Pharmaceutical solution composition and oral mist inhaler comprising the same

Abstract

To provide a pharmaceutical solution composition and an oral mist inhaler comprising the same.SOLUTION: A pharmaceutical solution composition provided by the present invention includes a therapeutically effective amount of molnupiravir or a metabolite thereof and a solvent. An oral mist inhaler further provided by the present invention includes a soft mist inhaler and the above pharmaceutical solution composition loaded in the soft mist inhaler. The pharmaceutical solution composition of the present invention has high stability and generates a relatively small amount of impurities. The oral mist inhaler provided by the present invention allows a user to directly inhale the above pharmaceutical solution composition, so that the composition can be rapidly absorbed and the metabolic process of the drug in the body is reduced, thereby significantly improving the bioavailability of the drug. The particles formed by atomizing the composition are extremely small, and a large amount of mist is sprayed. Compared with a conventional oral administration method, the oral mist inhaler of the present invention is easy to use and can improve comfort and convenience during medicine consumption for a user.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a pharmaceutical solution composition, particularly to a pharmaceutical solution composition for treating viral infections, and further to an oral atomization inhalation dosage form containing the pharmaceutical solution composition and related uses thereof.

Background Art

[0002] Viral infection is one of the main causes of human diseases, posing a serious threat to global public health and affecting social stability and economic development. Viruses are extremely tiny infectious structures composed of a protein shell and the nucleic acid contained therein, and completely depend on the energy and metabolic systems of host cells to obtain the substances and energy necessary for life activities.

[0003] The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019 has spread to each continent in a short period due to its high infectivity and strong pathogenicity. The classification of COVID-19 as a pandemic by the WHO has brought huge changes to people's lives.

[0004] The most common symptoms of the diseases caused by COVID-19 include fever, dry cough, dyspnea, etc., but COVID-19 may also affect the digestive system, liver, cardiovascular system, kidneys, nervous system and other organs. Since the morbidity and mortality rates of COVID-19 were very high, scientists have also actively conducted research on various pharmaceuticals, vaccines or biological agents to find a treatment method for the diseases caused by this virus.

[0005] In antiviral drugs, molecular pharmaceuticals such as Avigan (Favipiravir), Remdesivir, Molnupiravir, and GS-441524 have become the first-choice drugs in the treatment of COVID-19 virus. Among them, Molnupiravir (MK-4482 / EIDD-2801) is an orally active antiviral drug and has been used in the treatment of hepatitis and influenza. EIDD-2801 is an isopropyl ester prodrug of the synthetic nucleoside derivative N4-hydroxycytidine (molecular formula C 13 H 19 N3O7, molecular weight 329.31 g·mol -1 ), which is hydrolyzed in the body to the intermediate EIDD-1931 (NHC or -DN4-hydroxycytidine) and distributed intracellularly. Further, a pharmacologically active 5'-triphosphate (EIDD-1931-5'-triphosphate or NHC-TP) is formed by the phosphorylation action of the host kinase. NHC-TP binds to SARS-CoV-2 RNA by the action of the viral RNA polymerase (nsp12), accumulates errors in the viral genome, and inhibits the replication function. This process is called viral error catastrophe.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The summary of the invention in the present invention aims to briefly summarize the present invention and enable the reader to obtain a basic understanding of the present invention. The summary of the invention in the present invention does not describe the present invention completely, nor does it intend to point out the important / principal components of the embodiments of the present invention or define the scope of the present invention.

[0007] Molnupiravir is regarded as a therapeutic drug for COVID-19. Most of it is administered to patients in an oral form. Molnupiravir taken orally needs to be absorbed through organs such as the gastrointestinal tract. The drug is sent into the bloodstream, enabling host cells to absorb the metabolites of Molnupiravir. Such a process might reduce the drug absorption rate of the host.

