WO2017069721A1

WO2017069721A1 - Antiviral pharmaceutical composition

Info

Publication number: WO2017069721A1
Application number: PCT/UA2016/000122
Authority: WO
Inventors: Yuriy Zakharovych TOLCHEYEV; Vadym Oleksiiovych KOZLOVSKYI
Original assignee: Tolcheyev Yuriy Zakharovych; Kozlovskyi Vadym Oleksiiovych
Priority date: 2015-10-22
Filing date: 2016-10-24
Publication date: 2017-04-27
Also published as: RU2017125688A3; EA036809B1; EA201800266A1; RU2701514C2; UA118192C2; RU2017125688A

Abstract

The invention relates to a pharmaceutical industry and particularly deals with antiviral pharmaceutical compositions. The claimed antiviral pharmaceutical composition comprises beta- glucan preferably as carboxymethyl beta-glucan of sodium salt and iota- carrageenan in the weight ratio from approximately 1-0.5 to approximately 1-5. The antiviral pharmaceutical composition can be used in a spray form to be delivered by a dosing inhaler for nasal or vaginal spray or in the form of powder for insufflation in the interior of the human body or in the form of gel.

Description

ANTIVIRAL PHARMACEUTICAL COMPOSITION

The invention relates to pharmaceutical industry and applies, in particular, to pharmaceutical compositions in the form that is suitable for nasal, ocular or vaginal administration.

In addition, the invention relates to a pharmaceutical product that comprises iota-carrageenan and beta-glucan in spray form composition to be delivered via a nasal or vaginal dosing spray.

The said combination of active components produces mutual enhancement of their stability and provides higher efficiency.

This invention relates to pharmaceutical products and compositions, in particular, to pharmaceutical products and compositions that can be used to prevent or minimize manifestations and consequences of viral diseases. Preferably this invention relates to pharmaceutical products and compositions for nasal, vaginal, and ophthalmic administration.

Viral diseases, as a rule, include local symptoms related to activation of viral particles that is caused by reduction (among the other factors ) in local immunity and vasomotor symptoms (hyperemia, edema, itching, exudative allocation). The said symptoms are independent of the virus type and are common to viral infections.

Use of antiviral drug products for local administration in the form of ointment, cream, and gel is well known from the prior art. Normal ly, these products are chemical substances with a different mechanism of action.

For example, the main antiviral drug products such as acyclovir, bonaphton, rimantadine, idoxuridine are used in the form of local applications, in particular in the form of ointment.

However in fact said substances are not used in spray form, because they are not soluble in water and in solvents used to produce sprays or cannot be dosed easily or are unstable in such form. Patent application CA, 1273576 Al discloses the method for use of antiviral agent (bactericidal agent) and anesthetic for treatment of diseases caused by herpes simplex virus. However, they can be used only for local skin administration that may result in damage of nasal mucosa, oral cavity, or vagina {{opcit. : Author(s): M. Azim Khan. Effects of Phenol, Benzalkonium Chloride, Oxymetazoline, Tobacco and Formalin on Nasal Mucosa of Albino Rat // Journal of the Anatomical Society of India, Vol. 55, No. 1 (2006-01 - 2006-07). Meggs WJ (1994). RADS and RUDS~the toxic induction of asthma and rhinitis. J. Toxicol. Clin.Toxicol. 32 (5): 487-501.)

All the above makes to search for and development of efficient and safe agents that have effect on viral pathogens, in particular those that are transmitted by aerosol or direct contact.

International application WO2005/039623 Al discloses administration of interferons, in particular, of alpha type, in spray form for treatment and prevention of viral diseases.

However, such use of interferon can be accompanied with a number of undesirable side effects related to systemic manifestations of its effect, such as muscular pain, increase in body temperature, or the like.

Therefore attempts to develop agents having local effect that would prevent penetration of a virus from the local infection site are of current interest.

Relatively recently, similar properties of beta-glucan have been unexpectedly revealed .

The administration experience of beta-glucan to prevent viral infections has been known since the end of the 20^st century (Wakshull B., D. Brunke- Reese, J. Lindermuth, L. Fisette, R.S. Nathans, J.J. Crowley, J.C. Zimmermann, W. Mackin, S. Adams, PGG-glucan, a soluble beta-(l-3)-glucan enhances the oxidative burst response, microbicidal activity, and activates an NF-kappa B- like factor in human PMN: evidence for a glycosphigolipid beta(l-3)-glucan receptor. Immunopharmacology 1999; 41 : 89-107). Beta-glucans are a family of polysaccharide monomers of D-glucose bound via beta-glycosidic bonds, whereby they have different molecular weight, density, three-dimensional structure, and some medicinal properties.

