Antiviral agent for external use on the basis of hyaluronic acid

 

(57) Abstract:

The invention relates to medicine and relates to antiviral agents for external use, with anti-herpes activity, wound healing and antiviral action. The invention lies in the fact that the product contains hyaluronic acid, trimekain, glycerin and polyethylene oxide. The drug is produced in the form of a gel or ointment. View of the dosage form depends on the molecular weight of the used polyethylene oxide. The invention provides improved therapeutic activity, enhances transdermal effect. 1 C. p. F.-ly, 1 table.

The invention relates to medicine and relates to antiviral agents for external use based on hyaluronic acid, which has anti-herpes activity, wound healing and anti-inflammatory action.

Hyaluronic acid is a natural mucopolysaccharide. Biological significance of her is that she is one of the most important components of connective tissue, is involved in almost all vital processes of the body. Hyaluronic acid is a high molecular weight, vyakarnam and wound-healing effect. Due to its unique properties it finds application in various fields of medicine, cosmetics and veterinary medicine. A promising direction is the use of its in pharmacy as prolongator effects of prescription drugs. In recent years, hyaluronic acid is used as a biological protector for eye operations and inflammatory diseases of the eye, used to stimulate bone formation and to replace the synovial fluid in the joints. Hyaluronic acid has proven to be an effective tool in the treatment of patients with malignant neoplasms. Hyaluronic acid is widely used in the manufacture of cosmetics, because due to the high hydrophilicity forms with water high viscosity gel, with a unique ability to moisturize the skin and mucous membranes. The presence of hyaluronic acid disinfectant and wound healing actions, as well as the ability to induce regeneration of the epithelium is allowed to create effective and safe drugs for the treatment of burns, ulcers and radiation injuries of the skin. Treatment with hyaluronic acid has a number of features, most important of which are high the th of therapeutic action. Data are available about the use of hyaluronic acid and its derivatives as antiviral agents for treatment of herpes virus [1] .

Herpes viruses is a large DNA-containing viruses. Primary infection with herpes simplex virus is a contact way. When the reproduction of the virus in the body develops clinical picture of the disease in the form of fever with the appearance of herpetic vesicles, which are located on the skin and mucous membranes. The disease often does not end with the liberation of the body from the virus enters a latent form with frequent exacerbations. Therefore, the problem of the treatment of persistent viral infections continues to be very relevant. To ensure herpesvirus infections range of products is small. All of the known drugs can be divided into three groups: 1 - nucleoside analogues, with mainly local effects, these drugs have a selective inhibitory effect on virus replication, does not induce the production of interferon, do not prevent the penetration of the virus into the cell; 2 - preparations of vegetable and synthetic origin, causing degradation of extracellular viruses; 3 - drugs, actica the drug acyclovir (domestic analogue - ribamidil), produced in the form of solution for injection, tablets, capsules, suspensions, lotions, eye ointments. Low toxicity of acyclovir is due to the fact that he becomes active in the presence of virusspecific timedancing, affecting thus only in infected cells, thereby blocking the synthesis of viral DNA and protecting uninfected cells. The drug inhibits the human herpes virus [2] . The main drawbacks of the drug: low bioavailability, are contraindicated in patients with hypersensitivity, pregnant and lactating women, in addition, the treatment process very quickly develops resistance to viruses, and the observed side effects: vomiting, headache, diarrhea, allergic rashes.

Known close to the acyclovir drugs, such as ganciclovir, vidarabine, ribavirin, idoxuridine, and so on [2,3] . The disadvantages of these drugs are the possible changes in the blood picture, cardiovascular and nervous system, gastrointestinal tract, allergic reactions, alopecia, hypercalcemia, thrombophlebitis. Drugs contraindicated in children.

Known anti-herpes drug, produced in the form of lip qararat zinc), as well as other additives, in particular politicsservicesemail ester of fatty acid and polyethylene glycol, molecular weight ranging from 300 to 4000 [4] . The drug has a very complex composition, which leads to certain difficulties in the production and affects its cost. The drug has a number of contraindications, as the application of sodium heparin and zinc salts are observed side effects, which makes it widely used.

For the treatment of viral herpes apply hyaluronic acid. The plot of the epithelium is affected by this virus, the cause of hyaluronic acid or biocompatible salt form [5] . The disadvantages of this drug can be attributed to poor transdermal properties, the drug is rapidly dries, tightens the skin, while the exposure time is it on the affected area is very limited.

