CN113350323A

CN113350323A - Inhalant for inhibiting coronavirus, and preparation method and application thereof

Info

Publication number: CN113350323A
Application number: CN202110239168.8A
Authority: CN
Inventors: 胡芳; 李德耀; 陈永奇; 周溢谦; 韩飞; 王霆; 黄敏瑜; 康宁; 周晓峰
Original assignee: Guangzhou Henovcom Bioscience Co ltd; Shenzhen Rispril Biopharmaceutical Co ltd
Current assignee: Guangzhou Henovcom Bioscience Co ltd; Shenzhen Rispril Biopharmaceutical Co ltd
Priority date: 2020-03-06
Filing date: 2021-03-04
Publication date: 2021-09-07

Abstract

The invention relates to an inhalant for inhibiting coronavirus, a preparation method and application thereof, belonging to the technical field of pharmaceutical preparations. The inhalant comprises Reidesciclovir and/or a pharmaceutically acceptable salt thereof. The inhalant for inhibiting coronavirus can achieve effective lung administration concentration when micronized or gas atomized Reidesvir is inhaled due to the adoption of small-dose lung administration, effectively exerts the effect of inhibiting coronavirus, especially novel coronavirus, overcomes the defects of narrow treatment window and poor safety in the prior art, can form an effective virus inhibiting effect in the lung by repeatedly administering small doses, and can improve the curative effect or reduce the dosage of the Reidesvir so as to reduce the potential side effect.

Description

Inhalant for inhibiting coronavirus, and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to an inhalant for inhibiting coronavirus, and a preparation method and application thereof.

Background

Coronavirus is an enveloped, nonsegmented, plus-sense, single-stranded RNA virus whose genome varies in size from 26 to 32kb and is known to be the largest RNA virus genome. The virion has genomic RNA and phosphorylated nucleocapsid (N) proteins, externally wrapped by a phospholipid bilayer and covered by two different types of spinous process proteins: the spinous process glycoprotein trimer (S) found in all covs and the Hemagglutinin Esterase (HE) present in some covs. The membrane (M) protein, a type III transmembrane glycoprotein, and the envelope (E) protein are located between the S proteins in the viral envelope.

In recent years, coronavirus has periodically appeared around the world. The emergence of coronaviruses is unexpected, easily transmitted, and has had catastrophic consequences, posing a continuing threat to humans and economy.

The coronavirus is capable of infecting human because the envelope of the coronavirus is fused with the human cell membrane and then enters cells, more importantly, the genetic material RNA single strand of the coronavirus is released in the human cells and is continuously replicated to generate new coronavirus particles, the coronavirus particles are secreted to the outside of the cells through Golgi bodies to infect the new cells, each infected cell generates thousands of new virus particles to spread to the trachea and the bronchus, and finally the new virus particles reach alveoli to cause pneumonia. Therefore, blocking the propagation of the virus in the cell is also a key point for screening effective drugs.

Reidesciclovir is a nucleotide analogue prodrug with broad spectrum antiviral activity, capable of inhibiting RNA synthase (RdRp) dependent RNA viruses. In vitro experiment, it has inhibitory effect on various viruses, such as coronavirus, hepatitis C virus, HIV virus and Ebola virus, and can be used for inhibiting virus proliferation in vitro in primary culture of human airway epithelial cell, wherein the virus proliferation is dose-dependent, and IC of SARS-CoV is inhibited₅₀Is 0.069. mu.M, IC for MERS-CoV₅₀It was 0.074. mu.M. The in vitro test on the novel coronavirus shows that₅₀Value of 0.77 μ M) can block new coronavirus infection of cells at very low concentrations. Clinical tests show that the Reidesciclovir has obvious curative effect on the novel coronavirus, and can reduce the deterioration of a severe group to a critically ill group.

The existing preparation of the Reidesciclovir is an injection, the treatment window of the injection is narrow, the safety is poor, the Phase I data SAD is 3-225mg, the Phase I data SAD is larger than that of the conventional antiviral injection, in addition, the existing anti-new crown/Ebola administration scheme is close to the safety limit of the Reidesciclovir (200 mg is firstly infused intravenously, and 100mg is injected on days 2-9), the safety hazard is larger, and the safety is more worried particularly for the elderly patients with the weak autoimmune recovery of basic diseases.

In terms of pharmacodynamics, to inhibit further spread of viral infection, a prerequisite is that the "focal site" must reach an "effective drug concentration" for inhibiting viral infection. From the pathological observation that coronavirus infects human, the coronavirus is mainly transmitted through respiratory tract, and the virus is mainly concentrated in the lower respiratory tract of lung after infection, therefore, the key of antivirus is how to ensure that the lower respiratory tract of lung has effective medicine concentration for inhibiting virus replication. From the existing pharmacological analysis, the Reidesvir injection can cause serious liver injury to human body under the condition of keeping the effective drug concentration in lung, the effect of prognosis recovery cannot be expected, and the drug administration mode is changed, so that less dosage is adopted for concentrated lung drug administration, the blood drug concentration of target organs is improved, the blood drug concentration of non-target organs is reduced, the organ selectivity is improved and the toxic and side effects are reduced under the condition of ensuring the effectiveness; can ensure the effective drug concentration in the lung, exert antiviral effect, reduce the exposure of the whole body, and reduce side effects. In addition, the injection is systemically administered and rapidly reaches the peak, and the inhalant is locally administered, so that high concentration or transient impact concentration cannot be rapidly formed in the heart, and the aim of reducing the toxicity of the heart, other organs and vessel wall barriers can be fulfilled; the pharmacokinetic characteristics of the Rudesivir injection show that: phase I clinical data show plasma t of Reidesciclovir_1/2About 1 hour, but its metabolic activity product triphosphor compound is in t of peripheral mononuclear cell_1/2About 40 hours, the inhalant can form accumulation in the lung by a small-dose multi-administration mode by virtue of the characteristic of long half-life of the metabolite, and a good treatment effect can be achieved by equivalent AUC.