There are known beta-glucan (1-3), beta-glucan( 1 -3 l\ -6), and beta- glucan(l-3/l-4). The figures in brackets indicate the type of beta glycosidic bonds. The most biologically active form of beta-glucan is deemed to be beta 1 , 3/1 ,6 -glucan, glucose molecules in which are bound in positions 1 and 3, and the molecule of which has branching in positions 1 and 6 (Bohn J. A., BeMille J.N., 1995).

However beta-glucan 1 ,3/1 ,6 and 1 ,3/1 ,4, is hardly soluble in water that produces some difficulties in development of pharmaceutical forms for local administration.

Beta-glucans preferably having 1 -3 bonds are better soluble in water, but are less efficient in anti-viral protection.

Much attempts are made to improve efficiency of beta-glucan using other ingredients.

For example , international application WO2010/095 1 58 Al describes a combination of beta-glucan and microcolloidal silver for treatment of nasal mucosal diseases.

But Stephen Barrett, MD who has been paying special attention to protection of consumers' rights, medical ethics and scientific skepticism in his paper Colloidal Silver: Risk Without Benefit (Alternative Medicine Digest) has concluded that: "... There is little evidence to support therapeutic effects made for colloidal silver products. The risk to consumers of silver toxicity outweighs the value of trying an unsubstantiated treatment, and bacterial resistance to silver can occur. Efforts should be made to curb the illegal availability of colloidal silver products, which is a significant public health issue." The same point of view arises from such publication as Fung MC, Bo wen DL. Silver products for medical indications: risk-benefit assessment. Journal of Toxicology and Clinical Toxicology 34: 1 19-26, 1996.

The above conclusion was confirmed by the Regulation Acts that regulate the application of colloidal silver (Regulation of colloidal silver and related products. Therapeutic Goods Administration Website, Aug 19, 2003 and FDA overview. Final rule: Over-the-counter drug products containing colloidal silver ingredients or silver salts. Federal Register 64:44653-44658, 1 99).

Therefore deficiencies of the known agent include possible health risk and relatively expensive price for these products.

Attempts have been made to use carboxymethylated form of 1 ,3/1 ,6 beta-glucan.

There is a known agent based on beta-glucan that is used in the form of nasal spray and produced under the trademark «Immuwash»

However beta-glucan of itself , being absolutely safe in local administration, cannot solve the problem of prevention and treatment of viral diseases in spite of the fact that it demonstrates significant medicinal potential.

It is known (Curr Med Res Opin. 2014 Oct; 30(10): 1931 -5. doi : 10.1185/03007995.2014.938731. Epub 2014 Jul 7.) that addition of antioxidant (resveratrol) to the carboxymethylated form of 1,3/1 ,6 beta-glucan significantly reduces severity of symptoms related to acute viral diseases in children.

However it is also known that resveratrol has a potential to cause a number of severe side effects. GlaxoSmith line that is engaged in development and promotion of resveratrol-based drug product announced in 2011 that further work on the said product is stopped because of increase in the number of adverse effects found in its administration (GS Abandons Resveratrol, Focuses on Next Generation Compounds).

Therefore, there is a necessity to search for substances that would strengthen the protective effects of beta-glucan against viruses. The object of this invention is to produce an efficient antiviral agent for external administration with wide range of applications.

The claimed drug product has no toxic components, while its active ingredients stimulate reparative processes thus restoring the morphologically and biochemically normal structure of tissues. These substances are used in insignificant quantity that reduces the probability of toxic or allergic reaction on them practically to zero.

In the course of experiments, the authors unexpectedly found that addition of iota-carrageenan to beta-glucans produces substancial increase of antiviral protection.

According to the claimed invention, in addition to beta-glucan, preferably in the form of carboxymethyl beta-glucan of sodium salt, the antiviral pharmaceutical composition comprises iota-carrageenan in the weight ratio from approximately 1-0.5 to approximately 1-5 and is produced as a spray to be delivered by using a dosing inhaler or in the form of nasal or vaginal spray, powder for insufflation in the interior of the body, or gel.

As it will be demonstrated by Examples below, the claimed combination can provide antiviral properties upon single administration or multiple-dose regimen without any significant mutual effect of its components or side effects at the site of administration .