When herpes conditions apply product containing urea in an amount of 0.1-40%, hyaluronic acid or its salt in an amount of 0.05-25%, and a pharmaceutically acceptable carrier. The tool get in the form of ointment or gel [6] . When using urea in the composition of the drug may experience unwanted side effects, in addition, S="ptx2">

Closest to the claimed means - the prototype is the product on the basis of hyaluronate and polyethylene oxide. Hyaluronate has a molecular weight of 50,000 - 5000000, and the polymer -1000000 [7] . Preparation prepare water-based.

The disadvantages of this drug are:

- suboptimal dosage form in aqueous solution, which leads to a high consumption of substances in the treatment and reduces the contact time of the drug with the affected area because of its fast drying;

- lack of analgesic effect;

- poor transdermal properties.

The objective of the invention is to increase therapeutic activity of the drug, which has antiviral and analgesic action.

The problem is solved by obtaining antiviral agents for external application on the basis of hyaluronic acid containing mucopolysaccharide and the polyethylene oxide used in the form of ointment or gel. As mucopolysaccharide use hialuronowy acid. The preparation additionally contains a local anesthetic agent - trimekain, softening and prolonging tool - glycerine in the following ratio, wt. %:

- the steel

The drug is produced in the form of a gel or ointment. View of the dosage form depends on the molecular weight of the used polyethylene oxide and quantitative correlation with other components of the drug.

Part of the hyaluronic acid is derived from the crests of birds (TU 9316-014-0566401) in a known manner [8,9] . Hyaluronic acid has a high viscosity and elasticity, when mixed with water, forms a viscous gel that moisturizes the skin and mucous membranes. In composition it has antiviral, wound healing and anti-inflammatory, promotes regeneration of the epithelium, reduces puffiness and reduces itchy skin, does not cause clinical complications. Hyaluronic acid has a pronounced anti-inflammatory properties and as a consequence reduces pain. At the same time, hyaluronic acid performs a purely mechanical protection of the affected areas, as it forms thin film that prevents the penetration into the wound environmental factors - disease-causing agents. A pronounced antiviral effect observed at a concentration of hyaluronic acid 5.0 mg/ml or more (see table).

As aneste the EU ETS, reduce or completely suppress the excitability of sensory nerve endings and inhibiting conduction of excitation along the nerve fibers. Trimekain an active local anesthetic substance that causes severe and prolonged conduction and infiltration anesthesia. Trimekain little toxic, has an analgesic effect, it is a local loss of sensation.

Glycerin is included in the drug as a solvent and a base. It is hygroscopic, water and alcohol are miscible in any ratio. Glycerin reduces the irritant effects of many drugs, almost not absorbed through the skin, but is well absorbed mucous membranes. Used in medicine chiefly as an external agent.

As the carrier used indifferent synthetic polymer is polyethylene oxide with a molecular weight of 1000-6000 mm. Yes, mostly 1500 Yes authorized for use in medicine (Pharmacopeia 42-1885-82 "polyethylene oxide 1500"). The polyethylene oxide is a white or gray mass, easily soluble in water, alcohol, chloroform, forms a transparent or slightly turbid solutions. Used as a component for the preparation of the ointment basis has significant advantages over the fat bases, because it has high penetrating power, accelerating the absorption of intact skin and mucous membranes, the active substance of this drug. The polyethylene oxide is non-toxic, soluble in water.

Antiviral agent for external use on the basis of hyaluronic acid obtained by mechanical mixing to the formation of homogeneous mass. Ready the product is a homogeneous, colorless mass of gel-like or buttery consistency.

During the development of this drug was a study of antiviral activity of hyaluronic acid on the herpes virus, studied the effects of hyaluronic acid directly to the virus and its reproduction within the cell. Tested in a clinical setting. It is shown that the obtained product has a strong antiviral, wound healing and anti-inflammatory action and can be recommended in clinical practice for the treatment of herpesvirus infections.

New compared to the prototype is:

- the use of trimekainom to obtain an anesthetic effect;

- the use of glycerol as solvent and base, as well as for umaczenie drug in ointment form or in gel form.

In the search for sources of patent and scientific and technical information is not revealed information about the drug with antiviral effect, similarly claimed.

The invention is illustrated by examples of specific formulations of the proposed drug and the study of its antiviral activity and application.

Example 1.

