IT202100002003A1 - NEW ANTIVIRAL COMPOSITIONS AND THEIR USE IN THERAPY AND TREATMENT OF VIRAL INFECTIONS - Google Patents

Description

?New antiviral compositions and their use in therapy and treatment of viral infections?

Summary

The present invention relates to new pharmaceutical compositions in powder form comprising antiviral drugs alone or in combination, as well as the use of said compositions in therapy, in particular for the treatment and/or prevention of respiratory tract infections.

Technical context

The pandemic caused by the new coronavirus SARS-CoV-2 has led to the disease called COVID-19 by WHO which has led to an immense study on the discovery of a treatment not only for vaccines for prevention, but also for the need for vaccination. to have a quick medical facility for people who have contracted the infection. In this direction yes? went in search of known drugs that could show an?activity? of containment of the spread and of the symptomatological manifestations that accompany a viral infection such as that of SARS-CoV-2.

No specific antiviral treatments against coronaviruses have been approved to date. However, a large number of known pharmacologically active substances been empirically used to counteract the replication of the virus, in particular some authorized as antimalarials, antivirals, antiparasitics or antibiotics for concomitant infections caused by bacteria. These drugs have been studied in limited clinical trials with questionable success, both because of the small number of patients involved and because enrolled patients were in the pulmonary phase of the disease with hypoxia (inflammatory stage). At this stage, the pathogenicity? Viral was a minor aspect of the overall pathophysiology, with host inflammatory responses being the predominant pathology.

Antiviral drugs are usually administered systemically in the treatment of infections caused by various viruses. Due to their small size, viruses are often very infectious, so the most appropriate medical approach? effective for viral diseases remains vaccination. Also in availability? of the vaccine, the possibility? to suffer the? infection in the future requires the simultaneous availability? of drug treatment to quickly treat and/or prevent the infection from developing.

After months of full-blown infection, the evolution of the COVID-19 disease is known. Virus entry and viral replication occur primarily in the upper airways. We now know that the vast majority of COVID-19 patients experience asymptomatic or mildly ill infection with fever, loss of taste and smell, and respiratory and gastrointestinal symptoms, which are managed with minimal supportive care. Severe illness occurs in a minority of people with an exaggerated immune response 5-7 days after the onset of symptoms due to the onset of viral pneumonia. An analysis of the dynamics of viral replication has revealed that there is a window of opportunity during the infectious phase. antiviral where to insert adequate countermeasures to avoid the worsening of the disease.

Few antiviral drugs to date have been developed that act selectively on specific viruses. For example, neuraminidase inhibitors are currently authorized in the European Union for the treatment and prophylaxis of seasonal, pandemic and zoonotic influenza, with debate on their efficacy and safety and consequently, also on the appropriateness of using these drugs for future pandemics influence them. Healthcare public underlines that they are not an alternative to vaccination and must always be taken on prescription and under medical supervision, promptly with respect to the onset of symptoms of the infection.

For example, the two classes of antiviral drugs for the prophylaxis and treatment of influenza are neuraminidase inhibitors (oseltamivir and zanamivir) and viral M2 protein inhibitors (amantadine and rimantadine). The prophylactic use of antivirals is not recommended as a routine during seasonal influenza epidemics, due to the risk of creating resistance. Nonetheless, recent influenza research has indicated that antiviral drugs given before or shortly after the onset of symptoms can reduce infection and contagiousness. towards other people.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are drugs widely used for the prevention of malaria. HCQ has shown excellent in vitro results and a clear antiviral action against coronaviruses in primate cells, even at low concentrations. Being drugs with potential activity? antiviral and being already? widely used in antimalarial therapy, their pharmacokinetic and toxicological profile ? known. No data to date has indicated that the activity? in vitro against SARS-CoV-2 of CQ and HCQ translated into clinical efficacy after systemic administration. The studies done on the clinical efficacy of the administration of CQ or HCQ in the COVID-19 disease have often shown contradictory results, also because were performed on hospitalized patients with severe respiratory syndrome. Furthermore, ? It has been noted that these studies have been performed exclusively for systemic administration of the drugs (orally or by injection), in the face of the fact that the virus enters the human body through the respiratory tract, ie? from the mouth and nose. Systemic administration leads to a low drug concentration at the site of infection which, in case of dose escalation, poses the risk of amplifying adverse effects.

Is there therefore a need? to provide new therapeutic tools that solve the problems of current antiviral therapies, in particular for the treatment and prevention of respiratory tract diseases.