Means for Solving the Problem

[0008] In view of the above-mentioned needs for the treatment of SARS-CoV-2, in the present invention, a composition containing Molnupiravir or its metabolite is utilized, and the composition is atomized so that an individual can directly inhale it from the oral cavity or nasal cavity, thereby reducing the metabolic process required for oral administration and increasing the drug utilization rate in the individual.

[0009] Accordingly, the present invention provides a pharmaceutical solution composition as one aspect, which contains a therapeutically effective amount of Molnupiravir or its metabolite and a solvent.

[0010] According to one embodiment of the present invention, the metabolite of Molnupiravir is EIDD-1931 (beta-D-N4-hydroxycytidine).

[0011] According to one embodiment of the present invention, the solvent is water.

[0012] According to one embodiment of the present invention, the pharmaceutical solution composition further contains a pharmaceutically acceptable excipient.

[0013] According to one embodiment of the present invention, the excipient is a preservative or a chelating agent.

[0014] According to one embodiment of the present invention, the preservative is benzalkonium chloride (BKC), benzethonium chloride, benzododecinium bromide, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride (CPC), metacresol, methylparaben (MP), phenol, potassium sorbate, propylparaben, sodium borate, sorbic acid or thimerosal, and the chelating agent is ethylenediaminetetraacetic acid (EDTA), calcium disodium edetate hydrate, calcium disodium edetate anhydrous, disodium edetate (EDTA-2Na), gluceptate sodium, pentetic acid or salts thereof.

[0015] According to one embodiment of the present invention, the concentration of molnupiravir or its metabolite is 2 mg / ml, 5 mg / ml or 10 mg / ml.

[0016] According to one embodiment of the present invention, the pharmaceutical solution composition is administered using the methods of nasal drops, nebulizer, nasal spray, soft mist inhaler (SMI), metered dose inhaler (MDI).

[0017] In another aspect, the present invention provides an oral nebulization inhalation dosage form, which includes a soft mist inhaler and the above-mentioned pharmaceutical solution composition filled in the soft mist inhaler.

[0018] According to one embodiment of the present invention, the pharmaceutical solution composition has an average spray amount of the nebulized particles formed after nebulization by the soft mist inhaler of 13 mg or more.

[0019] According to one embodiment of the present invention, among the nebulized particles formed after nebulization by the soft mist inhaler, the particles less than 5.8 μm account for 50% or more of the total particles.

[0020] According to one embodiment of the present invention, the particles less than 5.8 μm account for 60% or more of the total particles.

Advantages of the Invention

[0021] The present invention has the following features. The pharmaceutical solution composition of the present invention has good stability and relatively small amounts of generated impurities. Further, the pharmaceutical solution composition is used in an oral nebulization inhalation dosage form. When the user inhales the oral nebulization inhalation dosage form, the composition is inhaled into the lungs and rapidly absorbed due to the characteristics of the capillaries spread in the lungs, reducing the metabolic process of the drug in the body and significantly improving the utilization rate of the human body. Furthermore, the particles formed after nebulization of the composition are extremely small, and the spray amount can reach 13 mg or more. Compared with the conventional oral form, the oral nebulization inhalation dosage form of the present invention has a simple usage method and can improve the comfort and convenience of the user's medication.

[0022] In order to more clearly understand the above-mentioned present invention and other objectives, features, advantages and embodiments, the drawings will be described below.

Brief Description of the Drawings

[0023]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0024] Regarding the detailed description and technical content of the present invention, it will be described as follows based on the figures. Regarding the ratios of the drawings in the present invention, for the sake of simplicity of explanation, they are not drawn at the actual ratios, and it should be understood in advance that the drawings and ratios do not limit the scope of the present invention.

[0025] Unless otherwise defined, the meanings of all technical and scientific terms used in this specification are the same as those generally understood by those skilled in the art. The following terms used throughout this specification have the following meanings.