In conclusion, the Redexi Wei injection has better curative effect on coronavirus, particularly novel coronavirus, but has narrow treatment window, low systemic administration target organ selectivity and higher safety risk, and can form effective virus inhibition concentration in lung through multiple times of small-dose pulmonary administration, thereby achieving low-dose safety and effectiveness.

Disclosure of Invention

Therefore, it is necessary to provide an inhalant for inhibiting coronavirus and a preparation method and application thereof, wherein the inhalant is administered by inhalation, so that target administration is achieved, the inhalant directly acts on the lung, a lower dose can be used for reaching the lung, the systemic exposure is reduced, and the inhalant has the advantage of light systemic adverse reaction.

An inhalant for inhibiting coronavirus comprising Reidesciclovir and/or a pharmaceutically acceptable salt thereof.

The inhalant for inhibiting the coronavirus is carried out by using an inhalation administration mode, so that target spot direct administration is realized, and the inhalant directly acts on the lung. Target here refers to cells that are locally infected in the lung or the virus itself in the lung where the coronavirus, especially the novel coronavirus, is located.

Compared with the traditional route administration mode, the inhalation administration mode provided by the invention can reach the lung with lower dose, reduce the systemic exposure and has the advantage of light systemic adverse reaction. Avoids the problem that the prior injection is administrated systemically, forms high concentration or transient impact concentration in the heart, reduces the high hepatotoxicity of the injection, and has the advantages of slight side effect, convenience, rapidness, safety and reliability. The medicament of the invention is delivered to the lesion part of the lung in a mode of solid particles, fog drops or sol particles, so that the medicament has long retention time in the lung, is administered for multiple times in small dose, and effectively inhibits the virus concentration in the lung, thereby achieving the effects of low dose, safety and effectiveness.

For injection or intravenous drip, the drug is first absorbed, dissolved into the blood, then passes through the liver metabolism and the systemic circulation of the blood to reach the lung, so the dosage requirement is large. The reported side effects of Reidesciclovir are many due to its narrow therapeutic window, poor safety, and its potential hepatotoxicity and its post-healing efficacy are difficult to determine.

The coronavirus is characterized in that the coronavirus enters human lung through respiratory tract, envelope of the coronavirus is fused with human cell membrane and then enters cells, more importantly, genetic material RNA single chain of the coronavirus is released in the human cells and is continuously replicated to generate new coronavirus particles, the coronavirus particles are secreted outside the cells through Golgi bodies to infect the new cells, each infected cell generates thousands of new virus particles to spread to trachea and bronchus, and finally the new virus particles reach alveolus to cause pneumonia. Therefore, blocking the propagation of the virus in the cell is also a key point for screening effective drugs.

In one embodiment, the inhalant is administered in an amount of 0.05-50 mg/day on a reed-seivir basis. For example, 1mg, 5mg, 10mg, 12mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, etc.

It will be appreciated that each dose is inhaled from 1 to 5 inhalations and can be adjusted depending on the drug loading and effective dose of the delivery device.

The dosage of the present invention for an adult may be administered by inhalation in the range of 0.05mg to 50mg per day, suitably 1mg to 30mg per day, more suitably 5mg to 20mg per day. In the present invention, it is preferred that an adult human is administered a dose of 10mg of inhaled ridciclovir, optionally in the form of ridciclovir or a pharmaceutically acceptable salt thereof, preferably ridciclovir.

In one embodiment, the formulation of the inhalant is: dry powder inhalants, dry aerosols, metered dose inhalants or nebulizers.

It will be appreciated that administration of the above dosage forms may be accomplished by means of a Dry Powder Inhaler (Dry Powder Inhaler) or a Powder blower (Inhaler), Metered Dose Inhaler (Metered Dose Inhaler) or Nebulizer (Nebulizer).

The invention relates to a method for inhibiting and killing coronavirus by dispersing a Reidesciclovir and/or an inhalable auxiliary material into fog particles or particles by an inhaler and inhaling the medicament by inhalation action, wherein the fog particles or the particles are deposited in different levels of bronchus and alveolus.

The form of the Reidesciclovir or pharmaceutically acceptable salt thereof required for use in the present invention can be determined by the subject to be treated, the severity of the disease, the therapeutic effect to be achieved, the particular route of respiratory administration used (e.g., dry powder inhaler, powder blower, metered dose inhaler, or nebulizer).