Purposes of the invention

? a first object of the invention is to provide new inhalation pharmaceutical compositions of substances with active antiviral, individually or in combination with other substances, in the form of a respirable powder.

? another object of the invention is to provide said compositions in a nasal inhaler at a dose lower than the oral or parenteral dosage.

? a further object of the invention is to provide said compositions to be used in therapy, in particular for the treatment and/or prevention of viral infections of the upper respiratory tract, for example, but not only, of coronavirus infections, such as COVID-19 .

Brief description of the Figures

Figure 1 shows the permeation profiles through rabbit nasal mucosa of hydroxychloroquine, starting from a saturated solution and hydroxychloroquine powder in the form of microparticles.

Figure 2 shows the amount of hydroxychloroquine present in the rabbit nasal mucosa at the end of the permeation experiment (4 hours).

Figure 3 shows the aerodynamic behavior of a composition representative of the invention (Example 1) after being insufflated with a passive inhalation device.

Figure 4 shows the SEM image of the powder microparticles of Example 1, consisting of 99% chloroquine and 1% sodium stearate.

Figure 5 shows the SEM image of the powder microparticles of Example 2, consisting of phosphate chloroquine, zinc gluconate and lactoferrin.

Description of the invention

According to a first aspect, the invention relates to a pharmaceutical composition in the form of a powder with at least 90% of microparticles having a volume diameter of less than 20 microns, comprising at least one antiviral agent, for administration by the nasal route. According to a preferred embodiment, the invention relates to a pharmaceutical composition in powder form consisting of microparticles comprising at least one antiviral agent and at least one agent selected from an activity enhancer agent. antiviral and a bioadhesive agent.

According to a preferred embodiment, the invention relates to a pharmaceutical composition in powder form of microparticles comprising at least one antiviral agent and at least one activity enhancer agent. antiviral and/or at least a bioadhesive agent, such a powder to be administered by nasal inspiration.

According to a preferred embodiment, the pharmaceutical composition in microparticle powder of the invention comprises at least one antiviral agent, at least one enhancer of the activity antiviral and at least one bioadhesive agent.

According to one embodiment, the invention relates to a pharmaceutical composition in powder form constituted by microparticles comprising at least one antiviral agent and at least one agent selected as enhancer of the viral activity. antiviral, said composition not comprising any bioadhesive agent.

According to one embodiment, the invention relates to a pharmaceutical composition in powder form consisting of microparticles comprising an antiviral agent and at least one bioadhesive agent, said composition not including any activity enhancer agent. antiviral.

The pharmaceutical composition in microparticle powder of the invention? also indicated here simply as the ?composition of the invention? or the ?composition?.

The composition of the invention ? suitable for nasal inspiration, preferably through a device, for example through known devices for buccal inhalation.

The term ?nasal inspiration? here indicates the inhalation through the nose obtained by placing a suitable device in one nostril of the nose and inhaling through the nose.

The expression ?powder composition of microparticles? ? well known in the art and indicates a mixture of substances in the form of particles of micrometric dimensions. Pi? specifically, the composition has at least 90% of the particles with a size, as volume diameter, of less than 20 microns, preferably between 1 and 20 microns.

According to a preferred embodiment, the microparticles of the composition have a median diameter of from 1 to 10 microns, more? preferably from 1 to 7 microns.

According to a more preferred embodiment, the microparticles of the composition have a median aerodynamic diameter of from 4 to 7 microns; this particle size allows to obtain a fine dispersion of particles emitted by the device following an inspiratory act through the nose, thus forming a stable aerosol of powder, which can? easily enter the upper respiratory tract through the nose and deposit by successively lining the respiratory mucous membranes of at least the nose, throat and trachea.

A powder as defined above, i.e. containing microparticles with an aerodynamic diameter from 1 to 7 microns, ? commonly called ?respirable dust?.

The composition of the invention ? usable in therapy for the treatment and prevention of diseases of the respiratory tract, for example viral diseases of the respiratory tract such as, but not limited to, infections caused by coronaviruses, for example, but not limited to, the disease COVID-19.

The at least one antiviral agent according to the invention ? a drug suitable for the treatment and/or prevention of viral diseases of the respiratory tract, for example known drugs which have shown activity during past infections? against coronaviruses, or new antiviral drugs. For example, the following can be used as antiviral agents: the antimalarials chloroquine and hydroxychloroquine, the antiparasitic ivermectin, the antibiotic azithromycin, the antivirals remdesivir, ribavirin, lopinavir and other drugs proposed for other viral infections such as oseltamivir, zanamivir, molnupiravir or viral protein M2 amantadine and rimantadine, as well as mixtures of antiviral agents. These substances have the advantage of being already? known for their activity?, toxicity? and side effects.