[0026] Unless otherwise clearly described, the term "or" means "and / or". "Comprising" means that the presence or addition of one or more other components, steps, operations or elements on the described components, steps, operations or elements is not excluded. As used herein, "include", "comprise", "contain", "involve", "have" are interchangeable with each other and not limited. As used in this specification and the appended claims, the singular forms "a", "said" include the plural unless the context clearly dictates otherwise. For example, the terms "a", "said", "one or more", "at least one" are used interchangeably in the specification.

[0027] In one aspect, the present invention provides a pharmaceutical solution composition, which comprises a therapeutically effective amount of molnupiravir or its metabolite and a solvent. In one preferred embodiment, the metabolite of molnupiravir is EIDD-1931 (beta-D-N4-hydroxycytidine). According to one example of the present invention, the solvent is water, glycerin, propylene glycol, polyethylene glycol, polypropylene glycol, ethanol, isopropanol, mineral oil or peanut oil. In one preferred embodiment, the solvent is water.

[0028] According to one embodiment of the present invention, the pharmaceutical solution composition further comprises a pharmaceutically acceptable excipient. In one preferred embodiment, the excipient is a preservative or a chelating agent. Specifically, the preservative is Benzalkonium chloride (BKC), Benzethonium chloride, Benzododecinium bromide, Benzoic acid, Benzyl alcohol, butylparaben, Cetylpyridinium chloride (CPC), Metacresol, Methylparaben (MP), Phenol, Potassium sorbate, Propylparaben, Sodium borate, Sorbic acid or Thimerosal. In one preferred embodiment, the preservative is Benzalkonium chloride (BKC). The chelating agent is Ethylenediaminetetraacetic acid (EDTA), Edetate calcium disodium hydrate, Edetate calcium disodium anhydrous, Edetate disodium (EDTA-2Na), Gluceptate sodium, Pentetic acid or salts thereof. In one preferred embodiment, the chelating agent is Ethylenediaminetetraacetic acid (EDTA).

[0029] The pharmaceutical solution composition of the present invention contains molnupiravir or its metabolite, and by adding the above-mentioned solvent and excipient, it can be used for the treatment of diseases caused by viral infections such as SARS, MERS and COVID-19, which are coronaviruses, norovirus, chikungunya virus, Ebola virus, influenza virus, RSV, Venezuelan equine encephalitis virus (VEEV), diarrhea virus or hepatitis C virus. In one preferred embodiment, the pharmaceutical solution composition of the present invention is used for the treatment of diseases caused by COVID-19.

[0030] According to one example of the present invention, the concentration of molnupiravir or its metabolite is 2 to 20 mg / ml, such as 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml or 20 mg / ml, without limitation. In one preferred embodiment, the concentration of molnupiravir or its metabolite is 2 mg / ml, 5 mg / ml or 10 mg / ml. The inventor of the present application has found through a series of experiments that the concentration of molnupiravir or its metabolite in the pharmaceutical solution composition can reach a maximum solubility of 20 mg / ml, and the pharmaceutical solution compositions with a content concentration of 2 mg / ml, 5 mg / ml and 10 mg / ml have the best drug stability and do not cause the problem of drug precipitation.

[0031] According to one embodiment of the present invention, the pharmaceutical solution composition is administered using the methods of nasal drops, nebulizer, nasal spray, soft mist inhaler (SMI), or metered dose inhaler (MDI). The present invention replaces the conventional method of taking pharmaceuticals orally and administers the pharmaceutical solution composition into an individual by spraying or atomizing. Since its molecules are small, when an individual inhales the pharmaceutical solution composition into the lungs using an inhalation preparation, due to the large contact area of the lungs and the presence of capillaries throughout, the composition can be rapidly absorbed, significantly improving the drug absorption rate. Furthermore, the method of administering the pharmaceutical is not limited to oral administration, and it can also be administered by nasal administration, providing a new method of administration for patients with dysphagia or fear of swallowing pharmaceuticals, enhancing the convenience of taking pharmaceuticals.