In one embodiment, the content of the Reidesciclovir and/or the pharmaceutically acceptable salt thereof is 0.2-96 wt%. Preferably 1.0 wt% to 90 wt%, more preferably 5.0 wt% to 50 wt%, 20 wt% to 40 wt%.

The total daily dose of the invention may be inhaled 1-6 times, preferably 3 to 4 times, with 1 puff per inhalation with an inhaler, for example a dry powder inhaler or a metered dose inhaler or a nebulizer, or more than 1 puff, for example 2,3, 4 puffs or "puffs".

The components of a Dry Powder Inhaler are used for administration in Dry Powder inhalers (Dry Powder Inhaler) or dusters (injectors), and Dry powders may be loaded into capsules and chambers, such as gelatin capsules, or laminated aluminum foil blisters, and may also be used in reservoir Dry Powder inhalers. The formulation for the above inhalation device may be that the raw drug is processed into micro powder and then inhaled directly for administration, preferably, each of the Reidesciclovir and/or physiologically acceptable salt thereof is inhaled as an active ingredient component of the pharmaceutical preparation.

In one embodiment, the formulation of the inhalant is: a dry powder inhaler further comprising a diluent and/or a lubricant; the diluent is selected from: at least one of lactose, trehalose, starch, xylitol, mannitol, and hydrophobic amino acids; the lubricant is selected from: at least one of magnesium stearate and sodium stearyl fumarate; the hydrophobic amino acids include valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, etc.

In one embodiment, the lubricant has a particle size d90 < 40 μm; the particle size of the diluent is d 10-3-20 μm, d 50-40-80 μm, d 90-160 μm.

In one embodiment, the average particle size of the Reidesciclovir is 1.5-3.0 μm, preferably 1.8-2.5, more preferably 2.0-2.5, and the average particle size of the lubricant is 1.5-3.0 μm, preferably 1.8-2.5, more preferably 2.0-2.5.

In one embodiment, the diluent is lactose in an amount of 0-98 wt% and the lubricant is magnesium stearate in an amount of 0.1-7 wt%.

In one embodiment, the diluent is lactose in an amount of 60-98 wt%, preferably 60-70 wt%, and the lubricant is magnesium stearate in an amount of 0.01-0.30 wt%, preferably 0.05-0.5 wt%, more preferably 0.2-0.3 wt%.

In one embodiment, the metered dose inhaler and nebulizer further comprises: a propellant, a co-solvent and/or a surfactant.

Preferably, the inhalant of the metered dose inhaler or the nebuliser of said nebuliser further comprises a propellant. Wherein the inhalant or nebuliser of the metered dose inhaler may be in spray form, an aqueous solution or suspension, or as an aerosol provided from a pressurised container. For suspension aerosols, the active ingredient should be micronized, which may be prepared by any technique known in the pharmaceutical art, such as jet milling, spray drying, spray freeze drying, supercritical fluids.

Also, the inactive components of the nebulant may be formulated with an aqueous carrier, such as an acid or base, a buffer salt, an isotonicity adjusting agent or the addition of an antimicrobial agent, such as disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80; may be sterilized by filtration or heat in an autoclave, or as a non-sterile product. Micronization of the active ingredient may be carried out by any technique known in the pharmaceutical art, such as jet milling, spray drying, spray freeze drying, supercritical fluids.

In one embodiment, the co-solvent is present in an amount of 0.1 to 15 wt%, such as 0.5 wt%, 1.1 wt%, 1.8 wt%, 3 wt%, 6 wt%, 8 wt%, 10 wt%, 12 wt%, 14 wt%, etc., and the surfactant is present in an amount of 0.001 to 0.5 wt%, such as 0.004 wt%, 0.008 wt%, 0.01 wt%, 0.06 wt%, 0.09 wt%, 0.14 wt%, 0.18 wt%, 0.26 wt%, 0.31 wt%, 0.37 wt%, 0.41 wt%, 0.46 wt%, 0.48 wt%, etc., and more preferably 0.01 to 0.1 wt%.

In one embodiment, the propellant is selected from: at least one of carbon dioxide, 1,1,1, 2-tetrafluoroethane, 1,1,1,2,3,3, 3-heptafluoropropane, monofluorotrichloromethane, dichlorodifluoromethane, chlorofluorocarbon, or a derivative thereof; hydrofluoroalkanes are preferred, 1,1, 2-tetrafluoroethane and/or 1,1,1,2,3,3, 3-heptafluoropropane are more preferred.

The cosolvent is selected from: at least one of ethanol, isopropanol, and propylene glycol;

the surfactant is selected from: at least one of oleic acid, lecithin or span 85.

In one embodiment, the maximum particle size of the Reidesciclovir and/or pharmaceutically acceptable salt thereof in the inhalant is not more than 50 μm, preferably not more than 20 μm, more preferably 1-10 μm, and especially preferably 1-5 μm.

The invention also discloses a preparation method of the inhalant for inhibiting coronavirus, which comprises the following steps:

micronization: independently micronizing the Reidesciclovir and/or the pharmaceutically acceptable salt thereof or micronizing the Reidesciclovir and/or the pharmaceutically acceptable salt thereof together after mixing with a proper amount of magnesium stearate;

mixing: and uniformly mixing the micronized reidoxir and/or pharmaceutically acceptable salt thereof or a sample subjected to co-micronization with magnesium stearate with other pharmaceutically acceptable auxiliary materials.