According to a preferred embodiment, the at least one antiviral agent is chosen from chloroquine, hydroxychloroquine, amantadine, remdesivir and their mixtures.

The expression ?activity enhancer? viral? indicates a substance able to strengthen and increase the activity? antiviral of the antiviral agent in the composition of the invention.

In one embodiment, the activity enhancer? antiviral ? one or more other antiviral agents.

In one embodiment, the activity enhancer? antiviral can be an active agent towards the viral proteins that enhances the activity? antiviral of? own antiviral agent, and pu? be for example selected from a pharmaceutically acceptable salt of zinc such as zinc chloride, zinc gluconate and zinc acetate, preferably zinc gluconate or zinc chloride. Blends of enhancers can also be included in the composition of the invention.

According to a preferred embodiment, in the composition the molar ratio of the at least one antiviral agent to the moles of the zinc salt enhancer ranges from 3.25 to 1.0, plus? preferably from 3.25 to 2.0.

The term ?bioadhesive? identify the ability of a compound to prolong contact of the composition with the epithelia of the upper airways and herein means a biocompatible polymeric or oligomeric substance, such as a medium-high viscosity water-soluble polymer, so? that the 7.5% solution in water at 25? C has a viscosity? between 400 to 1000 mPa s. Suitable bioadhesive agents are, for example, sodium hyaluronate, cyclodextrins, sodium chondroitin sulphate, alginic acid, collagen, chitosan, soluble cellulose derivatives or lactoferrin. According to a preferred embodiment, said bioadhesive agent ? chosen between sodium hyaluronate and lactoferrin.

According to a preferred embodiment of the invention, sodium hyaluronate advantageously has an average molecular weight advantageously ranging from 700 to 1,300 kDa, while lactoferrin advantageously has a molecular weight ranging from 80 to 100 kDa.

According to a preferred embodiment, the pharmaceutical composition in microparticle powder of the invention comprises at least one antiviral agent as defined herein, a pharmaceutically acceptable zinc salt and a bioadhesive, preferably selected from sodium hyaluronate and lactoferrin.

Preferably, when present, the bioadhesive? present in the composition in a percentage from 10 to 20%, with respect to the total weight of the composition.

All the components of the composition are commercially available or can be prepared according to known methods and techniques.

Pharmaceutically acceptable excipients, known in the art, can be added to the composition of the invention.

According to a preferred embodiment, the composition consists of:

- from 60.00 to 100% of at least one antiviral agent, preferably from 65.00 to 99.95%; - from zero to 20.00% of at least one enhancer of? activity? antiviral selected from pharmaceutically acceptable zinc salts, for example from 10.00 to 20.00%;

- from zero to 20.0% of a bioadhesive, for example from 10.00 to 18.00%;

- from zero to 5% of pharmaceutically acceptable excipients;

said % being expressed as the weight of each component with respect to the total weight of the composition.

Some excipients which improve the organoleptic characteristics of the composition can be added to the composition of the invention. In a preferred embodiment said excipient ? a sugar-derived sweetener, such as mannitol, xylitol, or sorbitol. According to a preferred embodiment, said excipient ? mannitol, which can? be present in a quantity? less than 5% by weight, with respect to the total weight of the composition.

The composition can also contain other excipients used to enhance the physical characteristics of the nasal powder and its aerosolization, such as for example sodium stearate, leucine and isoleucine. Furthermore, the composition can contain corrective excipients of the properties? organoleptic properties and preservatives such as chlorhexidine, which also has properties antivirals. According to a preferred embodiment, the composition also comprises further optional excipients such as perfumes and/or other preservatives

According to another of its aspects, the invention relates to the composition as defined above for its use through nasal administration.

According to another of its aspects, the invention relates to the composition as defined above for its use in therapy, preferably in the treatment and/or prevention of viral diseases of the airways, such as for example coronavirus infections, for example but not only from SARS-CoV-2 (COVID-19 disease).

According to another of its aspects, the invention relates to a method for the treatment and/or prevention of viral diseases of the airways, such as for example coronavirus infections, for example but not only from SARS-CoV-2 (disease COVID-19) which comprises the administration to a subject who needs it, of a composition of the invention as defined above, preferably by means of an insufflator device or by nasal inspiration. The composition of the invention ? to be administered by the nasal route to a mammalian subject, preferably the human being or a domestic animal or a livestock animal, for example cows, sheep, horses and the like.