[0032] As another aspect, the present invention provides an oral atomization inhalation dosage form, which includes a soft mist inhaler and the above-mentioned pharmaceutical solution composition filled in the soft mist inhaler. The oral atomization inhalation dosage form atomizes the pharmaceutical solution composition to make the composition form small molecules for easier absorption. Specifically, the oral atomization inhalation dosage form allows the user to directly inhale it in the form of fine particles from the oral cavity. Compared with the oral administration form, the oral atomization inhalation dosage form of the present invention can reduce the metabolic process of molnupiravir in the body, promote the absorption effect, increase the utilization rate in the human body, and improve the comfort and convenience of the user in taking the medicine. In addition, the oral atomization inhalation dosage form has a simple usage method and is suitable for patients of various age groups.

[0033] According to one embodiment of the present invention, in the pharmaceutical solution composition, the average spray amount of the atomized particles formed after atomization by a soft mist inhaler is 13 mg or more, and for example, 3 mg or more, 14 mg or more, 15 mg or more, 16 mg or more, 17 mg or more, 18 mg or more, 19 mg or more, 20 mg or more, 21 mg or more, 22 mg or more, 23 mg or more, 24 mg or more, or 25 mg or more, without limitation.

[0034] According to one embodiment of the present invention, in the pharmaceutical solution composition, among the atomized particles formed after atomization by a soft mist inhaler, particles less than 5.8 μm account for 50% or more of the total particles, and for example, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, or 99% or more, without limitation. In one preferred embodiment, particles less than 5.8 μm account for 60% or more of the total particles. Since it has been experimentally demonstrated that the oral aerosol inhalation dosage form of the present invention has a sufficient spray amount, it is possible to avoid the problem of insufficient spray amount and uneven drug supply when used by patients. In addition, after the formation of the atomized particles in the composition, since particles less than 5.8 μm account for 60% or more of the total particles, it can be seen that the small molecular size of the pharmaceutical solution composition helps the drug to enter the host respiratory tract and increases the absorption rate of the drug by the patient.

Examples

[0035] The examples and embodiments described in this specification are only for illustrative purposes and suggest various modifications or changes to those skilled in the art. It should be understood that those modifications or changes belong to the spirit and scope of this application and the appended claims. All published applications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety for all purposes.

[0036] 1. Preparation of Pharmaceutical Solution Composition

[0037] The pharmaceutical solution composition used in this test (hereinafter referred to as the composition) contains an effective amount of an active ingredient, a solvent, a preservative, and a chelating agent. The details of the formulation ratios are as shown in Table 1 below.

[0038]

Table 1

[0039] 1-1. pH value stability

[0040] Please refer to Figure 1. The stability of the above composition at different pH values was measured. Among them, citrate buffer was used for pH 3 - 6, and Tris buffer was used for pH 7 - 9. The stability test was a 7-day stress test at 60°C. As a result, compared with the control group (day 0), the R01-1 group (without pH adjustment) was the most stable and had the least generation of impurities (single impurity 0.07, total impurities 0.13).

[0041] 1-2. Spray volume test

[0042] From the pH value stability test, it was found that the R01-1 composition had the best stability and the least impurities. Therefore, in the subsequent experiment, a spray volume test was carried out with the R01-1 composition. In the spray volume test, a spray volume test of the R01-1 composition was carried out using a Mei Rui Zi Inhaler M-100 (Non-sterile), and the spray volume for each time was recorded. After 5 preliminary tests were carried out before the start of the test, 55 spray volume tests were carried out. The results are as shown in Table 2 below.

[0043]

Table 2

[0044] 1-3. Particle size distribution test (PSD)

[0045] Please refer to it in conjunction with Figure 2. The particle size distribution test measures the particle size distribution range after the above composition is atomized. In this test, the R01-1 composition was prepared in a 1000 ml solution, and the particle size distribution test was carried out using a laser diffraction particle size analyzer. This test was repeated three times. The results are as shown in Table 3 and Figure 2 below.