The formulations are prepared by first micronising the active ingredient so that the active ingredient in the powder formulation substantially enters the lungs after administration by inhalation, the micronisation of the active ingredient may be prepared by any of the techniques well known in the art of pharmacy, for example jet milling, spray drying, spray freeze drying, supercritical fluids and the like, preferably jet milling. The prepared active component micro powder is mixed with proper auxiliary material powder to form a formula which is suitable for inhalation administration and has a certain microstructure, wherein the microstructure refers to proper attachment of active component particles to auxiliary material component particles, so that administration carriers such as capsules, bubble caps or reservoirs are added into the formula to have good fluidity, the active component particles and the auxiliary material component particles are not separated, and after inhalation action is generated, the active component particles and the auxiliary material are easy to separate, so that the active component enters and settles in the lung along with inhalation airflow, and the large auxiliary material particles are left in the throat.

The dry powder inhalants of the present invention can also be prepared by simultaneously processing the Reidesciclovir and/or a physiologically acceptable salt thereof with a technical process well known in the pharmaceutical field of pharmaceutical excipients, such as jet milling, spray drying, spray freeze drying, so that the prepared preparation does not need to be mixed with auxiliary materials in a second step, and can be directly used for loading into capsules and medicine compartments, such as gelatin capsules, or laminated aluminum foil blisters, or directly into a dry powder inhaler for storage. The active components and the auxiliary materials of the preparation prepared by the method are organically combined together, and after the inhalation administration, the active components and the auxiliary materials enter the lung together and are deposited in the lung.

In one embodiment, the method further comprises a step of encapsulating, wherein the evenly mixed Reidesciclovir and/or pharmaceutically acceptable salt thereof and auxiliary materials are encapsulated according to the prescription amount, and the capsule is used for matching with a powder spray inhaler.

In one embodiment, in the encapsulating step, the mixed reidesavir and/or the pharmaceutically acceptable salt thereof and the auxiliary materials are subjected to low-pressure airflow dispersion treatment and then encapsulated. Preferably, the low-pressure dispersion treatment is: and (3) passing the mixed raw and auxiliary materials through a spiral jet mill, setting the crushing pressure to be 0bar and the Venturi pressure to be 1-3 bar, and adopting dry nitrogen as an air source to disperse the powder balls existing in the mixed micro powder at low pressure to obtain a mixture with better dispersion performance.

It will be appreciated that the specific selection of the comminution pressure and venturi pressure may be adjusted to the actual sample conditions to disperse any powder globules that may be present.

In one embodiment, in the micronization step, airflow micronization is carried out, so that the particle size of the redexivir and/or the pharmaceutically acceptable salt thereof meets the following requirements: d 10-0.4-1.0 μm, d 50-1.3-2.5 μm, and d 90-3.0-5.0 μm.

In one embodiment, the inhalant is a quantitative inhalant, in the mixing step, the pharmaceutically acceptable auxiliary material is a propellant, the micronized reidecivir and/or the pharmaceutically acceptable salt thereof are/is filled into an inhaler can, and a metering valve is installed after the propellant is added.

The invention also discloses application of the inhalant for inhibiting coronavirus in preparation of an anti-COVID-19 medicament.

The pharmaceutical preparation provided by the invention is used for treating pneumonia caused by coronavirus, especially novel coronavirus (COVID-19), on the basis of 2-6 times, preferably 3-4 times per day.

Compared with the prior art, the invention has the following beneficial effects:

the inhalant for inhibiting the coronavirus can achieve effective pulmonary administration concentration when micronized or gas atomized Reidcisvir is inhaled due to the adoption of small-dose pulmonary administration, effectively exerts the effect of inhibiting the coronavirus, particularly the novel coronavirus, overcomes the defects of narrow treatment window and poor safety in the prior art, meanwhile, due to the pharmacokinetic characteristic of the Reidesvir injection, the Reidesvir injection can be quickly distributed in the whole body and has shorter time to reach peak, the pulmonary administration is local administration, the medicine is mainly concentrated in the lung at first, high concentration cannot be formed in the heart, the aim of reducing the heart or transient impact concentration and the toxicity of other organs and vessel wall barriers can be achieved, small doses are given for multiple times, the effective virus inhibiting effect can be formed in the lung in an accumulated mode, thereby improving the therapeutic effect or reducing the dosage of the ridciclovir and thus reducing the potential side effect.

The invention has the advantages of small administration dosage, direct drug to the lung target, quick effect, high local concentration of the drug in the lung, less systemic absorption and slight side effect, and the drug reaches the lung in the form of solid particles, fog drops or sol particles through multiple administration and is accumulated in the virus accumulation area of the lung to form the drug concentration for effectively inhibiting the coronavirus. The critical patient can inhale through the atomizer, convenient and fast, safe and reliable's advantage.

Drawings

FIG. 1 is a graph of the average concentration of Reidcvir (HNC1053) in lung tissue versus time following a single inhalation administration of Reidcvir in example 13;

fig. 2 is a graph of the average concentration of the metabolites of ridciclovir triphosphate (HNC1062) in lung tissue versus time after a single inhalation administration of ridciclovir in example 13.