According to a preferred embodiment, the composition of the invention is packaged in pre-measured rigid capsules containing a single dose of the composition, for example packaged in blisters, which can be marketed as such or together with a sample of the device to be used for nasal inhalation.

Each single dose can preferably comprising from 20 to 65 mg of powder comprising: - from 10 to 40 mg, preferably from 20 to 30 mg of at least one antiviral agent;

and possibly also including:

- 0.5 to 5.0 mg, preferably 1.0 to 3.0 mg, for example about 2 mg, of at least one activity enhancer antiviral, preferably a pharmaceutically acceptable salt of zinc, for example selected from zinc chloride, zinc gluconate and mixtures thereof; and/or

- from 1.0 to 15 mg, preferably from 3.0 to 7.0 mg, for example about 5 mg, of at least one bioadhesive, preferably selected from lactoferrin and sodium hyaluronate; possibly together with one or more? pharmaceutically acceptable excipients.

It is understood from the composition shown above, that said composition can? include one or more antiviral agents alone or in combination with one or more enhancers and/or one or more? bioadhesives.

As mentioned, in addition to the aforementioned substances, pharmaceutically acceptable excipients such as preservatives, sweeteners and/or perfumes may be present, in quantities generally less than 5% by weight with respect to the total weight of the composition.

Even where not expressly indicated, all the components present in the composition of the invention must be pharmaceutically acceptable.

Have the present inventors understood that the therapeutic challenge for respiratory infections, for example but not limited to COVID-19, is? represented by how to increase the concentration of antiviral drugs in the upper respiratory tract, exactly where the virus is? entered the epithelial cells of the nose and throat. A locally absorbed drug d? place locally at high concentrations, while maintaining low blood levels. because viruses infect the body through the upper airways, yes? thought of chasing the virus through the same route. Therefore, yes? devised the powder composition of the invention, to be used for insufflation, inhalation or nasal inspiration, as a new therapeutic approach for viral infections, such as for example coronavirus infections for example, but not limited to, COVID-19.

In general, an administration by inhalation requires the control of the deposition of the drug on the infected epithelium of the airways. In the initial phase of the infection, the localization of the virus is essentially in the upper airways, while at a later stage the reproduced virions can be distributed in the lung. Inhalation maneuvers appropriate to the place where the virus is located are necessary to control the nasal or pulmonary deposition of the drug.

Contrary to regulatory provisions for nasal powders, which have a limit for particles below 10 microns, ? The micronized powder composition of the invention has been designed for inhalation by nasal inspiration, which is deposited and remains for a long time in the nose and throat, for an active activity. local antiviral, and also as a protective/preventive for people at risk of infection. If the particles enter the bronchi, their effect will not be negative.

In fact, the composition of the invention activates an antiviral action against the virus that has penetrated the cells in the infected respiratory epithelia. The composition also performs a protective action against other individuals, since the viral load of the sputum and nasal mucus of the infected subject to whom the composition has been administered is significantly reduced.

A purpose of the invention? that of administering antiviral powders by nasal inhalation with an inhalation device that allows the powder to enter the airways by means of an inspiratory act through the nose for deep deposition, or by insufflation for a deeper deposition. localized.

An important element of the invention ? was to use nasal powders in the form of microparticles, for example prepared with a spray drying technique of a composition in solution, capable of depositing in different positions of the airways depending on the size distribution of the powder and the device used.

? in fact, it is known that the compositions for nasal administration to solve local problems are not micronized powders because they are micronization allows the dust to pass the nose and down through the upper respiratory tract, which in fact is not? desired for the solution of problems at the nasal level only.

Therefore an original aspect of the invention ? been to devise a composition to inhale through the nose an antiviral agent, said agent being able to deposit locally, cio? on the nasal mucosa, in the throat and in the upper airways depending on the size of the powder particles and the inhalation technique used.

The invention consists of compositions of antiviral drugs in powder form to be administered by nasal inhalation in the initial phase of viral disease, such as coronavirus diseases such as, but not limited to, COVID-19.

The composition of the invention can be administered with a dry powder nasal device of the passive type for inspiration or of the active type for insufflation.