[0046]

Table 3

[0047] As a result, it was shown that the average spray amount in the formal test was 13.5 mg ± 0.6 mg (Table 2). Also, as a result of the PSD test, it was shown that the number of average effective particle diameters (particles less than 5.8 μm) accounted for 64.55% of the total particles (Table 3 and Figure 2). From this, it can be seen that the particles formed through the atomization of the pharmaceutical solution composition of the present invention have a small particle size and the spray amount can reach 13 mg or more.

[0048] 1-4. Accelerated stability test

[0049] Next, the accelerated stabilities of the R01-1 composition at 40 °C for 0, 1, 3, and 6 months were measured. The results are as shown in Table 4 below.

[0050]

Table 4

[0051] From the above experimental results, it was found that the stability of the R01-1 composition at 40 °C for 6 months suggested that the impurity Uridine increased to 0.49%. However, since Uridine is an endogenous substance in the human body and there is 3-8 μm and 0.5-5 μm of Uridine in the bodies of general adults and children respectively, in the present invention, the Uridine concentration in the impurities was obtained using the following formula.

[0052]

Equation

[0053] Calculation showed that the Uridine concentration in the impurities of the composition of the present invention was 0.00108 μM, accounting for about 0.216% of the concentration (0.5 μM) in children's blood. Therefore, the present invention set the concentration of impurity Uridine at 2%, and any amount of impurity generation within 2% was considered acceptable for the human body.

[0054] 1-5. Most preferred formulation of the pharmaceutical solution composition

[0055] From the above test results, it was found that there was a problem of component precipitation when preparing the drug with 20 mg / ml of EIDD-1931. Therefore, in the following tests, the concentration of EIDD-1931 was adjusted and then the stress test was performed again to evaluate the degradation states at 7 days and 14 days from the drug formulation. The results are as shown in Table 5 below.

[0056]

Table 5

[0057] As a result, although an increase in impurities was observed 7 days and 14 days after the formulation in the stress test at 60°C for the above drug, it was shown that the amount of generation was within the acceptable range (2%). Therefore, in subsequent animal experiments, tests were conducted with compositions at 2 mg / ml, 5 mg / ml, and 10 mg / ml.

[0058] After analyzing the stability and most preferred formulation of the pharmaceutical solution composition by the above tests, animal experiments were then conducted to test the effects of the composition in the body. In this test, first, a virus plaque test was performed to test the antiviral effect of the composition. Next, an intranasal pharmacokinetics (PK) study on hamsters was conducted to measure the concentration of EIDD-1931 in plasma. Finally, a challenge test was performed on the animals, and they were sacrificed 3 days after virus infection to observe the pathological tissue sections of the lung tissue of the hamsters to obtain the action state of the composition in the lungs.

[0059] 2. Virus plaque test

[0060] First, in order to measure the antiviral effect of the pharmaceutical solution composition of the present invention against SARS-CoV-2, a virus plaque assay was performed. The virus strain used in this test was SARS-CoV-2 Omicron BA.5, the cells to be infected were Vero E6, the concentrations of the composition were 0.3 μM, 1.5 μM, and 3 μM respectively, and a dose control group and a virus control group were included.

[0061] The test method is as follows. Vero E6 cells were inoculated into a 24-well plate at a concentration of 2x105 cells per well and placed in DMEM containing 10% FBS, 100 units / mL of penicillin G sodium, 100 μg / mL of streptomycin sulfate, and 250 ng / mL of amphotericin B for 1 day. Next, on the day of virus infection, the cells were treated with the pharmaceutical solution composition at a specified concentration for 1 hour, then the composition was removed, and the cells were infected with SARS-CoV-2 Omicron BA.5 virus at 37 °C for 1 hour. Thereafter, the cell culture medium was removed, the cells were washed once with PBS, and then cultured in a culture medium containing 1% methylcellulose for 5 days. The cells were fixed with 10% formaldehyde for 1 hour, then the culture medium was removed, the cells were stained with 0.5% crystal violet, and the number of plaques was calculated.