The preferred embodiments of the compositions according to the invention include nasal drops, ocular drops, nasal sprays, solutions or sprays for nasal inhaling or insufflation powders.

One of the another preferred embodiment of the invention can include stable water solutions of carboxymethyl beta-glucan or one or more of its salts in combination with iota-carrageenan that can be used in the form of solution for inhaling, pressurized spray, ocular drops, or nasal drops and in some desired alternative embodiments of the invention in spray form (preferably nasal spray).

A spray can be obtained by using a normal flacon for compression or pump sprinkler. In addition, compressed gas sprays can also be used. In additional preferred embodiment of the invention, 0.03-3 mg of beta-glucan and 0.05-0.15 mg of iota-carrageenan should be released under single administration.

The compositions according to the invention preferably comprise preservative agent and/or stabilizing agent. They include, for example, ethylenediaminetetraacetic acid (edetic acid) and its alkali salts ( dialkali salts, such as disodium salt, calcium salt, calcium sodium salt), p-hydroxybenzoate of lower alkyls, chlorhexidine ( in the form of acetate or gluconate), and phenylmercuric borate.

Other, but not necessarily suitable, preservative agents include pharmaceutical quaternary compounds of ammonium, such as cetylpyridinium chloride, tetradecyltrimethylammonium bromide, commonly known as 'cetrimide', benzyldimethyl-[2-[2-[p-(l , l ,3,3-tetramethylbutyl)phenoxy]ethoxy ] ammonium chloride, commonly known as 'benzethonium chloride,' and myristylpicoline chloride. Each of those compounds can be used in a standard concentration that is used in order to achieve the preservative effect.

However, among the most preferred quaternary compounds of ammonium as a preservative agent include alkyl benzyldimethyl ammonium chloride and its mixtures, such as the compound commonly known as 'benzalkonium chloride.'

If a preservative agent is used, the following preferred quantities of individual substances can be used: thimerosal (0.002-0.02%); benzalkonium chloride (0.002-0.02%) (in combination with thimerosal, quantity of thimerosal is 0.002-0.005%); acetate or gluconatechlorhexidine (0.01-0.02%); phenylmercuric nitrate, borate, acetate 0.002-0.004%; complex ether of p- hydroxybenzoic acid (such as a mixture of methyl ether and propyl ether in 7:3 ratio) , preferably 0.05-0.15, more preferably 0.1%.

In the case of solutions/suspensions, normally specified percentage is that of weight/volume; in the case of solid or semi-solid compositions, that of - weight/weight.

The following preferred excipients can be used in compositions according to the invention: polyvinylpyrrolidone, complex ethers of sorbitol and fatty acid, such as trioleate sorbitol, polyethoxylated ethers of sorbitol and fatty acid (such as polyethoxylated trioleate sorbitol), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers of octylphenol formaldehyde condensation products, phosphatides, such as lecithin, polyethoxylated fats, polyethoxylated oleotriglyceryls, and polyethoxylated fatty alcohols.

Hereinwith the term 'polyethoxylated' means that the relevant substances contain polyethoxylated chains, the degree of polymerization of which is normally 2-40, preferably , 10-20. Such substances are used preferably to enhance solubility of the beta-glucan component.

Additional isotonic agents can be used optionally. Isotonic agents that preferably can be used include sucrose, glucose, glycerin, sorbitol, 1.2- propylene glycol, or NaCl.

Isotonic agents adjust osmotic pressure of the composition to the osmotic pressure of nasal discharges. That is why such substances should be used in every particular case in those quantities, by using which for example in the case of solution, reduction in freezing temperature by 0.50-0.56 degrees Celsius in comparison with clean water is achieved.

In addition, buffer substances, such as citric acid/ hydrosulphatc sodium borate buffer, phosphates (sodium hydroorthophosphate, disodium hydrophosphate), trometamol or equivalent normal buffers can be added to the claimed composition for adjusting the composition preferably to pl l 3-7, and more preferably to 4.5-6.5.

In example 1 given below , glucose (3.81 g); sucrose (6.35 g); glycerin (2.2 g); 1.2-propylene glycol (1.617 g); sorbitol (3.84 g) can be used instead of NaCl per 100 ml of the solution (in the case of mixtures of substances, they, accordingly, can be used in lower quantities if desired). Moreover, thickeners can be added to the solutions according to this invention to prevent overly fast spilling of the solution from the nose and to make the solution more viscous at approximately 1.5-3 mPa, preferably 2 mPa.

