Ointment with bee moth larvae extract and propolis extract for prevention and integrated treatment of viral infection

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely an antiviral agent. An agent for influenza virus comprises an active substance in the form of an alcohol extract of bee moth larvae, an alcohol extract of propolis and an ointment base containing styrene maleic anhydride copolymer, Vaselin, emulsifier T-2, Cremophore RH-40 and Lutrol F-68, and purified water in certain proportions.

EFFECT: ointment shows manifested antiviral action on influenza virus.

3 dwg, 3 tbl, 6 ex

The present invention relates to medicine, namely to the pharmacy, and concerns the development of an ointment containing extracts of large larvae of the wax moth (LBVM) and propolis, and can be used for prevention and complex treatment of acute respiratory viral infections (ARVI), caused by the influenza virus.

Known antiviral agent-based recombinant interferon in the form of an ointment, gel, suppository, cream, liniment containing grease-forming the basis of adding nipagina and polyvinylpyrrolidone, and the trylon B, butylacetyl, DMSO and tween-80 [patent RU 2150291, 2000].

Known means in the form of a gel or ointment for external use, with anti-herpes activity, wound healing and antiviral action, which contains hyaluronic acid, trimekain, glycerin and polyethylene oxide [patent RU 2178693, 2002].

Known antiviral agent in the form of a gel containing leukocyte interferon of man as the basis of a 2%solution of a copolymer of styrene and maleic anhydride, nipagin [patent RU 2302881, 2007].

Known remedy for external use for the treatment of diseases of the skin and mucous membranes caused by herpes simplex virus, containing as an active ingredient the peptide SEQ ID NO:1 (allostatic-1), and as in pologitelnui substances glycerin, allantoin, urea, triethanolamine, carbopol 21, kemben [patent RU 2338553, 2008].

Known immunocorrigirutee tool for the treatment of diseases of viral etiology, which contains human recombinant interferon alpha and/or beta and/or gamma, anti-oxidant complex of tocopherol acetate and its derivatives, including water-soluble, and salts of ascorbic acid, calcium Pantothenate, anti-virus components, as well as support and formative components when a certain ratio of 1 g of the medicinal product, the tool includes as antiviral components - Arbidol and its derivatives, rimantadine, oseltamivir, ribavirin, an inosine pranobex (isoprinosine), glycyrrhizinic acid and its derivatives, nucleosides from series - famvir, valacyclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, lobucavir, sorivudin, brivudin, antiretrovirus - lamivudine, zidovudine, lopinavir, stavudine. The tool is made in the form of a rectal-vaginal suppositories, gel, ointment, liquid [patent RU 2411039, 2011]. The invention provides a high therapeutic effect and a high degree of bioavailability.

Known antiviral drug in the form of ointment Acyclovir 5% (Registration number R N001595/01)containing 1 g of preparation: the active substance - acyclovi is - 0.05 g; excipients: propylene glycol, medical vaseline, vaseline oil, polyethylene oxide, emulsifier [Reference Vidal. Drugs in Russia. Attraversare, 2009, strb-316]. Ointment Acyclovir 5% is used as antiviral agents for treatment of herpes simplex skin, genital herpes, localized herpes zoster (secondary treatment); varicella.

Known oxolinic ointment is a synthetic drug, active ingredient - oksolina (1,2,3,4-tetrahydro-1,2,3,4-tetractinellida dehydrate). Released: 0.25% of oxolinic ointment in tubes of 10 g; and 0.50%, 1%, 2% and 3% oxolinic ointment in tubes of 10 g, 30 g and 50 g Flu and flu prevention. Viral diseases of the skin and eyes: viral rhinitis, keratoconjunctivitis, keratitis, herpes simplex and herpes zoster, genital warts, warts, molluscum contagiosum [http://www.citopsor.com/index.php?option=com_content&task=view&id=117; http://www.piluli.ru/product/Oksolinovaya_maz]. This tool has antimicrobial, bacteriostatic action, used in therapy for the prevention and treatment of SARS, however, the absorbability of the drug when applied externally insignificant, it does not have anti-inflammatory and prolonged action.

The closest analogue of the present invention is an ointment with ionol and propolis extract for treatment the inflammatory diseases in the field of gynecology, containing BHT, oil extract of propolis 15%, a copolymer of styrene with maleic anhydride and water, purified as the hydrophilic base in the following ratio, wt.%: BHT 5,0, oil extract of propolis 15% 5,0, a copolymer of styrene with maleic anhydride 2,0, purified water up to 100.0. This tool has a durable regenerating, anti-inflammatory, antiviral action, good fixation and a uniform distribution on the mucous surface when plugging the sick, convenient and hygienic in use [patent RU 2372093, 2009].

The objective of the invention is the development of effective antibacterial and antiviral agents, the expansion of the means of local treatment of SARS.