[0062] The calculation formula for the inhibition rate is as follows. In the formula, VD and VC represent the number of plaques in the presence of the test composition and the corresponding solvent, respectively.

[0063]

Number

[0064] The half-maximal effective concentration (EC 50 ) of the test solution was obtained using the following formula. In the formula, ConcH represents the concentration that inhibits the virus by 50% or more, and ConcL represents the concentration that inhibits the virus by less than 50%.

[0065] [Number]

[0066] As shown in Figure 3 and Table 6 below, the pharmaceutical solution compositions with concentrations of 1.5 μM and 3 μM have a 100% viral strain inhibitory effect compared to the solvent control group, and their EC 50 was 0.543 ± 0.065 μM.

[0067] [Table 6]

[0068] 3. Pharmacokinetics study

[0069] Next, a pharmacokinetics study was conducted to confirm whether the main component (EIDD-1931) of intranasal administration could be measured in the blood. The animal model used in this study was hamsters. The hamsters were grouped as follows. 1. Virus non-infected and non-administered group 2. Virus non-infected and EIDD-1931 5 mg / ml administered group (n = 6)

[0070] Here, the administration route was intranasal administration, and the dose was 50 μl of EIDD-1931 5 mg / ml. During the breeding period, blood samples were collected at 0 hours (before administration), 1 hour after administration, and 24 hours after administration. The animals were sacrificed 24 hours after administration, and blood and lung tissues were collected. For blood samples, the concentration of EIDD-1931 in the plasma samples of hamsters was measured by liquid chromatography / tandem mass spectrometry (LCMS / MS). When the main component in the blood reached a high concentration (1 μm) 24 hours after administration, the challenge test, which was the next step, was conducted.

[0071] For lung tissues, they were fixed and stored in paraformaldehyde. Furthermore, when observing, trimming, processing, paraffin embedding were performed on them, the sections were made about 5 micrometers thick, and observation was carried out using hematoxylin and eosin staining.

[0072] As shown in Fig. 4, no abnormalities were found in the lung tissues of any of the hamsters in the non-administered group (Figs. 4A - 4C). On the other hand, among the six hamsters with administration (5 mg / ml) (Figs. 4D - 4I), ossification was observed in the alveoli of three hamsters (arrows in Figs. 4D, 4E, 4H). However, this is presumed to be spontaneous (non-drug) or a background condition (what was present before administration) and is unrelated to the composition of the present invention. No abnormalities were found in the lung tissues of the remaining hamsters with administration (Figs. 4F, 4G, 4I).

[0073] 4. Challenge test on animals

[0074] Finally, a challenge test was conducted. The animal model used was a hamster, and the groups were divided as follows. 1. Virus non-infected and non-administered group (n = 6) 2. Virus-infected and non-administered group (n = 6) 3. Low-dose (1 mg / ml) EIDD-1931 + virus-infected group (n = 6) 4. High-dose (5 mg / ml) EIDD-1931 + virus-infected group (n = 6)

[0075] Here, the administration route was intranasal administration at 0.5 hours, 8.5 hours, 24.5 hours, and 48.5 hours after virus infection, and the dosages were 1 mg / ml and 5 mg / ml of 50 μl of EIDD-1931. In this test, the animals were sacrificed 72 hours after virus infection, and lung tissues were collected. The lung tissues of the hamsters were taken out, the virus amount was examined by PCR, and pathological observation was performed on the sections to check whether there was no necrosis or degenerative changes of inflammatory cells and epithelial cells accompanied by wetness of the bronchioles.