Such thickeners can be preferably cellulose derivatives (for instance, cellulose ethers), in which hydroxy groups of cellulose are partially etherized with lower unsaturated aliphatic alcohols and/or lower unsaturated aliphatic oxyalcohols (such as methyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, ethyl cellulose (water-soluble bonding and thickening substances based on ethyl cellulose), alginic acid, polyvinyl alcohols, polyacrylic acid, pectin, and equivalent agents. If such substances contain acidic groups, the relevant physiologically acceptable salts can also be used.

If hydroxypropylcellulose is used for that purpose, it can be used preferably in the amount of 0.1 % of the composition by weight.

If Avicel RC 591 or CLII is used for that purpose, they can be used preferably in the amount of 0.65-3.0 weight % of the composition .

Nasal administration can be provided preferably by using a solution or suspension in spray form, in other words, in the form of fine dispersion in air or another normal gas (carrying agent), by using preferably a normal pump spray bottle

However, administration in the form of dosed spray, is also possible and desired.

A dosing spray is defined as a spray package that contains beta-glucan or its salts or ethers in combination with iota-carrageenan, dissolved preferably in water in a so-called 'propellant'.

A propellant can be liquid chlorinated, fluoridated hydrocarbon or a mixture of various chlorinated, fluoridated hydrocarbons that are under pressure, and propane, butane, isobutyl or their mixture with one or more of chlorinated, fluoridated hydrocarbons that are gaseous at the atmospheric pressure and room temperature. Hydrofluorocarbons (HFCs), such as HFC 134a and HFC 227a, also can be used for providing better environmental protection.

A spray package has a dosing device or a dosing valve that, when actuated, releases some quantity of the solution or medicinal product in the form of suspension. As a result, very fast evaporation of the propellant disrupts the solution or suspension into fine droplets or particles that can be sprayed nasally or made available for nasal inhaling. Some plastic applicators can be used to actuate the valve and transfer the sprayed suspension to the nose.

In the case of administration in the form of spray, a normal connecting device can also be used.

The most preferred embodiments of the invention are described below, and, normally, it should be understood that the above description of the relevant ingredients and characteristics of the composition can be also applied to the claimed pharmaceutical products.

It should be understood, therefore, that this invention also provides a pharmaceutical product that includes (i) beta-glucan or its pharmaceutically acceptable salt, solvate, or physiologically active functional derivative, delivered as a spray composition, preferably together with a propellant, normally capable of being delivered by using MDI, and (ii) at least one iota-carrageenan or its pharmaceutically acceptable salt, solvate or physiologically active functional derivative delivered in a spray composition, mostly together with a propellant, normally capable of being delivered by using MDI as a combined drug product for simultaneous, separate, or sequential administration in treatment of conditions caused by viruses.

This invention also provides a spray composition that is preferably suitable to be delivered by using MDI that includes (i) azelastine or its pharmaceutically acceptable salt, solvate or physiologically functional derivative, and (ii) at least one steroid or its pharmaceutically acceptable salt, solvate or physiologically functional derivative, together with a propellant. In addition, it should be understood that the relevant therapeutic agents of the combined drug product can be administered simultaneously, in the same or different pharmaceutical compositions, or separately or sequentially. In the case of separate or sequential administration, it should be understood also thai therapeutic agents should be administered to a patient sequentially over a period so that to achieve or, in particular, optimize the above-described beneficial synergic therapeutic effect of the combined drug product that is present in the pharmaceutical product according to this invention.

The pharmaceutical spray composition according to the invention also preferably includes polar co-solvents, such as C2-6-aliphatic alcohols and polyols, such as ethanol, isopropanol, and propylene glycol, ethanol being the most preferred. The concentration of co-solvents is preferably set in the range of approximately 2-10% by weight, normally approximately up to 5% of the total weight of composition.

The pharmaceutical spray composition according to the invention can also include one or more surfactants. Such surfactants can be included to stabilize the composition and lubricate the valve system. Some of the most commonly used surfactants in spray compositions are oils obtained from natural sources, such as corn oil, olive oil, cotton oil, sunflower oil, and phospholipids. The relevant surfactants can include lecithin, oleic acid, and sorbitol oleate.

Additional preferred embodiment of the invention provides the composition or product to be delivered in the form of insufflated powder, wherein the largest particles of the substances, accordingly, are preferably below 10 μπι . Beta-glucan or its salts and iota-carrageenan can be mixed with inert carrying agents or placed in inert carrying agents. Carrying agents that can be used, include sugars, such as glucose, sucrose, lactose, and fructose. In addition, starches or their derivatives, oligosaccharides, such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (such as ether cellulose), sugar alcohols, such as mannitol or sorbitol, calcium carbonate, calcium phosphate and the like.

In the other embodiment of the invention therapeutic agents can be used with particle size less than approximately 10 μηι, preferably less than 5 μηι.

The use of insufflation powders can provide another one of the preferred embodiment of the invention - a medicinal product that includes (i) beta-glucan or its pharmaceutically acceptable salt, solvate or physiologically active functional derivative delivered in the form of insufflation powder, and (ii) iota- carrageenan, solvate or physiologically active functional derivative delivered in the form of insufflation powder as a combined drug product for simultaneous, separate, or sequential administration in treatment of conditions induced by viral intoxication.

Compositions of dry insufflation powder according to the invention can be beneficial, when therapeutic agents need to be retained in the nasal cavity and systemic side effects can be minimized or removed. Moreover, insufflation powder compositions according to this invention can be beneficial due to better retention of beta-glucan or its pharmaceutically acceptable salts, solvate or physiologically active functional derivative on nasal mucosa and unpleasant taste related to liquid antiviral compositions is significantly reduced; that being the case, they also demonstrate synergic therapeutic effect related to the combinations of beta-glucan/iota-carrageenan to be achieved by this invention.

By providing a composition of dry insufflation powder of beta-glucan together with iota-carrageenan that has average particle size approximately smaller than 10 μιη, therapeutic agents can be directed mostly to the desired target organ, nasal mucosa, oral cavity, or vagina.

The composition of dry insufflation powder according to this invention can be administered by using an insufflator that can produce fine sprayed cloud of the dry powder. The insufflator is mostly provided by means to ensure that some prepared quantity of the composition or product that is provided by this invention should be administered. The powder can be used directly with the insufflator that is supplied from a flacon or container of the powder or the powder can be placed in a capsule or cartridge, such as a gelatin capsule or another single dose device adapted for the administration. In most cases, the insufflator has means for opening of the capsule or another dosing device.

Among the other embodiments the claimed invention can provide the composition in the form of gel. In one alternative embodiment of the invention, thickening agents are added to the solvated therapeutic agents that are used thus ensuring stable gel base. In most cases, but not necessarily, a gelation agent can be Carbopols and/or carboxymethyl cellulose preferably in the form of sodium salt in lipophilic solvate medium; mostly glycerin or its acetic ether in this embodyment.

The composition according to this invention can be applied locally on skin, mucosa or administered in external cavities of the body.

The combinations of therapeutic agents that are used in pharmaceutical products and compositions according to this invention (in particular, nasal sprays or drops, aerosols, gels or insufflation products and compositions as described above) can include any of claimed combinations.

This invention also provides a medicinal product that includes (i) beta- glucan or its pharmaceutically acceptable salt and (u) iota-carrageenan in the form of combined drug product for simultaneous, separate, or sequential administration in treatment of conditions, for which the administration of one or more antiviral agents is indicated.

This invention also provides a pharmaceutical composition that contains (i) beta-glucan or its pharmaceutically acceptable salt and (n) iota-carrageenan together with a carrying agent or excipient that is pharmaceutically acceptable for them.

In the case of nasal spray, the most preferred composition according to the invention comprises preferably carboxymethyl beta-glucan of sodium or its another pharmaceutically acceptable salt together with iota-carrageenan in water medium of the osmotic agent, stabilizing agent, preferably ethylenediaminetetraacetic acid disodium salt, preservative agent, preferably Thiomersal, and a buffer of hydrogen ions, preferably sodium and/or potassium phosphate in order to achieve pH 6.0-7.0.

In addition, this invention provides a method for prevention or treatment of a mammal, such as a human that have conditions caused by viral agents; the said method includes administration of therapeutically efficient quantity of the medicinal product described below on the merits, in the form of combined drug product for simultaneous, separate, or sequential administration in the interior of the body.

This invention also provides a method for obtaining a pharmaceutical composition described above on the merits; the said method includes mixing of pharmaceutically acceptable carrying agent or excipient with (i) beta-glucan or its pharmaceutically acceptable salt, solvates or physiologically active functional derivative and with (ii) iota-carrageenan, solvates or physiologically active functional derivatives. Pharmaceutical compositions according to this invention preferably can include compositions of insufflation powder, nasal sprays, solutions or sprays for nasal inhaling, vaginal irrigation and administrations as described above on the merits.