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

In the following examples, the Reidesciclovir micronization adopts airflow ultramicro pulverization to ensure that the particle size meets the requirements: d10 ═ 0.4-1.0 μm, d50 ═ 1.3-2.5 μm, d90 ═ 3.0-5.0 μm; the particle size of the carrier lactose is as follows: d 10-3-20 μm, d 50-40-80 μm, d 90-110-160 μm, and the particle size of magnesium stearate is d90 < 40 μm;

mixing with Turbula T2F three-dimensional mixer at 34rpm for 15min, standing for 5min, taking out, and encapsulating. Wherein, the split charging adopts No. 3 plant capsules (product of Zhongmei Suzhou capsules Co., Ltd., trade name: Vcaps), and each example is fed according to 1000 capsules. The capsule of the powder cloud agent is filled into a bubble cap type aluminum plastic package, and is taken out when in use and is filled into a powder cloud agent inhaler for use.

Example 1

10mg of dry powder inhalation of Reidesvir.

10g of Rudexiwei micro powder is taken and put into No. 3 hard capsules, and each capsule is 10mg, and the total number of capsules is 1000.

Example 2

1mg of Rudesivir dry powder inhalant.

1g of the Rudexiwei micro powder and 19g of the lactose are put into a Turbula T2F mixer for mixing, and the mixture is evenly distributed and packaged into No. 3 capsules, wherein each capsule is 20 mg.

TABLE 1 prescription amounts

Components	The dosage of each granule	1000 granules of the composition
			Ruidexiwei (Ridexil)	1mg	1g
Lactose	19mg	19g

Example 3

0.5mg of dry powder inhalation of reed-seivir.

0.5g of the Reidesvir micropowder and 19.5g of lactose are put into a Turbula T2F mixer for mixing, and the mixture is evenly distributed and packaged into No. 3 capsules, wherein each capsule is 20 mg.

TABLE 2 prescription amounts

Components	The dosage of each granule	1000 granules of the composition
			Ruidexiwei (Ridexil)	0.5mg	0.5g
Lactose	19.5mg	19.5g

Example 4

1mg of Rudesivir dry powder inhalant.

2g of the Reidesvir micropowder and 1% of magnesium stearate are subjected to co-micronization. Crushing pressure: 4bar, the particle size of the co-micronised Reidesvir and magnesium stearate was measured by laser diffraction using a HELOS particle size analyser from Sympatec GmbH (Germany) and was found to have an average particle size of 1.8 microns.

1.010g of a co-micropowder sample (1 g of Reidcisvir and 0.01g of magnesium stearate) and 18.99g of lactose were put into a Turbula T2F mixer and mixed, and the mixture was divided into 20mg per capsule in a No. 3 capsule.

TABLE 3 prescription amounts

Components	The dosage of each granule	1000 granules of the composition
			Ruidexiwei (Ridexil)	1mg	1g
Magnesium stearate	0.01mg	0.01g
			Lactose	18.99mg	18.99g

Example 5

1.5mg of dry powder inhalation of Rudexiwei.

2g of Rudexiwei micro powder and 3% of magnesium stearate are subjected to co-micronization, and the crushing pressure is as follows: 4bar, the particle size of the co-micronised Reidesvir and magnesium stearate was measured by laser diffraction using a HELOS particle size analyser from Sympatec GmbH (Germany) and was found to have an average particle size of 1.8 microns.

1.546g of the co-micropowder sample (wherein, 1.5g of Reidesvir and 0.046g of magnesium stearate) and 18.454g of lactose were put into a Turbula T2F mixer for mixing, and the mixture was divided into 20mg capsules each for filling into No. 3 capsules.

TABLE 3 prescription amounts

Components	The dosage of each granule	1000 granules of the composition
			Ruidexiwei (Ridexil)	1.5mg	1.5g
Magnesium stearate	0.046mg	0.046g
			Lactose	18.454mg	18.454g

Example 6

10mg of dry powder inhalation of Reidesvir.

Co-micronization of 15g of Reidesciclovir with 0.8% magnesium stearate, crushing pressure: 4bar, the particle size of the co-micronised Reidesvir and magnesium stearate was measured by laser diffraction using a HELOS particle size analyser from Sympatec GmbH (Germany) and was found to have an average particle size of 2.2 microns.

Taking 10.08g of a co-micropowder sample (wherein the content of the Reidsievir is 10g, and the content of the magnesium stearate is 0.08g) and 19.92g of lactose, putting the co-micropowder sample and the lactose into a Turbula T2F mixer for mixing, enabling the mixed sample to pass through a spiral airflow pulverizer, setting the pulverizing pressure to be 0bar and the Venturi pressure to be 1-3 bar, adopting dry nitrogen as an air source, performing low-pressure dispersion on powder balls existing in micropowder obtained after Turbula mixing to obtain a mixture with better dispersion performance, and encapsulating the mixture into No. 3 capsules, wherein each capsule is 30 mg.

TABLE 4 prescription amounts

Components	The dosage of each granule	1000 granules of the composition
			Ruidexiwei (Ridexil)	10mg	10g
Magnesium stearate	0.08mg	0.08g
			Lactose	19.92mg	19.92g

Example 7

Determination of the aerodynamic particle size distribution (lung deposition rate).

1. A method.

20 powder aerosol capsules prepared in examples 1 to 5 were taken, respectively, and the lung deposition rate of the powder aerosol was measured using a british kopril new generation drug multistage impactor NGI (flow rate: 90L/min, time: 2.4s), and the results of each group were averaged.

The content of effective components is measured by liquid chromatography under the following chromatographic conditions:

a chromatographic column: phenomenex Gemini C18,5um, 50 × 4.6 mm.

Mobile phase: a: 0.1% trifluoroacetic acid-water; b: 0.1% trifluoroacetic acid-acetonitrile ratio a: B ═ 60: 40, run time 6 minutes.

Diluent agent: acetonitrile: 50 parts of water: 50, flow rate: 1ml/min, column temperature: 25 ℃, detection wavelength: 238 nm.

2. Results

The results are shown in the following table:

TABLE 4 pulmonary deposition Rate

Group of	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6
							Pulmonary deposition Rate (%)	29.52	30.33	31.68	36.72	37.38	55.78

The above results show that the formulations of examples 4-6, with the addition of magnesium stearate, increase the lung deposition rate, and that the formulation of example 6, with the addition of jet milling prior to encapsulation, further increases the lung deposition rate.

Example 8

And (4) measuring the emptying rate.

The emptying rate of the aerosol powder capsules prepared by implementing 1-5 is measured according to the method disclosed in the general rule 0111 of the four ministries of the Chinese pharmacopoeia 2015 edition, and the result is shown in the following table:

TABLE 5 evacuation Rate

Group of	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6
							Evacuation Rate (%)	95.7	96.2	96.8	97.5	99.2	99.8

Example 9

And testing the stability of the powder spray capsule.

Test drugs: the control group adopted the dry powder capsules prepared according to the technical scheme (direct physical mixing method) disclosed in example 2, and the capsules used were No. 3 capsules. The obtained powder spray capsule contains 1mg of Rudexilvir and 19mg of lactose.

Experimental groups the powder aerosol capsules prepared by the embodiment of the invention have the following conditions:

TABLE 6 stability test grouping

The experimental method comprises the following steps: 20 capsules of the control group and 20 capsules of the experimental group are respectively taken, firstly, 10 capsules of each group are randomly taken to measure the lung deposition rate, and the rest 10 capsules of each group are stored for 15 days in a dark place at 40 +/-5 ℃ under the condition of relative humidity of 75 +/-5 percent to measure the lung deposition rate. And the lung deposition rate data before and after storage were subjected to a t-test in a sps.

The results of the experiment are shown in the following table: (X. + -. s, n ═ 10)

TABLE 7 stability test results

Control group

Experimental group 1

Experimental group 2

Experimental group 3

Experimental group 4

Experimental group 5

Before storage

30.40±1.05

29.38±1.58

31.32±1.19

36.62±1.03

37.79±1.33

55.92±1.07

After storage

28.17±2.89

26.22±3.81

28.45±2.93

36.01±1.88

37.25±2.05

55.32±1.22

The experimental data show that the lung deposition rate of the control group experimental group 1 and the experimental group 2 is remarkably reduced (P is less than 0.05) before and after storage, while the lung deposition rate of the

experimental groups

3, 4 and 5 is not remarkably reduced before and after storage, which indicates that the stability of the sample in the storage period is lower when the pure Reidesvir micropowder, the Reidesvir micropowder and the carrier lactose are mixed and filled, the stability of the Reidesvir dry powder inhalant in the storage period can be better improved by adding a certain amount of magnesium stearate, and the stable lung delivery effect of the dry powder inhalant can be kept along with the increase of the addition amount of the magnesium stearate.

In addition, in the implementation process, a certain amount of powder balls are found in the mixture obtained after the mixture is mixed by a Turbula T2F mixer, and as can be seen from a emptying rate test, the existence of the powder balls does not affect the emptying rate, but through better technology and equipment improvement, the powder ball phenomenon is improved, a better lung deposition rate can be obtained, and the lung deposition rate has better stability, and because the effective lung deposition rate of the lung administration is generally considered to be higher than 30%, a good quality effect can be exerted, in the embodiment, the embodiments 4 to 6 can be considered as better schemes.

Example 10

1mg of an inhalant for a ridciclovir metered dose inhaler.

TABLE 8 metered dose inhaler formulations

Components	Every suction
		Ruidexiwei (Ridexil)	1mg
HFA134a	Adding to 75.0mg

The micronized active ingredient was weighed into an aluminum can, Hydrofluoroalkane (HFA)134a was then added from a vacuum volumetric flask, and the metering valve was pressed into place. Similar methods can be used in the formulations of examples 10 to 11.

The above addition of 75.0mg means that HFA134a is added so that the total weight of Reidesvir and HFA134a is 75.0 mg. The following "add" means the same.

Example 11

5mg of an inhalant for a ruideseivir metered dose inhaler.

TABLE 9 metered dose inhaler formulations

Components	Every suction
		Ruidexiwei (Ridexil)	5mg
HFA227	Adding to 75.0mg

Example 12

10mg of an inhalant for a ridciclovir metered dose inhaler.

TABLE 10 metered dose inhaler formulations

Components	Every suction
		Ruidexiwei (Ridexil)	10mg
HFA134a	Adding to 75.0mg

Example 13

The samples prepared in the embodiments 9 to 11 are measured according to the project method of aerosol quality standard in the appendix of the 2015 edition of Chinese pharmacopoeia, and the detection results are as follows:

TABLE 11 Aerosol quality Standard Property measurements

Quality characteristics	Example 9	Example 10	Example 11
				Dose uniformity	Meets the requirements of pharmacopoeia	Compound medicineTypical requirements	Meets the requirements of pharmacopoeia
Droplet (particle) distribution	35％	33％	32％
				Leakage rate	2.3％	2.7％	2.5％
Content of the principal drug at each dose	98.7％	98.3％	97.2％

The above results show that the dosing quality of the quantitative aerosol meets the requirements of pharmacopoeia of 2015 edition.

Example 14

Pharmacokinetic experiments.

1. Test methods.

SD rats 160 (81 males and 79 females) are tested and weighed before administration, and the 1 st to 3 rd groups are respectively administered with injection Reidesvir freeze-dried powder injection (refer to patent US2018041482 preparation: a prescribed amount of sulfobutyl-beta-cyclodextrin is added into injection water for dissolving, the pH is adjusted to 1.5 by 10% (W/W) hydrochloric acid solution, a prescribed amount of HNC1053 is added for stirring and dissolving, the pH is adjusted to 3.5 by sodium hydroxide solution, injection water is added to a prescribed amount and stirring is carried out, a 0.22 mu m filter membrane is used for filling into penicillin bottles, a half-pressing plug is used for freezing and drying in a freezing dryer, the obtained product is obtained by pressing and rolling a cover), Reidesvir inhalant (prepared by example 6), Reidesvir (raw material, 97.8 percent of purity), the administration dosage is 18mg/kg, 21 animals are used for each group, administration is carried out once, group 1 adopts intravenous infusion mode, groups 2-3 were administered by inhalation.

Blood collection time points: group 1 was bled before dosing, 10min, 30min, 1h, 2h, 4h, 8h, 24h after infusion; groups 2-3 collected blood before administration, 10min, 30min, 1h, 2h, 4h, 8h, 24h after inhalation administration. 3 animals at each time point, the same animal at the time point before administration and at the time point 10min after completion of instillation; blood samples were subjected to heparin sodium anticoagulation centrifugation to separate plasma.

Time points for lung tissue collection per group: group 1 was bled 10min, 30min, 1h, 2h, 4h, 8h, 24h after infusion, groups 2-3 were bled 10min, 30min, 1h, 2h, 4h, 8h, 24h after inhalation dosing, with 3 animals per time point.

And (3) processing and detecting the sample by using a verified LC-MS/MS analysis method, wherein target analytes are Reidesvir (HNC1053) and Reidesvir triphosphate metabolite (HNC1062), and the structural formula is as follows.

Wherein, the RudeSeviru is detected by LC-MS/MS (603.300/200.000), and the structure of the RudeSeviru triphosphate metabolite is as follows, and LC-MS/MS (530.100/158.900) is selected for detection.

Detailed clinical observations were made for all animals during the trial.

2. And (5) experimental results.

1) The conventional indexes are as follows:

the rats which are successfully dosed are not abnormal; the weight average of the animals was within the normal range.

2) Pharmacokinetic parameters:

the main pharmacokinetic parameters of Reidesciclovir in lung tissue following a single administration of 18mg/kg Reidesciclovir inhalant or raw material by intratracheal inhalation are shown in the table below.

TABLE 1 major pharmacokinetic parameters of Reidesciclovir in lung tissue following single inhalation administration of Reidesciclovir in SD rats

Note: G2-F is a group 2 (Reidesciclovir inhalant group) female, G2-M is a group 2 male, G3-F is a group 3 (Reidesciclovir raw material group) female, and G3-M is a group 3 male.

The main pharmacokinetic parameters of the metabolites of ridciclovir triphosphate in lung tissue after a single intratracheal inhalation administration of 18mg/kg of the ridciclovir inhalant or starting material are shown in the table below.

TABLE 2 Primary pharmacokinetic parameters of the metabolites of Reidsivir triphosphate in pulmonary tissue after single inhalation administration of Reidsivir in SD rats

After the injection RudeSewei freeze-dried powder injection of 18mg/kg is administered to male and female animals by intravenous infusion, no research significance is realized because sample detection is not detected or only trace detection is detected, and data statistical analysis is not performed.

The exposure of male and female animals to 18mg/kg of each of the Reidesciclovir inhalant and the starting material by single intratracheal inhalation was compared and the results are shown in the following table, showing no gender difference in exposure.

TABLE 3 Exposure comparison

The results of the pharmaceutical study show that: the lung deposition rate of the Reidesciclovir inhalant in vitro is up to more than 30 percent. The results show that compared with the injection administration, after the rat is administrated by atomizing to form aerosol, the plasma drug concentration is low or almost no proto-drug is detected in the inhalation administration mode under the condition that the concentration of the injected Rdsievir is lower, but the lung proto-drug concentration is as high as 14641.05h nmol/kg, and the lung tissue drug concentration of the effective drug Rdsievir triphosphate metabolite is 1087.4h nmol/kg; no injection administration, either the proto-drug or the metabolites of the Reidsievir triphosphate, was detected.

Rats which are successfully administrated are not abnormal, the weight average of animals is in a normal value range, and animal death and other adverse reaction symptoms are not seen, so that the inhalation administration mode has less exposure, the effective drug concentration of local administration in the lung is improved, and the safety and the effectiveness are possibly higher.

Example 15

Low dose administration experiments.

1. Experimental methods.

18 male SD rats were tested, weighed before dosing, given a Reidesciclovir inhalant at a dose of 3mg/kg in a single dose.

Lung tissue collection time points: samples were taken 10min, 30min, 2h, 8h, 24h, 48h after the end of the inhalation administration, 3 animals per time point.

Samples were processed and tested using the LC-MS analysis method of example 13, with the target analytes being reed-seivir and the metabolites of reed-seivir triphosphate. All animals were subjected to detailed clinical observation and weighing during the trial.

2. And (5) experimental results.

No abnormality was observed in the rats successfully dosed, and the weight average of the animals was within the normal range.

After male animals are administrated with 3mg/kg of Rudexilvir inhalant by single intratracheal atomization inhalation, the main drug generation parameters of the Rudexilvir in lung tissues are t respectively_1/2Is 11.56h, C_max85049.40ng/g (141.14. mu. mol/kg), T_max0.5h, AUC_(0-t)835.22h μmol/kg.

Male animals were given 3mg/kg Reid by single intratracheal nebulization inhalationAfter the inhalation of the cider, the main pharmacokinetic parameters of the metabolites of the Rudecider triphosphate in the lung tissue are respectively C_max27.25ng/g (0.05. mu. mol/kg or 50nmol/kg), T_maxIs 0.5 h.

The above data show that at reduced inhaled ridciclovir doses (6-fold reduction), lung tissue concentration remains 835.22h μmol/kg, and lung concentration of the effective drug, the metabolite of ridciclovir triphosphate, remains high. The rats which are successfully administrated are not abnormal, the weight average of animals is in a normal value range, and animal death and other adverse reaction symptoms are not seen, so that the effective drug concentration of local administration of the lung is still higher under the condition of lower concentration in an inhalation administration mode, and the safety and the effectiveness are possibly higher.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. An inhalant for inhibiting coronavirus, comprising Reidesciclovir and/or a pharmaceutically acceptable salt thereof.

2. The inhalant for inhibiting coronavirus according to claim 1, wherein the inhalant is administered in an amount of 0.05-50 mg/day in terms of Reidsievir.

3. The inhalant for inhibiting coronavirus according to claim 1, wherein the content of the Reidesciclovir and/or the pharmaceutically acceptable salt thereof is 0.2-96 wt%.

4. The inhalant for inhibiting coronavirus according to claim 3, wherein the inhalant is in the form of: a dry powder inhaler further comprising a diluent and/or a lubricant, the diluent being selected from: at least one of lactose, trehalose, starch, xylitol, mannitol, and hydrophobic amino acids; the lubricant is selected from: at least one of magnesium stearate and sodium stearyl fumarate.

5. The inhalant for inhibiting coronavirus according to claim 4, wherein the lubricant has a particle size of d90 < 40 μm; the particle size of the diluent is d 10-3-20 μm, d 50-40-80 μm, d 90-160 μm.

6. The inhalant for inhibiting coronavirus according to claim 4, wherein the average particle size of the Reidesciclovir is 1.5-3.0 μm, and the average particle size of the lubricant is 1.5-3.0 μm.

7. The inhalant for inhibiting coronavirus according to claim 4, wherein the diluent is lactose and the lubricant is magnesium stearate in an amount of 0.1-7 wt%.

8. The inhalant for inhibiting coronavirus according to claim 4, wherein the diluent is lactose and the lubricant is magnesium stearate in an amount of 60-98 wt% and 0.01-0.30 wt%.

9. An inhalant for inhibiting coronavirus according to any one of claims 1 to 8, wherein the maximum particle size of the Reidesciclovir and/or a pharmaceutically acceptable salt thereof in the inhalant is not more than 50 μm.

10. A process for the preparation of an inhalant for inhibiting coronavirus according to any one of claims 1 to 9, comprising the steps of:

11. The method for preparing an inhalant for inhibiting coronavirus according to claim 10, wherein the micronization step comprises micronization with air flow to make particle size of redexivir and/or its pharmaceutically acceptable salt meet the following requirements: d 10-0.4-1.0 μm, d 50-1.3-2.5 μm, and d 90-3.0-5.0 μm.

12. The method of claim 10, further comprising a step of encapsulating the evenly mixed Reidesciclovir and/or pharmaceutically acceptable salt thereof and an auxiliary material in a capsule in an amount prescribed for use with a powder aerosol inhaler.

13. The method of claim 12, wherein the step of encapsulating comprises dispersing the mixed Reidesciclovir and/or pharmaceutically acceptable salt thereof and adjuvant with air flow under low pressure, and encapsulating.

14. Use of an inhalant for inhibiting coronavirus according to any one of claims 1-9 for the preparation of an anti-COVID-19 medicament.