[0076] The related lesions caused by inoculation with the SARS-CoV-2 virus may include (1) mixed cell inflammation, peribronchial wetness, perivascular wetness, (2) degeneration / necrosis of bronchial epithelial cells, inflammation / wetness of bronchioles, (3) necrosis of cell walls, (4) vasculitis and endocarditis, (5) bleeding and edema from the lungs. Therefore, in this test, the above-mentioned tissues were observed.

[0077] As shown in Fig. 5, compared with the virus-infected and non-administered group (Figs. 5D to 5F), after the hamsters infected with the virus were treated by administering low-dose (Figs. 5G to 5I) and high-dose (Figs. 5J to 5L) drugs, the inflammation of the pulmonary interstitium and the necrosis or degeneration of the bronchiolar epithelial cells were both reduced, indicating that the pharmaceutical solution composition of the present invention has a definite therapeutic effect.

[0078] In summary, the pharmaceutical solution composition provided by the present invention has good stability and relatively small amounts of generated impurities. Further, the pharmaceutical solution composition is used in an oral atomization inhalation dosage form. When the user inhales the oral atomization inhalation dosage form, the composition is inhaled into the lungs, and due to the characteristics of the capillaries spread in the lungs, the composition is rapidly absorbed, reducing the metabolic process of the drug in the body and significantly improving the utilization rate of the human body. Furthermore, the particles formed through atomization of the composition are extremely small, and the spray amount can reach 13 mg or more. Compared with the conventional oral administration form, the oral atomization inhalation dosage form of the present invention has a simple usage method and can improve the comfort and convenience of the user in taking the medicine.

[0079] Although the present invention has been described in detail above, the above are only preferred embodiments of the present invention and do not limit the scope of implementation of the present invention. Any equivalent changes and modifications based on the claims of the present invention belong to the scope of the claims of the present invention.

Claims

1. a therapeutically effective amount of Molnupiravir or a metabolite thereof; A pharmaceutical solution composition comprising:

2. The pharmaceutical solution composition of claim 1, wherein the metabolite of molnupiravir is EIDD-1931 (beta-D-N4-hydroxycytidine).

3. The pharmaceutical solution composition of claim 1 , wherein the solvent is water.

4. 4. The pharmaceutical solution composition of claim 1, further comprising a pharma-ceutically acceptable excipient.

5. The pharmaceutical solution composition of claim 4 , wherein the excipient is a preservative or a chelating agent.

6. The preservatives include benzalkonium chloride (BKC), benzethonium chloride, benzododecinium bromide, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride (CPC), metacresol, methylparaben (MP), phenol, potassium sorbate, propylparaben, and sodium borate.

6. The pharmaceutical solution composition according to claim 5, wherein the active ingredient is ethylenediaminetetraacetic acid (EDTA), edetate calcium disodium hydrate, edetate calcium disodium anhydrous, edetate disodium (EDTA-2Na), gluceptate sodium, pentetic acid or a salt thereof.

7. 4. The pharmaceutical solution composition of claim 1, wherein the concentration of molnupiravir or its metabolite is 2 mg / ml, 5 mg / ml or 10 mg / ml.

8. The pharmaceutical solution composition according to any one of claims 1 to 3, which is administered by the following means: nasal drops, nebulizer, nasal spray, soft mist inhaler (SMI), or metered dose inhaler (MDI).

9. A soft mist inhaler, 9. An oral nebulized inhalation dosage form comprising: a pharmaceutical solution composition according to claim 1 , filled in said soft mist inhaler.

10. 10. The oral nebulized inhalation dosage form of claim 9, wherein the pharmaceutical solution composition has an average atomized amount of 13 mg or more of the atomized particles formed after atomization by the soft mist inhaler.

11. The oral nebulization inhalation dosage form of claim 9, wherein the pharmaceutical solution composition is nebulized by the soft mist inhaler, and among the particles formed by the nebulization, particles smaller than 5.8 μm account for 50% or more of the total particles.

12. The oral nebulized inhalation dosage form of claim 11, wherein the particles smaller than 5.8 μm account for 60% or more of the total particles.

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