This invention is further described using the examples below that do not narrow the scope of the invention . In examples, where the ingredients of the composition according to the invention are only listed, such compositions are produced by using the methods that are well known in this field of technique.

EXAMPLES

1.

Material % of the composition

Purified Water 98.500 Iota-Carrageenan 0.1200

Carboxymethyl beta-glucan 0.1000

Sodium chloride 0.9000

Disodium EDTA 0.1000

Potassium diphosphate 0.0500

Potassium phosphate 0.2300

2

Examples of Anti-Viral Effect Examination: Examination of antiviral activity of beta-glucan and carrageenan obtained by the claimed method.

A herpesvirus variant that is cytopathogenic for the swine embryo kidney (SNEV) cell cultures isolated from the blood serum of a patient with herpetic infection was used for the analysis of antiviral activity of the pharmaceutical composition. The virus-containing material was a cell culture fluid taken from SNEV cell cultures infected with herpes simplex virus at the developed level of cytopathologic manifestations. The prechallenge level of virus was 7.51 g of 50% tissue culture infective dose / 100 μΐ.

The dose of herpesvirus equal to 10.0 and 1.0 of 50% tissue cytopathic dose was used in the experiments.

Cell Cultures. Examination of antiviral activity of drug product was conducted in SNEV cell cultures sensitive to replication of herpesvirus, which were cultivated in the form of single-day cell culture monolayer in 24-slot panel on Medium 199 with addition of 7% cattle serum, penicillin, and streptomycin (100 IU/ml).

The pharmaceutical composition in various concentrations was added to the nourishing medium of SNEV cell cultures; then viability and proliferative activity of cells were observed over 4 days. The results were recorded as the percentage of viable cells and their proliferative activity.

Antiviral effect of the pharmaceutical composition on infection caused by Herpes virus in SN H V cell cultures.

50% Concentration of pharmaceutical composition (mg/ml), / % of cells that perished tissue cell culture monolayer cytop

5 2.5 1.25 0.67 0.31 0.15 Control athic

mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml

dose

10.0 55% 15% * 20% * 100% 75 % 100% 100%

1.0 25%* 0 %* 0 ^Λ 0 25% 0 %*^A 90%

Concentration of beta-glucan (mg/ml), /% of cells that perished in the cell culture monolayer

5 2.5 1.25 0.67 0.31 0.15 Control mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml

10.0 75 % 50% 50% 100% 100% 100% 100%

1.0 50% 35% 10% 0% 25% 50% 100%

Concentration of iota-carrageenan (mg/ml), % of cells that perished in the cell culture monolayer

5 2.5 1.25 0.67 0.31 0.15 Control mg/ml mg/ml mg/ml mg/ml mg/ml mg/ml

10.0 50% 50 % 50 % 75% 100% 100% 100%

1.0 50% 15% 50% 0% 15% 25 % 90%

Note: Digits in bold font show significant difference with the control

(p<0.05),

* - significant difference with beta-glucan group (p <0.05),

A - significant difference with carrageenan group (p <0.05) When a high dose of Herpes virus is used for infection of SNEV cells ( 10.0 50% tissue culture infective dose), intense antiviral effect was found when sufficient dose of the pharmaceutical composition is used that is in contrast to separate administration of beta-glucan and carrageenan that separately manifested only insignificant effect; that being the case, the effect of carrageenan was more intense.

Low dose of Herpes virus used for infection of SNEV cells (1.0 50% tissue culture infective dose) produced practically complete antiviral effect of the pharmaceutical composition.

The above data demonstrate intense additive (synergic) effect of the components in the claimed pharmaceutical composition.

Claims

1. An antiviral pharmaceutical composition comprising beta-glucan preferably as carboxymethyl beta-glucan of sodium salt and iota-carrageenan in the weight ratio from approximately 1-0.5 to approximately 1-5.

2. The antiviral pharmaceutical composition according to Claim 1 wherein it is capable for use in a spray form to be delivered by a dosing inhaler for nasal or vaginal spray.

3. The antiviral pharmaceutical composition according to Claim 1 wherein it is capable for use in the form of powder for insufflation in the interior of the human body.

4. The antiviral pharmaceutical composition according to Claim 1 wherein it is capable for use in the form of gel.