The technical result - the creation of new medicinal products domestic production in the form of ointments with severe prolonged anti-inflammatory antiviral regenerating and anti-bacterial action with good fixation on the mucous membrane of the nose and a uniform distribution on the surface, preventing side effects, convenience and hygiene applications.

This technical result is achieved by the fact that the tool against influenza virus containing propolis extract as an active substance in an amount of 5.0 wt.% and ointment base, is with a copolymer of styrene with maleic anhydride in the amount of 2.0 wt.% and purified water to 100 according to the invention additionally contains as active substance alcohol extract large larvae of the wax moth, as propolis extract contains alcohol extract of propolis and the base further comprises petrolatum, emulsifier T-2, cremophor RH40 and lotrel F-68 in the following ratio, wt.%:

The invention is illustrated in the figure, which shows the effect of different concentrations of the excipients of cremophor RH-40 on the release of the extracts.

All components included in the composition of ointments that are allowed for medical use.

Lotrel F-68 (Lutro F-68), BASF (Germany) 9003-11-6 improves dissolution (solubilization) of active substances in the composition.

Cremophor RH-40 (Cremofor® RH-40) BASF (Germany) No. 013635/01-2002 ethoxylated hydrogenated castor oil, improves the structure of the solvent increases the bioavailability of the incorporated active substances through the surface-active properties.

Emulsifier T-2 (Russia) THE 18-17-05-76.

A copolymer of styrene with maleic anhydride (SMA) or modified stromal "Plastigel" redkosty swollen polymer (TU 6-01-02274010913-01) is the product of copolymerization of styrene with maleic anhydride (SMA)modified with ammonia, is a white powder. The appearance of 2% solution of a copolymer of styrene in water - clear or slightly cloudy liquid - gel. Soluble in water swells, soluble in glycerin, alcohol. SMA in the form of an aqueous solution of 2% gel has a pronounced antiviral effect "for the treatment of herpetic keratitis" (patent No. 2135187, 1999, IPC A61K 31/765).

Introduction to the composition of propolis extract and extract large larvae of the wax moth increases antimicrobial activity ointments, contributes to the manifestation of antiviral, anti-inflammatory, reparative action and prolonged effect of the dosage form.

In addition to the manifestations known the properties of each component of the proposed structure together strengthens their influence, because, obviously, the effect of their synergies.

As a result of experimental studies, it was found that emulsion base provides reliable fixation of the drug to the mucosal surface when natalina application, contributes to a better distribution of extracts based, emulsion base increases the bioavailability of extracts due to surface-active properties. Giving the drug form of ointment provides convenience and hygiene applications, the drug forms Nicolaus film when natalina application, has expressed a prolonged effect and storage stability.

Example 1. The composition 100,0 ointment: the alcoholic extract of propolis - 5; extract large larvae of the wax moth alcoholic - 5; petroleum jelly - 4,8; emulsifier T-2 - 1,6; cremophor RH40 - 1,6; Lutron F-68 - 2,0; SMA - 2,0; purified water up to 100.0.

Get the ointment in the following way.

In purified water dissolve lotrel add SSM to obtain a gel. Melted on a water bath emulsifier T-2, vaseline, cremophor. Alloy and gel unite. The mixture is thoroughly mixed, add the extract large larvae of the wax moth and propolis extract. The resulting homogeneous ointment, satisfactory consistency, easily distributed on the skin surface, stable, with a density of 1.1 g/cm³pH ointment to 6.0. MAZ is easily applied on the mucous membranes of the covers with the formation of a smooth continuous stroke, Lis has a prolonged action, as well as the convenience and hygiene of application due to the proposed composition of the ingredients.

We studied the effect of concentration of cremophor RH40 - 1.6 g on the release of the extracts in vitro by thin layer chromatography (TLC). The definition of pharmaceutical availability were carried out in a solvent system selected earlier (table 1) ethyl acetate:ethanol:ammonia (85:10:5) in a chromatographic chamber bottom-up fashion on the plates of the brand "Silufol". Time-keeping records in the chamber was the same and amounted to 13 minutes.

Thus, the optimum content of cremophor in the ointment is the value of 1.6% (figure).

Example 2. The composition 100,0 ointment: the alcoholic extract of propolis - 5; extract large larvae of the wax moth alcoholic - 5; petroleum jelly - 4,8; emulsifier T-2 - 1,6; cremophor RH40 - 1,0; Lutron F-68 - 2,0; SMA - 2,0; purified water up to 100.0.

Make an ointment in a similar way. The resulting homogeneous ointment, satisfactory consistency, easily distributed on the skin surface, stable, density -1,1 g/cm³pH ointment to 6.0. The ointment is easy to apply on the mucous membranes of the covers with the formation of a smooth continuous stroke, has expressed prolonged action, as well as the convenience and hygiene of application due to the proposed composition of the ingredients.

We studied the effect of concentration the AI cremophor RH40 - 1.0 g on the release of the extracts in vitro by thin layer chromatography (TLC). The definition of pharmaceutical availability were carried out in a solvent system selected earlier (table 1), ethyl acetate:ethanol:ammonia (85:10:5) in a chromatographic chamber bottom-up fashion on the plates of the brand "Silufol". Time-keeping records in the chamber was the same and amounted to 13 minutes.