The microparticles of the powder composition, deposited on the respiratory epithelium of the airways, dissolve on site and the active substances are absorbed by the cells giving rise to antiviral concentrations in them which prevent the virus from reproducing. The deposition of the microparticles on the epithelium of the upper airways produces locally, in the cells, a high concentration of drug, which cannot be obtained with systemic administration. Furthermore, despite local absorption in the airways, the drug level in the blood remains significantly lower. low and therefore more safely compared to oral or injection administration.

Yes ? in fact it has been observed that the dose of drug to be administered by the nasal route to have a therapeutic effect is between 1/10 and 1/20 of the dose normally administered by the oral route or by other route of administration. It is understood that the decrease in dosage, the low level of the drug in the blood and the simultaneous high concentration of the drug in the airways together represent an important technical progress.

In inhaler devices, the composition can? be introduced pre-measured into a container, such as a pierceable hard capsule. The inhaler device can be of the active type, meaning that a flow of air, produced in a mechanical way, extracts the powder from the capsule and emits it as an aerosol. In a preferred alternative, the device can be of the passive type, meaning that the powder is extracted from the capsule thanks to an inspiratory act produced by the user with the nose through the nasal adapter of the device. The nasal adapter, to be inserted into the nostril, is a cylindrical portion of the device connected with the capsule. By closing the other nostril with a finger and inhaling sharply, sufficient airflow is produced to extract the powder and to direct the aerosol containing the powder into the nose.

The person skilled in the art easily understands that the powder composition of the invention, due to the size of its particles, is, in fact, a respirable powder such as those which can be administered through the mouth. Although nasal inhalation constitutes a main feature of the invention, for the reasons set out above, if desired or necessary, the composition of the invention can it can also be taken by buccal inhalation, using a suitable device.

The composition of the invention can be prepared by mixing the above components, preferably preparing a solution of the at least one antiviral agent, to which it can? adding, when present, the enhancer zinc salt and the bioadhesive in water, in which the mannitol and the further optional components of the invention have been dissolved under stirring, when present. Said solution is brought to volume with water so as to obtain a solid residue comprised between 0.5% w/v and 10.0% w/v. According to the preferred method, the solution is so? obtained is transformed into a micronized powder with the spray drying technique.

Therefore, according to the preferred embodiment, the composition of the invention is made by a process comprising the following steps:

the. dissolve at least one antiviral agent and, if necessary, at least one agent selected from an activity enhancer? antiviral and a bioadhesive, and additional optional components; once dissolved, add volume with water so as to obtain, if dried, a solid residue from 0.5 to 10.0% w/v;

ii. dry the solution cos? obtained, preferably with a spray dryer in order to obtain a dry powder of microparticles.

According to another alternative form of preparation, the solution of the composition can be dried by freeze-drying, obtaining a mass of powder that can? be ground, for example through a 400 mesh net.

A detailed description of the process of the invention ? reported in the Experimental Section below.

The composition ? particularly useful for treating and/or preventing the onset and spread of upper respiratory tract infections such as coronavirus infections, for example from SARS-CoV-2, not only in the airways, but also in the external environment.

As mentioned, when the powder composition of microparticles of the invention is inhaled or blown into the cavities? noses with an inhalation device, it is deposited on the surface of the respiratory epithelium of the nose, throat, trachea and even up to the bronchi. The microparticles deposited on the epithelia infected by the virus dissolve in the mucus on which they deposited and the drug molecules are absorbed by the cells.

In an ex vivo experiment in which an antiviral composition was deposited on the rabbit nasal mucosa, we found that the nasal mucosa rapidly absorbed the antiviral agent, in an amount? which locally produced a high concentration active against the virus. The uptake of hydroxychloroquine by rabbit nasal epithelial cells (Figure 1) is ? much more result intense when the composition deposited on the mucosa was in the form of microparticles, compared to a saturated solution of the antiviral agent.

For the treatment and/or prevention of pathological symptoms of the upper airways, such as cough, sneezing, inflammation, abundant nasal secretions or sore throat, the composition can be given more? times a day, at regular intervals, until the symptoms resolve. This dosage? made effective by the properties? bioadhesives of the micronized powder composition that promote the transport of the antiviral in the cells of the respiratory epithelium. The high local concentration of the drug? the very significant advantage of the nasal powder over the prior art of tablet or injection administration. The quantity? of active substance given by mouth, at least 10 times higher than the nasal dose, distributing itself throughout the body, it produces a much higher concentration in the upper airways. low.