To prepare 100 g of the drug to 93,5 g of polyethylene oxide added 0.5 g of hyaluronic acid, 1 g of trimekainom and 5 g of glycerin. The mixture was thoroughly stirred until a homogeneous mass and Packed in packagings made of dark glass. Stored for 6 months at a temperature of 4 to 10oC.

Example 2.

To prepare 100 g of the drug to 79 g of polyethylene oxide added 3 g of hyaluronic acid, 3 g of trimekainom and 15 g of glycerin. The mixture was thoroughly stirred until a homogeneous mass and Packed in packagings made of dark glass. Stored for 6 months at a temperature of 4 to 10oC.

Example 3.

A study of the effect of hyaluronic acid on the development of herpetic infection in cell culture. Hyaluronic acid is obtained from the crests of birds according to the method [8,9] . Use transplantable cell line 4647 (green monkey kidney) and herpes virus type II (HSV-2) with siyvaruli fruits cows. A supportive environment is reduced levels of serum to 2%.

To study the effects of hyaluronic acid on the reproduction of HSV-2 cell monolayer infected by a virus in Tigre 0,1 JRS50/cell treated with hyaluronic acid at a concentration of 0,5; 1,0; 2,5; 5,0; 10,0; 20,0 mg/ml Pronounced antiviral effect observed at a concentration of hyaluronic acid 5.0 mg/ml or more. The data presented in the table.

Example 4.

The group of patients with a diagnosis of herpes simplex skin treatment with the antiviral agent for external use based on hyaluronic acid of the following composition, wt. %: hyaluronic acid 0,5; trimekain 1,0; glycerol 5,0; polyethylene oxide 93,5. The drug used in the manifest forms of herpes infection of the skin with mild clinical symptoms. The use of this drug is recommended in the initial stage of the disease before the appearance of herpetic vesicles, in this case, to achieve a positive effect was enough for one application. The tool was applied topically in a thin layer to areas of epithelium affected by the herpes virus.

Example 5.

Patients with a diagnosis of herpetic lesions and kislota 3,0; trimekain 3,0; glycerin 15; polyethylene oxide 79,0. During treatment there was a characteristic pattern of disease with the appearance of herpetic vesicles, which were located on the border of the skin and mucous membranes. The areas affected by herpes virus, a thin layer was applied medication 5 times a day for 3-5 days. 2-3 days of treatment, the lesions cleared purulent-necrotic discharge, inflammation was reduced, began active epithelization of the affected surface, 4-5 days came full recovery. When treatment with this drug complications and recurrence was not observed.

Due to the presence of the proposed antiviral agent hyaluronic acid, trimekainom, glycerol and polyethylene oxide are pain relief and enhancement of therapeutic activity of the drug, which allows the tool to effectively influence herpesvirus infection, reduce inflammation, edema, hyperemia, and significantly reduce the activity of the bacterial flora and the proliferation of germs, accelerate epithelization and healing.

The inventive tool can be recommended for treatment and prophylaxis of herpes infections.

infection", Ed. by C. M. Granite, L. C. Sultanov, 70-80 C., Barnaul, 1996.

3. U.S. patent N 4499084 "Antiviral composition containing ARA-A and the method of its introduction, a 61 K 31/70.

4. European application N 0045252 "Antiherpes virus effect of current lip pencil, its use for treatment of diseases of the lips and other parts of the face, caused by human herpes virus, And 61 To 7/027.

5. The international application N 90/14095 "Method of local treatment of herpes virus in humans", a 61 K 31/715.

6. U.S. patent N 5631242 "Pharmaceutical preparations of hyaluronic acid and urea, used to treat skin", a 61 K 38/16.

7. U.S. patent N 5266563 a Mixture of jojoba and polyethylene oxide, And 61 To 7/15.

8. I. F. Radaev, G. A. Kostin "Getting hyaluronic acid from the crests of birds". Biotechnology, 5, S. 44-47,1996.

9. RF patent N 2102400 "Method of production of hyaluronic acid", 08 At 37/08.

1. Antiviral agent for external use, containing hyaluronic acid, pharmaceutically acceptable carrier in the form of ointment or gel, characterized in that it further contains glycerin, a local anesthetic agent, as the carrier of the polyethylene oxide 1500 in the following ratio of components, polyethylenoxide 1500 - Else

2. Means under item 1, characterized in that as a local anesthetic tools use trimekain.

 

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