Pharmaceutical composition with antiviral activity and its preparation

 

(57) Abstract:

The pharmaceutical composition comprises, in wt.%: as the active ingredients of acyclovir 0,1 - 10,0, as auxiliary substances hydrophobic component of 5.0 - 35,0, polyethylene oxide (mol.m. at least 900 0,1 - 10,0; propylene glycol 15,0 - 65,0; the emulsifier is 0.5 to 15.0 and water the rest. A new pharmaceutical composition get a consistent mixture of a hydrophobic component containing an emulsifier, an aqueous solution of polyethylene oxide and suspension of acyclovir in propylene glycol. A new pharmaceutical composition in the form of soft medicinal forms - ointment characterized by stability during storage and shows high penetration of acyclovir through the skin barrier and, consequently, a high therapeutic effect. 2 S. and 2 C. p. F.-ly, 3 tables.

The invention relates to medicine, specifically to pharmaceutical compositions for the treatment of viral diseases of the skin and mucous membranes caused by a simple virus or herpes zoster, and prevention of these diseases in patients with immune system disorders.

Creating drugs for the treatment of viral lesions of the skin and mucous membranes is especially the shaft of therapeutic agents. Acyclovir [9-(2-hydroxyethoxymethyl)guanine], inhibiting the multiplication of the herpes virus and with no impact on cellular metabolism uninfected cells, exhibits highly selective therapeutic effect [Mashkovsky M. D. Drugs, so 2, ed. 13th, Kharkov: Torsing, 1997, S. 357].

In the patent of the USSR N 1375113, 1988, describes an antiviral composition containing the following ingredients, wt.%:

Acyclovir - 5,0

The hydrophobic phase (paraffin) is 17.5

Propylene glycol - 40,0

Emulsifier - 7,5

Water - 30,0

For obtaining the known composition of the mixed acyclovir with water and propylene glycol and dispersed hydrophobic phase containing the emulsifier, at a temperature of 70oC.

However, this composition is characterized by a low level of release of the active substance and penetration through the skin.

Enhancing transdermal penetration of acyclovir through the skin barrier can be achieved by incorporating in the composition of the glycerol-formula (RF patent N 2128503, 1999). For example, the described composition of the following composition, wt.%:

Acyclovir - 5,0

Hydrophobic component, including

White petrolatum 12,65

Liquid paraffin - 11,4

Rina, stearic acid) - 8,0

Methyl ester of p-oksibenzoynoy acid (preservative) - 0,15

Propyl ester of p-oksibenzoynoy acid (preservative) - 0,08

Water - the rest

A well-known composition is obtained by dispersing at 57-63oC acyclovir in a mixture of water, clearinggmos and other organic solvent in which is dissolved preservatives, followed by emulsification with other ingredients in the specified temperature range.

The disadvantages of the known compositions should include multicomponent composition emulsion (more than 10 ingredients), which is caused by the need to ensure stability of the composition over time, as well as the need preservatives to prevent microbial contamination. In addition, a significant increase in the number of auxiliary substances complicates the technology of production.

The purpose of this invention is to provide pharmaceutical compositions in the form of soft medicinal forms - ointment with optimal qualitative and quantitative ratio of auxiliary substances.

The technical result obtained by implementing the present invention, is stability-high volt the VA through the skin barrier and, accordingly, a high therapeutic effect of the new structure.

This technical result is achieved by the fact that the proposed pharmaceutical composition comprising as the active ingredients of acyclovir and as auxiliary substances hydrophobic component, propylene glycol, emulsifier and water, further comprises a polyethylene oxide with a molecular weight of not less than 900 in the following ratio of ingredients, wt.%:

Acyclovir - 0,1-10,0

Hydrophobic component - 5,0-35,0

The polyethylene oxide with a molecular weight of at least 900 - 0,1-10,0

Propylene glycol - 15,0-65,0

The emulsifier is 0.5 to 15.0

Water - the Rest

The introduction into the composition of polyethylene oxide with a molecular weight of not less than 900 along with the use of any other claims of auxiliary substances in the specified ratio is achieved stability of the composition during storage, which gave the opportunity to increase the shelf life (over 3 years) compared with samples in which the above-mentioned type of polyethylene oxide is replaced by an equivalent amount of low-molecular-weight polyethylene oxide (average molecular weight of less than 900). At the same time improves the penetration of the active substance from the dosage form, allowing obessessive effects.

As the hydrophobic component can be used hydrocarbons such as vaseline, paraffin, vaseline oil, derivatives of fatty acids, such as lanolin, beeswax, castor oil, also known as hydrophobic bases commonly used in pharmaceutical practice, such as silicones, or mixtures of the above ingredients, preferably petrolatum or liquid paraffin, or a mixture.

As the emulsifier may be used surfactants of ionic or nonionic types, such as high molecular weight alcohols, their oxyalkylene derivatives, sodium salts of sulfonic ethers of these alcohols, the twins, spiny, zhirosahar or mixture of surfactants. Examples of emulsifiers are emulsifiers N 1 (mixture of primary higher fatty alcohols with a number of carbon atoms of 16 to 20 and sodium salts of sulfonic ethers of such alcohols) or emulsifier brand "Lanette" (a mixture of high molecular weight alcohols with the number of carbon atoms from 14 to 20, mainly cetyl and stearyl, and, optionally, sodium alkyl sulphates (mainly nutriceuticals and netresearchserver), or emulsifying wax (corresponding to the requirements of the British Pharmacopoeia 1998)

The way the ATOR, with an aqueous solution of polyethylene oxide with a molecular weight of at least 900 and a suspension of acyclovir in propylene glycol. The preferred temperature for carrying out the mixing of the ingredients is 50-60oC.