Thus, the number of 1.0 g of cremophor RH 40 in the ointment is not enough, as marked by reduced release of active substances - extracts of large larvae of the wax moth and propolis extract (figure).

Example 3. The composition 100,0 ointment: the alcoholic extract of propolis - 5; extract large larvae of the wax moth alcoholic - 5; petroleum jelly - 4,8; emulsifier T-2 - 1,6; cremophor RH40 - 2,0; Lutron F-68 - 2,0; SMA - 2,0; purified water up to 100.0.

Make an ointment in a similar way. The resulting homogeneous ointment, satisfactory consistency, easily distributed on the skin surface, stable, with a density of 1.1 g/cm³pH ointment to 6.0. The ointment is easy to apply on the mucous membranes of the covers with the formation of a smooth continuous stroke, has expressed prolonged action, as well as the convenience and hygiene of application due to the proposed composition of the ingredients.

We studied the effect of concentration of cremophor RH40 - 1.0 g on the release of the extracts in vitro by the method of thin-layer is cromatografia (TLC). The definition of pharmaceutical availability were carried out in a solvent system selected earlier (table 1), ethyl acetate:ethanol:ammonia (85:10:5) in a chromatographic chamber bottom-up fashion on the plates of the brand "Silufol". Time-keeping records in the chamber was the same and amounted to 13 minutes.

Thus, the amount of 2.0 g of cremophor RH40 in the ointment is redundant, as noted reduced release of active substances - extracts of large larvae of the wax moth and propolis extract (figure).

Example 4. The composition 100,0 ointment: the alcoholic extract of propolis - 5; extract large larvae of the wax moth alcoholic - 5; petroleum jelly - 4,8; emulsifier T-2 - 1,6; cremophor RH40 - 1,0; Lutron F-68 - 2,0; SMA - 1,0; purified water up to 100.0.

Make an ointment in a similar way. The resulting homogeneous ointment, liquid consistency, density 0.9 g/cm³pH ointment to 6.0. When applying drains from the surface, smear uneven, there is no effect of the extension.

Example 5. The composition 100,0 ointment: the alcoholic extract of propolis - 5; extract large larvae of the wax moth alcoholic - 5; petrolatum 22, 0mm; emulsifier T-2 - 10,0; cremophor RH40 - 10,0; Lutron F-68 - 8,0; SMA - 2,0; purified water up to 100.0.

Get the ointment in the following way.

In purified water add SSM to obtain a gel. Melted on a water bath emulsifier T-2, vaseline, cremophor, lotrel. Alloy and gel unite. The mixture is thoroughly mixed, add extract large larvae of the wax moth and propolis extract. The resulting ointment is homogeneous, dense consistency, with work distributed on the skin surface, stable, with a density of 1.6 g/cm³pH ointment to 6.0. To apply the ointment on the mucous coverings difficult, uneven smear.

Example 6. The composition 100,0 ointment: propolis extract alcohol - 5; extract large larvae of the wax moth alcohol - 5; petroleum jelly - 20,0; emulsifier T-2 - 10,0; cremophor RH40 - 10,0; Lutron F-68 - 20,0; purified water up to 100.0.

Get the ointment in the following way.

Melted on a water bath emulsifier T-2, vaseline, cremophor, lotrel. In parts add purified water. The mixture is thoroughly mixed, add the extract large larvae of the wax moth and propolis extract. The resulting homogeneous ointment, unsatisfactory viscous consistency, not evenly distributed on the surface of the skin, forming a viscous film, stable, with a density of 1.6 g/cm³pH ointment to 6.0. To apply the ointment on the mucous coverings difficult, uneven smear.

The given examples show that the optimal from the point of view of consistency, ease of use, effectiveness of treatment is the composition described in example 1.

Determination of antimicrobial activity ointment containing 5% propolis extract and 5% extract large larvae of the wax moth, conducted according to customers is avanian, requirements for dosage forms, namely antibacterial properties on the composition of the ointment of example 1. Studies of the antibacterial efficacy of the ointment was carried out according to the method described in the global Fund XII ed., CFC 42-0068-07 (Table 2).

The proposed dosage form is an ointment containing propolis extract and extract large larvae of the wax moth, easy to use and has a wide field of use in the prophylaxis and complex treatment of acute respiratory viral infection caused by the influenza virus.

Agent against influenza virus containing propolis extract as an active substance in an amount of 5.0 wt.% and ointment base comprising a copolymer of styrene with maleic anhydride in the amount of 2.0 wt.% and purified water, characterized in that it additionally contains as active substance alcohol extract large larvae of the wax moth, as propolis extract contains alcohol extract of propolis and the base further comprises petrolatum, emulsifier T-2, cremophor RH40 and lotrel F-68 in the following ratio, wt.%: