS or dried powder formulations, are generally used to treat viral infections, particularly those affecting the lungs. These include coronaviruses, influenza, respiratory syncytial virus, Zika fever, and dengue fever. In this embodiment, a clofazimine-containing composition for treating viral infections is provided for use in therapeutic treatment against SARS-CoV-2. The composition comprises clofazimine, a derivative of clofazimine, or a salt thereof, or a combination thereof, and a pharmaceutically acceptable carrier and / or pharmaceutical additive, for administration to a patient who has tested positive or been diagnosed with a viral infection. In one embodiment thereofazimine, the clofazimine composition is administered alone or in combination with other antiviral therapies such as ribavirin, acyclovir, remdesivir, interferon β1b, or lopinavir / ritonavir. In such combination embodiments, the clofazimine composition is administered alone by inhalation, and in secondary and / or tertiary therapy, it may be administered as an inhalable suspension, solution, or dry powder, or by other routes of administration such as oral tablets, oral capsules, injections, or intravenous administration. In some embodiments, the clofazimine-containing CIS or dry powder composition is administered in combination with other drugs such as hydroxychloroquine or invermectin, in the routes and doses indicated for those drugs.

[0022] In some embodiments, inhalable clofazimine compositions, such as CIS and dry powders, can be used for the treatment of other diseases, such as Hansen's disease and other bacterial infections, for example, the treatment of nontuberculous mycobacteriosis. In the treatment of bacterial infections using clofazimine capsules, this drug is relatively well tolerated, and the main side effects include skin jaundice and gastrointestinal disorders found in at least half of the patients.

[0023] The clofazimine inhalation suspension for inhalation administration in spray form optimizes the clofazimine treatment of pulmonary nontuberculous mycobacteriosis (NTM-PD) and tuberculosis (TB). By directly delivering the drug to the airway, it is expected that CIS will reach therapeutic concentrations in the lungs and reduce the occurrence of the main side effects (described above) without affecting the therapeutic effect. In preclinical trials, CIS has been evaluated for the treatment of NTM-PD and TB, and a series of toxicity tests have been carried out, showing that CIS is safe and well tolerated at doses of about 3.0 mg / kg or less (where the lung concentration reaches about 10 μg / g of clofazimine). From the available pharmacokinetic (PK) and pharmacodynamic (PD) studies of the clofazimine inhalation suspension, it has been shown that by performing a loading dose by inhalation for 1 or 2 days, a therapeutic lung concentration for treating COVID-19 disease can be reached and maintained for up to 2 weeks.

[0024] There are numerous advantages and superiority of the inhalable clofazimine composition. For example, targeted administration to the lungs to avoid side effects due to increased systemic concentrations of clofazimine (at a much lower dose than the oral dose); protecting / preventing cells forming the lung surface and the inside of the respiratory tract from viral lung infections; being able to perform inhalation therapy at home away from the medical environment for infectious diseases (infectious hospital setting); showing long-term activity when performing local "lung loading" administration for several days / several times due to the long half-life of clofazimine in the lungs; and so on.

[0025] The clofazimine composition produced in suspension is administered as an inhalation therapy to patients with clinical symptoms of COVID-19 disease, not only at home or in an isolation environment but also under intensive care. The clofazimine composition has been found to exhibit significant antiviral activity against SARS-CoV-2 in in vitro infection models such as VERO-6 cells in preclinical studies.

[0026] In certain embodiments, a method for treating pulmonary viral infection comprises delivering a large amount of clofazimine, a pharmaceutically acceptable derivative, or a salt thereof to the lungs via aerosol to create a depot that releases the drug over an extended period of time, thereby resulting in a treatment period of less than three weeks. In one aspect of this method, the composition comprises a suspension or a dry powder administered by a nebulizer. In the dry powder embodiment, the particle size can be from about 1 μm to about 100 μm, about 1 μm to about 50 μm, about 2.5 μm to about 25 μm, or from 1 μm to about 10 μm in diameter.

[0027] In one embodiment, the treatment method comprises administering a clofazimine composition to a subject at a dose of approximately 1 mg to 10 mg of clofazimine per day for a period of 1 to 14 days. In this embodiment, the treatment method comprises a clofazimine composition in which clofazimine, a pharmaceutically acceptable derivative, or a salt thereof is delivered in a single dose such that the active ingredient in the composition is approximately 3 mg to 8 mg. In certain embodiments, the clofazimine composition is administered in combination with one or more antiviral agents such as ribavirin, acyclovir, remdesivir, lopinavir / ritonavir, or interferon β1b to exert synergistic antiviral activity. In one embodiment, the inhalable clofazimine composition is administered together with one or more other drugs, such as daily oral macrolide antibiotics, inhalable amikacin, and other antibiotics selected from the group consisting of amikacin, azithromycin, clarithromycin, tigecycline, cefoxitine, imipenem, pyrazinamide, rifampin, moxifloxacin, levofloxacin, and other oral antibiotics such as para-aminosalicylic acid and bedaquiline, some of which are administered intravenously or by injection. When more than one combination of antibiotics is used, they may be administered simultaneously, subsequently, sequentially, or after a predetermined interval following the administration of an inhalable dose, in the prescribed dose and route. In some embodiments, the inhalable clofazimine composition can be used in combination with one or more drugs for simultaneous administration.

[0028] In another embodiment, a method for the prophylactic treatment of a viral infection of the lungs, the method comprising delivering an effective amount of clofazimine or a pharmaceutically acceptable derivative or salt to the patient's lungs by aerosol to create a drug reservoir in the lungs that releases the drug over a prolonged period, thereby preventing the viral infection of the lungs. Because the therapeutic dose of clofazimine administered to the patient is lower, this treatment avoids or reduces several adverse effects encountered with oral clofazimine therapy. Adverse effects of daily oral administration of clofazimine capsules at doses of 100 mg to approximately 300 mg for a period of 30 days to several years include swelling of the gastrointestinal lining, abdominal pain, diarrhea, itching, dry skin, skin discoloration, elevated blood glucose levels, skin hypersensitivity, and hepatotoxicity.

[0029] In other embodiments, a therapeutic method is provided for treating a subject having a viral infection, such as coronavirus, influenza, Ebola hemorrhagic fever, or other viral infection causing lung disease, the method comprising administering a dose of a pharmaceutical composition comprising a dry powder composition containing particles of clofazimine, a clofazimine derivative, or a salt of clofazimine and a pharmaceutically acceptable carrier and / or pharmaceutical additive to the subject using a dry powder inhaler. In this embodiment and other embodiments, the pharmaceutically acceptable carrier and / or pharmaceutical additive is of formula: [ka] The compound is (E)-4-[4-[(2S,5S)-5-[4-[[(E)-3-carboxyprop-2-enoyl]amino]butyl]-3,6-dioxopiperazine-2-yl]butylamino]-4-oxobut-2-enoic acid, 3,6-bis(N-furanyl-N(n-butyl)amino)-2,5-diketopiperazine, or a pharmaceutically acceptable salt thereof. The aerosolized formulation may include crystals, crystalline complexes, amorphous dry powders, or combinations thereof.

[0030] In exemplary embodiments, the inhalable clofazimine composition comprises fine particles containing clofazimine, a derivative of clofazimine, or a pharmaceutically acceptable salt thereof, or a combination thereof, with diketopiperazine, wherein the amount of clofazimine, a derivative, or a salt thereof in the composition is about 1 mg to about 10 mg wt.%.

[0031] In one embodiment, the inhalable dry powder composition may contain one or more carriers and / or pharmaceutical additives, the carrier or pharmaceutical additive being selected from the group consisting of at least one crystalline carbohydrate selected from the group consisting of glucose, arabinose, maltose, saccharose, dextrose, and lactose. In a particular embodiment, the carrier or pharmaceutical additive may include a surfactant containing a polysorbate, such as polysorbate 80; a phospholipid such as 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1,2-distearoyl-sn-glycero-3-phosphocholine; a polymer; and one or more agents selected from aliphatic amino acids such as glycine, leucine, isoleucine, and histidine.

[0032] In certain embodiments, the inhalable dry powder composition may contain a carrier or pharmaceutical additive, the carrier or pharmaceutical additive in the form of fine particles with a median mass diameter (MMD) in the range of 0.5 to 10 μm or 0.5 to 6 μm. In some embodiments, the inhalable dry powder composition contains a carrier in the form of coarse particles with a diameter of mass of 50 to 500 μm. In other embodiments, the inhalable dry powder composition containing clofazimine contains particles with an aerodynamic median mass diameter of less than 5 μm.

[0033] In exemplary embodiments, an inhalation pharmaceutical composition is provided comprising a therapeutically effective amount of clofazimine, a pharmaceutically acceptable derivative, or a salt of clofazimine, and an aqueous liquid carrier selected from water, isotonic saline, buffered saline, and an aqueous electrolyte solution. In this embodiment, the pharmaceutical composition comprises a clofazimine suspension, wherein the median mass diameter (MMD) of the clofazimine particles is <5 μm, preferably <2 μm. In one embodiment, the pharmaceutical composition containing clofazimine is solubilized in the form of a microemulsion or nanoemulsion, wherein the median mass diameter (MMD) of the emulsion droplet is less than 1 μm. In this embodiment, a pharmaceutical composition for a spray system for use in the treatment or prevention of viral infections of the lungs is provided, the system comprising the pharmaceutical composition and a nebulizer, the nebulizer being selected from the group consisting of a compressed air jet nebulizer, an ultrasonic nebulizer, a vibrating mesh nebulizer, a static mesh nebulizer, or a mechanical soft mist inhaler, the aerodynamic median mass diameter (MMAD) of the aerosol particles formed during use being 1 to 5 μm. In one embodiment, the spray system further controls the patient's inspiratory airflow by either an electrical or mechanical method, so that aerosol is generated only when the patient inhales.

[0034] In one embodiment, a treatment method is provided which includes administering a topical pharmaceutical composition containing a therapeutically effective amount of an antiviral agent such as clofazimine to a patient suffering from a lung bacterial infection other than a viral infection, and applying the composition to a body surface affected by a viral infection in which the pathogen is susceptible to each antiviral agent in the formulation.

[0035] This antiviral composition can also be used to treat many viral infections. For example, this composition containing clofazimine can be used in combination with pharmaceutically acceptable carriers and pharmaceutical additives to prepare various pharmaceuticals, including oral, nasal, intraocular, pulmonary, parenteral, topical, or mucosal formulations.

[0036] The following examples are included to illustrate examples of using the disclosed particles and compositions in the method. Those skilled in the art should understand that the techniques disclosed in the following examples are representative of the techniques that the inventors have found to work well in the practice of this disclosure and can therefore be considered to constitute a preferred mode for practicing them. However, those skilled in the art should understand that many modifications can be made to the specific embodiments disclosed in light of this disclosure, and that equivalent or similar results can still be obtained without departing from the scope of the invention. [Examples]

[0037] Example 1 Inhalable clofazimine composition for dry powder inhalers (DPIs): The Aerolizer DPI, a dry powder inhaler, is prepared together with clofazimine drug contained in a capsule. The clofazimine formulation is produced by micronizing clofazimine with a jet mill to produce particles with an MMD of <2 μm, and then blending them with larger lactose particles (MMD > 50 μm). The formulation contains approximately 10% by weight of clofazimine. Approximately 250 mg of the formulation (25 mg of clofazimine) is filled into a capsule. When inhaled via the Aerolizer DPI, 13% to 28% of the dose is deposited in the lungs (Meyer et al, J Aerosol Med, 2004, 17(1):43-49). Using this inhaler system, 3.25 mg to 7 mg of clofazimine is delivered to the lungs from the capsule. Those skilled in the art can envision numerous embodiments that, despite slight variations in the description, still have the same therapeutic effect, consistently delivering 3 mg to 8 mg of clofazimine to the lungs in a single capsule dose. Alternative forms of clofazimine inhalation powder can be prepared using pharmaceutically acceptable derivatives or salts of clofazimine.

[0038] The use of alternative inhalers for delivering inhalable formulations is achieved by manufacturing the formulations to be compatible with the use of any dry powder inhaler, including other capsule devices, blister strip inhalers, reservoir inhalers (metered), single-use inhalers, and reusable inhalers. This includes, by reference, all dry powder inhalers, including those disclosed in U.S. Patent No. 8,636,001 and U.S. Patent No. 8,485,180, and the entire relevant content of such disclosures is incorporated by reference.

[0039] Alternative particle sizes: Each inhaler has a different resistance to airflow, and the greater the resistance of the inhaler, the lower the inhalation flow rate. Choosing an inhaler with greater resistance (lower inhalation flow rate) allows for the use of larger particle sizes (up to 10 μm) for effective delivery to the lungs. Alternative formulation components: Many grades of lactose with different sizes and shapes are available for use in inhaled formulations. It is also possible to pre-blend small lactose particles to aid dispersion. It is also possible to replace lactose with a physiologically acceptable inert solid carrier. Additional pharmaceutical additives such as phospholipids, salts, surfactants, and polymers can be added to aid in aerosol dispersion. Alternative dosage forms: Alternatively, clofazimine and pharmaceutical additives can be dissolved in a solvent and spray-dried.

[0040] Example 2 PARI eFlow® Nebulizer Delivery Suspension: An alternative method for delivering a therapeutic dose of clofazimine to the lungs is to use a nebulizer. Because clofazimine has low solubility, clofazimine particles are pulverized to <2 μm by jet milling and mixed with isotonic saline so that the resulting formulation contains 9-20 mg / ml of clofazimine. PEG400 or polysorbate 80 may be added to stabilize the suspension. In this embodiment, approximately 2 mL of the formulation is loaded into a PARI eFlow® nebulizer. Since the lung dose from PARI eFlow® is approximately 25%, approximately 4.5 mg of clofazimine is deposited in the patient's lungs using this embodiment.

[0041] Similar to dry powder inhalers, those skilled in the art can envision numerous embodiments that, while varying slightly in description, still have the same therapeutic effect in delivering 3 mg to 80 mg of clofazimine to the lungs. Different nebulizers can be used to deliver the composition. Nebulizers capable of delivering the required therapeutically effective dose include jet nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers, non-vibrating mesh nebulizers, or mechanical soft mist metered-dose inhalers. Alternative forms of the clofazimine composition for use with nebulizers include powders prepared using pharmaceutically acceptable derivatives or salts of clofazimine. Depending on the dose to be administered, different concentrations of clofazimine in the formulation can be used, for example, the clofazimine concentration can be increased or decreased according to the patient's needs. In some embodiments, different pharmaceutical additives, such as surfactants, can be used instead of PEG400, or in combination with PEG400. The spray compositions can also be prepared at different osmolality concentrations by weight, for example, the formulation can be a high-osmolality solution, a low-osmolality solution, or a suspension.

[0042] To control the inhalation flow rate of particles in the inhalable composition, the composition is prepared so that the particles per dose are larger, resulting in approximately 3 mg to 8 mg of clofazimine being deposited in the lungs with an equal total drug amount after administration of this dose.

[0043] As described above, there are many advantages to delivering drugs to the lungs. However, delivering drugs to the lungs is difficult because it is challenging to ensure that the drug's volume and weight are uniform as it passes through natural physical barriers.

[0044] Example 3 Preparation of crystalline complex clofazimine dry powder A 15% clofazimine solution (the clofazimine concentration in this solution can be 1% to 15%) was prepared by adding clofazimine (0.20 g) to a 75% acetic acid solution (1.13 g) (the concentration of the acetic acid solution can be in the range of 75% to 100%). This clofazimine solution was added to a suspension of fumaryldiketopiperazine microcrystalline particles (XC) (solid content 1.31%, 175.57 g) (the solid content of the XC suspension can be in the range of 0.5% to 5%). This clofazimine XC suspension was spray-dried using a Buchi B-290 spray dryer under the conditions shown in Table 1 to produce 8% clofazimine XC powder.

[0045] Preparation of crystalline clofazimine dry powder A 15% clofazimine solution (the clofazimine concentration in this solution can be 1% to 15%) was prepared by adding clofazimine (0.20 g) to a 75% acetic acid solution (1.13 g) (the concentration of the acetic acid solution can be in the range of 75% to 100%). This clofazimine solution was added to a pre-formed suspension of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles (T suspension; solids content 11.04%, 20.83 g) (the solids content of the T suspension can be in the range of 0.5% to 20%). The clofazimine T suspension was then dried by spray drying to produce 8% clofazimine T powder. A Buchi B-290 spray dryer was used for spray drying of the powder under the conditions shown in Table 1.

[0046] [Table 1]

[0047] Powder Test The aerodynamic particle size distribution of the powder was evaluated using an Andersen-type cascade impactor (ACI). The powder was released into the ACI at 4 kPa from a Gen 2C cartridge (cartridge filling amount 10 mg). Table 2 shows the data for clofazimine powder prepared to date.

[0048] [Table 2]

[0049] As can be seen from Table 2, the process product yield of the spray-dried powder exceeded 50% for both methods, and the powder delivered from the delivery system, as evaluated by cartridge emptying (CE) measurements, averaged over 80%.

[0050] Unless otherwise specified, all numerical values ​​used in this specification and the claims, such as quantities of components, molecular weights, and other properties, as well as reaction conditions, should be understood to be modified in all cases with the word "approximately." Therefore, unless otherwise indicated, the numerical parameters described in the following specification and the appended claims are approximations that may vary depending on the desired properties to be obtained by the present invention. At a minimum, and without limiting the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted by applying ordinary rounding methods, taking into account at least the reported number of significant figures. While the numerical ranges and parameters describing the broad scope of the present invention are approximations, numerical values ​​describing specific examples are reported as accurately as possible. However, every numerical value inherently contains a certain degree of unavoidable error due to the standard deviation observed in the measurements of each test.

[0051] The terms “a,” “an,” and “the,” and similar demonstrative pronouns used in the context describing the present invention (particularly in the context of the following claims), shall be interpreted as including both singular and plural forms unless otherwise specified or unless clearly inconsistent with the context. The descriptions of value ranges herein are intended to serve as a way to simplify the description of each distinct value within that range individually. Unless otherwise specified herein, each individual value is incorporated herein as if it were described individually. All methods described herein may be carried out in any preferred order unless otherwise specified herein or unless clearly inconsistent with the context. The use of all examples or exemplary phrases provided herein (e.g., “etc.”) is intended merely to better illustrate the present invention and, unless otherwise asserted, does not limit the scope of the present invention. Nothing in this specification should be interpreted as suggesting that any unclaimed component is essential for carrying out the present invention.

[0052] This disclosure supports the definitions of "alternative only" and "and / or," however, where the term "or" is used in the claims, it is used to mean "and / or" unless it is explicitly indicated that it refers to only alternatives or that the options are mutually exclusive.

[0053] The grouping of alternative components or embodiments of the present invention disclosed herein should not be construed as limiting. Members of each group may be referred to or claimed individually, or in any combination with other members of that group or other components found herein. It is anticipated that one or more members of a group may be included in or excluded from a group for convenience and / or patentability reasons. Where such inclusion or exclusion occurs, the specification shall be deemed to include the thus modified groups and therefore satisfy the description requirements of any Markush group used in the appended claims.

[0054] This specification describes preferred embodiments of the Invention, including the best mode for carrying out the Invention as known to the inventors. Naturally, variations of these preferred embodiments will become apparent to those skilled in the art by reading the above description. The inventors anticipate that those skilled in the art will adopt such variations as needed, and they intend that the Invention may be carried out in ways different from those specifically described herein. Accordingly, the Invention encompasses, to the extent permitted by applicable law, all modifications and equivalents of the subject matter described in the claims appended herein. Furthermore, any combination of the components described above in any possible variations thereof is incorporated herein unless otherwise specified herein or unless it is clearly inconsistent with the context.

[0055] The specific embodiments disclosed herein may be further limited in the claims by using the phrases "consisting of" or "consisting essentially of". If the transitional clause "consisting of" is used in the claims, whether at the time of filing or through amendment, any components, steps, or ingredients not specified in the claims are excluded. The transitional clause "consisting essentially of" limits the claims to the specified material or step and any additions that do not substantially affect the basic and novel features. Embodiments of the present invention as thus claimed are described implicitly or explicitly herein and are implementable.

[0056] Furthermore, numerous patents and publications have been referenced throughout this specification. Each of the references and publications cited above is incorporated herein by reference as constituting a part of this specification.

[0057] Furthermore, the embodiments of the present invention disclosed herein should be understood as illustrative of the principles of the present invention. Other modifications that may be adopted are included within the scope of the invention. Therefore, alternative configurations of the present invention can be used, for example, in accordance with the teachings herein, but are not limited thereto. Thus, the present invention is not strictly limited to what is shown and described herein. This specification includes the disclosures in Appendix 1 to 20 below. (Note 1) An inhalable pharmaceutical composition comprising an antiviral agent selected from clofazimine, a pharmaceutically acceptable derivative of clofazimine, a clofazimine salt, or a polymorph of clofazimine, or a combination thereof, and a pharmaceutically acceptable carrier and / or pharmaceutical additive; the amount of the antiviral agent in the composition is 1 mg to 20 mg per dose. (Note 2) The antiviral agent and the pharmaceutically acceptable carrier and / or pharmaceutical additive are formulated for oral inhalation in the inhalable composition described in Appendix 1. (Note 3) The inhalable composition according to Appendix 2, wherein the antiviral agent and the pharmaceutically acceptable carrier and / or pharmaceutical additive are formulated as a suspension for delivery to the lungs by spraying, and the pharmaceutically acceptable carrier and / or pharmaceutical additive is an aqueous liquid carrier selected from water, isotonic saline, buffered saline, or an aqueous electrolyte solution. (Note 4) The inhalable composition described in Appendix 2, wherein the antiviral agent and the pharmaceutically acceptable carrier and / or pharmaceutical additive are formulated as a dry powder for oral inhalation. (Note 5) The antiviral agent is an orthorhombic polymorph of clofazimine, as described in Appendix 1, which is an inhalable composition. (Note 6) The inhalable composition according to Appendix 4, wherein the pharmaceutically acceptable carrier and / or pharmaceutical additive is diketopiperazine. (Note 7) The diketopiperazine is of the formula (E)-4-[4-[(2S,5S)-5-[4-[[(E)-3-carboxyprop-2-enoyl]amino]butyl]-3,6-dioxopiperazine-2-yl]butylamino]-4-oxobut-2-enoic acid, an inhalable composition as described in Appendix 4. (Note 8) The inhalable pharmaceutical composition according to any one of the appendices 1 to 7, characterized in that the composition is used in the manufacture of a pharmaceutical for treating a viral infection. (Note 9) An inhalable pharmaceutical composition as described in any one of the appendices 1 to 7, used for the treatment of SARS-CoV-2 lung virus infection. (Note 10) A method for treating a viral infection of the lungs, the method comprising delivering an orally inhalable therapeutically effective dose of a pharmaceutical composition comprising clofazimine, a pharmaceutically acceptable derivative of clofazimine, a polymorph of clofazimine, or a clofazimine salt, and a pharmaceutically acceptable carrier and / or pharmaceutical additive, to the lungs of a patient by aerosol from a dry powder inhaler or by a sprayed suspension. (Note 11) The therapeutically effective dose for oral inhalation is approximately 1 mg to 20 mg of clofazimine, a pharmaceutically acceptable derivative of clofazimine, a polymorph of clofazimine, or a clofazimine salt, as described in Appendix 10. (Note 12) The method according to Appendix 11, wherein the viral infection is a coronavirus, influenza, Ebola hemorrhagic fever, or another viral infection affecting the lungs, or a combination thereof, and the viral infection is further treated with one or more antiviral agents. (Note 13) The method according to Appendix 11, wherein 3 to 8 mg of clofazimine is delivered to the lungs. (Note 14) The method according to Appendix 11, wherein clofazimine, a pharmaceutically acceptable derivative of clofazimine, clofazimine polymorph, or clofazimine salt is administered to the patient at a dose of 3 mg to 8 mg once daily for 7 days, thereby creating a drug reservoir in the lungs that releases the drug over a long period, and the treatment period is less than 3 weeks. (Note 15) The carrier is an inhalable dry powder as described in Appendix 4, selected from the group consisting of at least one crystalline carbohydrate selected from the group consisting of glucose, arabinose, maltose, saccharose, dextrose, and lactose. (Note 16) The carrier is an inhalable dry powder as described in Appendix 15, in the form of fine particles having a median mass diameter (MMD) in the range of 0.5 to 10 μm. (Note 17) A pharmaceutical composition comprising a therapeutically effective amount of clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine, and an aqueous liquid carrier selected from water, isotonic saline, buffered saline, and an aqueous electrolyte solution. (Note 18) Furthermore, the pharmaceutical composition according to Appendix 17, wherein particles of clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine are contained in the suspension, and the median mass of the clofazimine particles is <5 μm, preferably <2 μm. (Note 19) The pharmaceutical composition according to Appendix 17, wherein the clofazimine, a pharmaceutically acceptable derivative, a polymorph of clofazimine, or a clofazimine salt is solubilized in the form of a microemulsion or nanoemulsion, and the median mass diameter (MMD) of the emulsion droplet is less than 1 μm. (Note 20) An inhalation system for use in the treatment or prevention of viral infections of the lungs, wherein the system comprises the pharmaceutical composition described in Appendix 17 and a nebulizer selected from a jet nebulizer, an ultrasonic nebulizer, a vibrating mesh nebulizer, a non-vibrating mesh nebulizer, or a mechanical soft mist metered-dose inhaler, wherein the aerodynamic median mass diameter (MMAD) of the generated aerosol particles is 1 to 5 μm.