Figure 2 shows the amount of hydroxychloroquine found inside the rabbit nasal mucosa at the end of the permeation experiment in Figure 1. By dissolving, the microparticles accumulate a high quantity of hydroxychloroquine in rabbit nasal mucosa where 0.35? 0.10 mg, quantity? at least three times higher than that found using the solution (0.11 ? 0.04 mg).

As said, when the dose of the composition? administered to a subject, following inhalation, an aerosol is produced in the nose which passes through the nose, enters the throat, descends into the trachea and possibly up to the bronchi and lungs. During this journey inside the respiratory system, the aerosol, depending on the size of the particles, deposits fractions of composition to cover the anatomical surfaces with which it comes into contact.

This process, which determines the deposition of the antiviral drug on the mucous membranes or epithelia potentially infected by the virus, requires a mechanical action for the extraction of the powder from the capsule and for the formation of the aerosol. Such action ? provided or caused by the inhalation device used, in particular by its construction characteristics. We have found that by using two types of commercial nasal powder devices, defined as active or passive, one can program the deposition of the powder dose on the structures identified as a target to counteract viral replication. The use of one or the other device produces a deposition useful to prevent infection or to treat existing infection.

In detail, the active device? an insufflator that uses a rubber bulb attached to the nasal adapter that holds the capsule. After piercing the capsule with a pin, the nasal adapter is inserted into the nose and, by squeezing the rubber bulb, a flow of air is produced which extracts the powder from the capsule and generates the aerosol which enters the nose. This insufflation is performed more? times, until complete emission of the powder from the capsule, alternating the two nasal nostrils. During insufflation into one nostril, the other is closed with external pressure from a finger. The user can passively undergo the emission of dust, but also inhale at the same time. In both cases, the deposition of the dust takes place mainly in the nose and to a lesser extent in the throat. This delivery technique? more suitable for an infection prevention action.

With the passive device the? operation ? similar, but the airflow that produces the powder aerosol is? provided by an intense inspiratory act through the nose by the user subject. In this case, the device does not have a rubber bulb, but only the nasal adapter where is it? inserted the capsule, drilled in a similar way to the active device. Even in this mode, the inhalation is performed more quickly. times, until complete extraction of the powder, alternating the two nostrils of the nose and closing the contralateral nostril during inspiration. This delivery technique? more suitable for the treatment of infection.

We have therefore found that nasal inhalation with the two types of devices leads to a different deposition of dust which, in the case of the active device or insufflator, occurs mainly in the nose and throat. Using the passive device, the deposition as well as in the nose and throat, can? reach the trachea and also the bronchi.

This different modality? of deposition which depends on the device used and also on the particle size of the composition, and conforms to the therapeutic intervention to be carried out, represents an important technical advantage.

because in the conditions of application the powder of the composition is deposited on a moist mucous surface, the conditions are created for a prolonged action of the product on the surfaces of the respiratory tract. We have found that the deposition of the solid state product ? strategic for? the effect, since? the dissolution of the solid microparticles over time produces a concentration on the epithelial cells which remains saturated until all the solid is dissolved. In fact, the comparison between the deposition of the composition in the solid state with respect to the deposition of the same composition as a saturated solution, produces a very high concentration in potentially infected cells and guarantees for a long time an activity? very effective antiviral.

Therefore, the composition of the invention ? capable of supplying the respiratory mucous membranes with microparticles of the antiviral product which contain antiviral agents that are enhanced by acting on different mechanisms of action against the replication of viruses, for example the SARS-CoV-2 virus. Antiviral agents could not enter infected cells if they were not kept in contact with those cells for sufficient time. Did we see that there? occurs thanks to the presence in the microparticles of bioadhesive substances generally of a polymeric nature, preferably of natural origin.

This ? a solution to increase the permanence of the composition on the surface of the cells where the virus? penetrated that, unexpectedly, ? been identified by comparing the capacity? of the powder composition to penetrate and accumulate in the cells where the virus is present. Having discovered that the solid state composition deposited on the rabbit nasal mucosa produces at least three times higher cell accumulation than the same dose of the composition applied in the liquid state? was unexpected, having never been shown for these types of active substances.

Furthermore, we found that two different types of nasal devices can determine active powder deposition that lends itself to the fight against viral infections, for example but not only the COVID-19 disease, at different levels of the airways. These devices are perfectly interchangeable depending on the required function in terms of the desired deposition site. In fact, the composition they can issue ? the same for each of the two devices if it is marketed pre-measured in a rigid capsule. This capsule is perfectly suited for insertion and use in both types of nasal devices, despite their different mechanism for emitting the powder contained in the capsule.

Combined with the active or passive device, the composition allows the treatment and protection of the wall of the nose, throat and trachea, not only against the replication of the virus, but during the infectious phase it protects the external environment from the dispersion of virions . Due to the powerful local antiviral action on the surface of the nasal and oral mucous membranes, no active virions are emitted with droplets from the mouth or nose.

The deposition of a dust in the airways following an inhalation? simulated and measured with an instrument called Next Generation Impactor (NGI), Copley Scientific, Nottingham, UK. The simulation makes it possible to quantify the fraction of the aerosolized and inhaled dose which could deposit in the nose, throat, bronchi and deep lung, depending on the size of the particles making up the aerosol.

Figure 3 illustrates in vitro the behavior of the powder of Example 1 inhaled and deposited on the stages which simulate the anatomical sequence from the nose to the lung. The dust, which leaves the device as an aerosol, has a size distribution which produces a deposition in quantitatively decreasing fractions in the respiratory tract starting from the smallest particles. large up to the pi? small. This deposition sequence reproduces what could occur in vivo from the nose to the throat, trachea, bronchi and lungs. These are the structures that can potentially be infected by the virus when? inhaled.

A detailed study of respirability? by Next Generation Impactor ? was carried out by dispensing three size 3 capsules loaded with 26.5 mg of the composition of Example 1, corresponding to 26.2 mg of chloroquine diphosphate. The capsules have been inserted into the nasal adapter of the passive Turbospin device, and, after puncturing the capsule, an inspiratory flow of 60 L/min ? been activated. The simulated nasal inspiratory act produced the result of causing the emission and deposition of different dimensional fractions of the powder particles in the various separator stages of the instrument which can be assimilated to different anatomical sites of the airways. Figure 3 illustrates the simulated physiological situation following inhalation of the aerosol through the nose. Can you? note that for the composition studied, approximately 10% of the dose remained in the device, nearly 30% was able to deposit between the nose and throat, approximately 20% between the throat and trachea, approximately 30% in the bronchi and the remaining amount? could reach the lung. The composition loaded into the capsule was deposited in the stages corresponding to the particle size gradually more and more? small and assignable to different airway structures.

The fractions deposited in the NGI made it possible to measure the median aerodynamic diameter of this dust which was 6.4 microns.

According to another aspect thereof, the invention relates to a kit comprising at least one composition of the invention, preferably in the form of a unit. dosage, and at least one device for the nasal administration of said composition. Preferably, in the kit of the invention the composition ? packaged in units? dosage as defined above. Pi? preferably, the kit of the invention also comprises an illustrative leaflet.

According to a preferred embodiment, the kit of the invention comprises at least three, preferably at least 10, plus? preferably from 10 to 30 units? of dosage.

The invention will come now illustrated by the following examples, which are not intended to limit the scope of protection of the invention.

Experimental section

Example 1

? An antiviral agent composition was produced with sodium stearate in a 99:1 w/w ratio, comprising:

Preparation procedure of 5 g of a composition according to the invention

i) Preparation of antiviral agent and sodium stearate solution

a) 4.95 g of chloroquine diphosphate, or of hydroxychloroquine sulphate, were dissolved in 350 ml of purified water at 30°C under stirring. The dissolution occurred rapidly in a few minutes and a clear solution was obtained. The pH of the solution was 7.0.

b) 0.05 g of sodium stearate was dissolved in 150 ml of ethanol 90? at 30?C. The complete dissolution took place after about 5 minutes maintaining the mechanical stirring at 300 rpm. c) The sodium stearate solution ? was added to the drug aqueous solution by continuing to stir magnetically at 300 rpm at 30°C until a clear solution with pH 6.5 was obtained.

ii) Spray drying

The final solution? was spray dried using a Spray Dryer (Buchi B-290) by setting the following process parameters: air inlet temperature was 125?C, nozzle airflow 600L/h, liquid feed rate of 3ml/min, the suction of 35 m<3>/h; the nozzle was 0.7mm and the air outlet temperature was 75?-80?C.

The outcome of the process? been about 70%. An image of the particles produced according to Example 1? shown in Figure 4.

Example 2

A chloroquine composition enhanced with zinc salt and made bioadhesive with the protein lactoferrin according to the invention is produced.