The obtained pharmaceutical composition complies with the requirements of the global Fund XI (in appearance, microbiological purity and other parameters), stable in storage and has a shelf life of over 3 years.

Study of antiviral activity of a new composition was conducted on the model of herpetic keratitis rabbits. For infection used the herpes virus simple type I strain "Koptev" with ceratotropis properties. In the work were used rabbits of the chinchilla breed weighing 2.0 to 2.5 kg of Infection of rabbits with herpes simplex virus produced on scarificing the cornea of the eye according to the standard technique (Maevskaya T. M., Kukhar E. E. Herpetic keratitis in rabbits. In the book: Methods of experimental chemotherapy. M. "Medicine", 1971, S. 281-285; Michuk Y. F. Viral diseases of the eye. M. "Medicine", 1981, S. 16-28).

For the evaluation of experimental infections were considered typical clinical picture of the destruction of the rabbits ' eyes. Once infected animals systematically the dynamics were evaluated by the main signs of herpetic keratoconjunctivitis in infected animals: the amount of infiltration and erosion of the cornea, development pericorneal injection of the vessels of the eyeball, hyperemia of the conjunctiva, swelling and redness of the eyelids, the vascularization of the cornea and inflammation of the iris. When assessing the magnitude of erosion and infiltration of the cornea defeat to 25% of its area was accepted for 1 point, from 25% to 50% - 2 points, more than 50% - 3 points.

Next, calculate the average index of clinical signs of keratitis in each group of rabbits. This summed up the points describing the defeat of all the infected eye in a group and divide by the number of eyes. Comparing the average index of clinical signs of keratitis in the groups of treated and control animals, judged the effect of the claimed composition on the clinical course of experimental infection. In addition, to calculate the integral index of clinical signs of keratitis since the start of treatment to cure the rabbits. This summarized the average indexes of clinical signs of keratitis on each observation day and divide by the number of observations. The difference value of the integral index of clinical symptoms of keratitis in the treated group of animals and the placebo group clearly demonstrates the effectiveness of the drug on the model of herpetic cerinah and treated rabbits.

Previously in intact rabbits was studied portability of the claimed composition. The application was performed twice a day for seven days. Daily visual inspection of rabbits using fluorescein sample was not marked irritation of the eye tissue of rabbits.

Treatment was started with clinically severe keratitis after 72 hours after inoculation of the virus in the cornea of the rabbit. Application of the ointment was performed 2 times a day every day for 7 days. When studying the antiherpetic activity of the claimed composition in the quality control used the group of animals receiving placebo (based ointment without active substance). Each group contained 6 infected rabbits ' eyes. Statistical analysis was performed using the criterion of the probability of the difference between the mean values for the Student.

The results are presented in tables 1, 2. As can be seen from the data presented in table 1, already 2 days after the start of treatment (day 5 after infection) the severity of experimental infection in the group treated rabbits was significantly lower than in control group of animals receiving placebo. Upon further observation paths a new composition marked regression of symptoms of keratoconjunctivitis. On day 11 after infection in patients with severe keratoconjunctivitis control animals (average index of clinical course was equal 8,50,7 points) defeat in the eyes treated rabbits were absent.

therapeutic effect of the claimed composition was manifested not only in reducing the severity of the clinical course of keratoconjunctivitis, but in a significant (2-fold) reduction of terms of treatment of animals (PL. 2).

Thus, the study of antiviral activity of the claimed composition in experimental herpetic keratitis rabbits showed that it has a pronounced therapeutic effect, reducing the severity of clinical course and duration of infection.

The invention is illustrated by the following examples (see Table 3):

Example 1. A mixture of vaseline medical (3.2 g, 3.14 wt.%), vaseline oil(1.9 g, of 1.86 wt.%) and emulsifier N 1 (3.1 g, 3.0 wt.%) heated to a temperature of 50-60oC. To the resulting melt consistently gain of 22.2 g of an aqueous solution of polyethylene oxide with average molecular weight of 1500 made from 2,05 g of polyethylene oxide 1500 (2.0 wt.%), and suspension of acyclovi laidout.

The resulting ointment meets pharmaceutical agent (in appearance, microbiological purity and other parameters).

Examples 2,3 perform similarly, with the difference that in example 2 is used, the polyethylene oxide with a molecular weight of 900 and an emulsifier "Lanette SX" and "example 3" - polyethylene oxide with a molecular weight of 4000. The obtained composition (ointment) satisfy the requirements of the pharmaceutical agent. Results the manufacture of ointments are presented in Table 3.

1. Pharmaceutical composition having antiviral activity, which comprises as the active ingredients of acyclovir and as auxiliary substances hydrophobic component, propylene glycol, emulsifier and water, characterized in that it further comprises a polyethylene oxide mol.m. not more than 900, the following ratio of ingredients, wt.%:

Acyclovir - 0,1 - 10,0

Hydrophobic component - 5,0 - 35,0

The polyethylene oxide is not less than 900 - 0,1 - 10,0

Propylene glycol - 15,0 - 65,0

The emulsifier is 0.5 to 15.0

Water - the Rest

2. The pharmaceutical composition under item 1, characterized in that it contains as a hydrophobic component petrolatum or liquid paraffin, or a mixture.

4. A method of obtaining a pharmaceutical composition, characterized in PP. 1 to 3, which includes the sequential mixing a hydrophobic component containing an emulsifier, an aqueous solution of polyethylene oxide (mol.m. at least 900 and a suspension of acyclovir in propylene glycol.

 

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