Claims

1. An inhalable dry powder pharmaceutical composition comprising about 8% to about 10% of an antiviral agent selected from clofazimine, clofazimine salts, or polymorphs of clofazimine, or combinations thereof, and diketopiperazine; wherein the amount of the antiviral agent in the composition is 1 mg to 20 mg per dose.

2. The inhalable dry powder pharmaceutical composition according to claim 1, wherein the antiviral agent and the diketopiperazine are formulated for oral inhalation.

3. The inhalable dry powder pharmaceutical composition according to claim 2, wherein the antiviral agent and the diketopiperazine are formulated as a dry powder for oral inhalation.

4. The inhalable dry powder pharmaceutical composition according to claim 1, wherein the antiviral agent is an orthorhombic polymorph of clofazimine.

5. The inhalable dry powder pharmaceutical composition according to claim 1, wherein the diketopiperazine is of the formula (E)-4-[4-[(2S,5S)-5-[4-[[(E)-3-carboxyprop-2-enoyl]amino]butyl]-3,6-dioxopiperazine-2-yl]butylamino]-4-oxobut-2-enoic acid.

6. The inhalable dry powder pharmaceutical composition according to any one of claims 1 to 5, characterized in that the composition is used in the manufacture of a pharmaceutical for treating a viral infection.

7. An inhalable dry powder pharmaceutical composition according to any one of claims 1 to 5, used for the treatment of SARS-CoV-2 lung virus infection.

8. An inhalable dry powder pharmaceutical composition according to any one of claims 1 to 7, for use in a method for treating a viral infection of the lung, wherein the method comprises delivering an orally inhalable therapeutically effective dose of the pharmaceutical composition to the lungs of a patient by aerosol from a dry powder inhaler or by a sprayed suspension.

9. The inhalable dry powder pharmaceutical composition according to claim 8, wherein the orally inhalable therapeutically effective dose is approximately 1 mg to 20 mg of clofazimine, a polymorph of clofazimine, or a clofazimine salt.

10. The inhalable dry powder pharmaceutical composition according to claim 9, wherein the viral infection is coronavirus, influenza, Ebola hemorrhagic fever, or another viral infection affecting the lungs, or a combination thereof, and the viral infection is further treated with one or more antiviral agents.

11. The inhalable dry powder pharmaceutical composition according to claim 9, wherein 3 to 8 mg of clofazimine is delivered to the lungs in the method described above.

12. The inhalable dry powder pharmaceutical composition according to claim 9, wherein, in the method described above, clofazimine, clofazimine polymorph, or clofazimine salt is administered to the patient once daily for 7 days at a dose of 3 mg to 8 mg, thereby creating a drug reservoir in the lungs that releases the drug over a long period of time, and the treatment period is less than 3 weeks.

13. The inhalable dry powder pharmaceutical composition according to claim 1, wherein the diketopiperazine is in the form of fine particles having a median mass (MMD) in the range of 0.5 to 10 μm.

14. The inhalable dry powder pharmaceutical composition according to claim 1, comprising one or more other antiviral agents selected from ribavirin, acyclovir, remdesivir, lopinavir / ritonavir, and interferon β1b.

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