Lactoferrin is dissolved in a 1% w/v solution containing chloroquine diphosphate and zinc gluconate, in a molar ratio of 3.25:1. Were weighed:

I. 986mg Chloroquine Diphosphate (MW: 515.86g/mol) 0.0019mol

II. 270 mg zinc gluconate (MW: 455.68 g/mol) 0.000587 mole

III. 200 mg of lactoferrin (MW: 80 kDa)

In 50 ml of water were 986 mg of chloroquine dissolved, completely dissolved? zinc chloride was added and finally lactoferrin, stirring with a magnetic bar.

Completely dissolved, yes? brought to a volume of 150 ml. The total solids content was 1.456 g in 150 ml of water. Such a solution? been spray dried using the following parameters: inlet air temperature 150?C; 0.7mm nozzle; nozzle air flow 600 L/h; liquid feed 3 ml/min (11%); suction 100% (35 m<3>/h). The outcome of the process? been around 80%. All the dust was in the collector and the cyclone remained clean. The residual water content was 1.3% w/w ( Figure 5 ).

What's the composition? obtained was in the form of a powder consisting of microparticles which, measured with a Spraytech laser particle analyzer, Malvern Instruments, UK, showed a median volume diameter value Dv(50) from 3.0 to 6.0 microns, a percentile Dv (10) from 1.5 to 2.3 microns and a Dv(90) percentile from 7.0 to 20 microns.

Example 3

? a solution to be dried at 1% w/v of chloroquine diphosphate and zinc chloride was also prepared keeping the molar ratio 3.25:1 according to the invention. In 50 ml of water were 986 mg of chloroquine dissolved, completely dissolved? been added 80 mg of zinc chloride (MW: 136.28 g/mol) and yes ? brought to a volume of 100 ml. The total solids content was 1.066 g in 100 ml of water. Such a solution? was spray dried using the same parameters as in Example 2.

Claims (10)

Claims 1. Pharmaceutical composition in the form of a powder of microparticles comprising at least one antiviral agent, wherein at least 90% of said microparticles has a volume diameter of less than 20 microns, preferably from 1 to 20 microns, for administration by the nasal route. The composition according to claim 1, which comprises at least one antiviral agent; at least one antiviral action enhancer, preferably selected from pharmaceutically acceptable zinc salts; and/or at least one bioadhesive agent, preferably selected from sodium hyaluronate and lactoferrin. 3. Composition according to claim 1 or 2, characterized in that the microparticles of the composition have a median diameter of from 1 to 10 microns, preferably from 1 to 7 microns. 4. Composition according to any one of claims 1 to 3, characterized in that said antiviral agent is selected from chloroquine and hydroxychloroquine, ivermectin, azithromycin, remdesivir, ribavirin, lopinavir and oseltamivir, zanamivir, molnupiravir, viral M2 protein inhibitors, amantadine, rimantadine, and mixtures thereof. 5. Composition according to any one of claims from 2 to 4, characterized in that said pharmaceutically acceptable zinc salt is? selected from zinc chloride, zinc gluconate and zinc acetate, preferably zinc gluconate, and said bioadhesive ? chosen between sodium hyaluronate and lactoferrin. 6. Composition according to any one of claims 1 to 5, characterized in that the composition consists of: - from 60.00 to 100% of at least one antiviral agent, preferably from 65.00 to 99.95%; - from zero to 20.00% of at least one enhancer of? activity? antiviral selected from pharmaceutically acceptable zinc salts; - from zero to 20.0% of at least one bioadhesive; zero to 5% pharmaceutically acceptable excipients; said % being expressed as the weight of each component with respect to the total weight of the composition. 7. Composition according to any one of claims from 1 to 6, characterized in that ? in unit form? dosage, each comprising: - from 10 to 40 mg, preferably from 20 to 30 mg, of at least one antiviral agent; and possibly also including: - 0.5 to 5.0 mg, preferably 1.0 to 3.0 mg, of at least one activity enhancer antiviral, preferably a pharmaceutically acceptable salt of zinc, for example selected from zinc chloride, zinc gluconate and mixtures thereof; and/or - from 1.0 to 15 mg, preferably from 3.0 to 7.0 mg, of at least one bioadhesive, preferably selected from lactoferrin and sodium hyaluronate, together with one or more pharmaceutically acceptable excipients. The composition according to any one of claims 1 to 7, for its use in therapy through a nasal administration. 9. Composition for use according to claim 8, in the treatment and/or prevention of viral diseases of the airways, preferably viral infections, more preferably from coronavirus. A kit comprising at least one composition according to any one of claims 1 to 7 and at least one device for nasal administration.