WO2011151667A1

WO2011151667A1 - Antiviral compositions

Info

Publication number: WO2011151667A1
Application number: PCT/IB2010/001872
Authority: WO
Inventors: Adbula Kurkayev
Original assignee: Adbula Kurkayev
Priority date: 2010-06-02
Filing date: 2010-06-02
Publication date: 2011-12-08

Abstract

The present invention relates to antimicrobial compositions. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxamer and auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio: Titanium dioxide or silicon dioxide or barium sulfate 0.05-5.0, HPBCD - 0.05-50, Excipient -0.1-20, Glycerol - 10-20, Purified water - up to 100. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxamer, auxiliary additives selected from a group containing glycerol, propylene glycol, and paraffin oil in following per cent ratio: Titanium dioxide or silicon dioxide or barium sulfate - 0.05-5.0, HPBCD - 0.05-50, Excipient -0.1-20, Glycerol -10-20, Paraffin oil -1.0-2.0, Purified water - up to 100. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient of polymeric origin selected from a group containing natural Sodium deoxyribonucleate (DNA) or gelatin and auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio: Titanium dioxide or silicon dioxide or barium sulfate -0.05-5.0, HPBCD -0.05-50, polymeric excipient -0.01-20, Glycerol -10-20, Purified water -up to 100. Nanocomposite formulations under the present invention reduce viral infections by a factor of 100, in vitro.

Description

ANTIVIRAL COMPOSITIONS

FIELD OF TECHNIQUE

The present invention relates to antimicrobial compositions, as well as household chemical, personal care and pharmaceutical products including the compositions and methods for making and using the compositions. Moreover, the present invention concerns compositions that exhibit improved antimicrobial potency via synergistic interaction between organic and inorganic components, thus are suitable for effectively decreasing the incidence of microbial, bacterial, fungal and viral infections. Such viral infections are in particular infections caused by envelope-type viruses, such as Hepres viruses, human immunodeficiency virus (HIV) different types of Influenza and Hepatitis viruses. The compositions according to the present invention moreover, are suitable for preventing and treating sexually-transmitted bacterial and fungal infections. Such inflections are for instance caused by Chlamydia trachomatis, different Aspergillus strains and Candida albicans, and these infections can be controlled both in a curative and preventive manner by local administration of parent and chemically modified cyclic oligosaccharides (called cyclodextrins) together with nano-sized metal or metalloid oxide particles (such as barium-oxide, barium-sulfate, titanium-dioxide, silicon-dioxide etc .) dispersed in water.

BACKGROUND OF THE INVENTION Antimicrobial effect of certain inorganic metal salts and metal oxides (titanium- dioxide, barium-sulfate and silicon-dioxide) used in various personal care products (skin care, sunscreen, dental hygiene products) and also in pharmaceuticals is well known.

Nanosized metal and metalloid oxides such as titanium-dioxide and silicon- dioxide - due to their unique submicrometer size and nano-crystalline state - possess various remarkable properties with physiological, pharmacological and therapeutic utilities, like inhibition of microbial growth, acting as preservative agents, prevention of reactive oxygen species (ROS) -related cellular damages.

Upon exposure to light/irradiation, these nanoparticles exhibit antimicrobial effects.

Cyclodextrins are enzyme-modified starch derivatives prepared from hydrolyzed starch by the action of CTG-ase (cyclodextrin-glycosyl transferase) enzyme. (Szejtli, J.: Cyclodextrin Technology, 1988. Kluwer Academic Publ. Co. Dordrecht, the Netherlands) Cyclodextrins comprise glucose units arranged to a torus, by alpha-1 ,4-glycosidic linkages.

The most commonly used types of cyclodextrins are 6-membered alpha- cyclodextrin, 7-membered beta-cyclodextrin, and 8-membered gamma- cyclodextrin, respectively. Cyclodextrins have been disclosed as being useful for decreasing viral infections alone and in combinations with antiviral pharmaceutical actives.

Cyclodextrins have also been used to form inclusion complexes with antimicrobial pharmaceutical active drugs as a means of ensuring the improved water solubility, enhanced delivery of the active compounds to a patient in need thereof as described, for example by the following examples: Cyclodextrin complexes with Itraconazol and combinations are described as formulations of improved aqueous solubility and better bioavailable forms of the antifungal drug. Clin. Pharmacol. (1998), 38(7), 593-602; Antimicrob. Agents Chemother. (1997), 41 (11 ), 2554-2558.

PCT Int. Appl. WO 2000023454 27 April 2000 discloses ribavirin/cyclodextrin combinations. A method for treating a patient having chronic hepatitis C infection to eradicate detectable HCV-RNA involving a combination therapy using a therapeutically effective amount of ribavirin derivatives in suitable combinations with hydroxypropyl-beta-cyclodextrins to improve the oral bioavailability of the antiviral drugs in vivo.

Besides linear polysaccharides, cyclic oligosaccharides including cycloaltrins, cyclofructins, cyclodextrins, cyclomannins etc. in their natural forms and in particular when bearing anionic substituents represent a class of substances that are known to interact with certain compounds occurring in cell surfaces and thus providing remarkable antimicrobial effects. In particular, sulfated- and sulfoalkylated, and carboxyalkylated negatively charged types of cyclic oligosaccharides are known to exert such a microbial potency.

PCT Int. Appl. WO 2008063634 A1 29 May 2008 relates to pharmaceutical formulations of benzodiazepine compounds, which are active against respiratory syncytial virus (RSV), suitable for parenteral administration for treatment of a RSV infection in pediatric patients. Thus, 6 mg/mL (S)-1-(2-fluorophenyl)-3-(2- oxo-5-phenyl-2,3-dihydro-1H- benzo[e][1 ,4]diazepin-3-yl)urea (free base equivalent) was dissolved in 40% hydroxypropyl beta-cyclodextrin, with addition of 15 mM phosphate buffer, pH 7. The lyophilized cake of this solution, was reconstituted with 3.8 mL of 5% dextrose solution, to obtain 4.4 mL of 3 mg/mL (S)-1-(2-fluorophenyl)-3-(2- oxo-5-phenyl-2,3-dihydro-1 H-benzo[e][1 ,4]diazepin-3- yl)urea in 20% HPbeta-CD.

Bencini M. et al in Journal of Controlled Release, 126(1), 17-25 2008 described preparation and use of poly(amidoamine) (PAA) copolymer with beta- cyclodextrin, by reacting 6-deoxy-6-amino-beta- cyclodextrin and 2- methylpiperazine to 2,2-bis(acrylamido)acetic acid. This beta-CD/PAA copolymer bears beta-Cyclodextrin units along the macromolecular chain, is water-soluble and non-cytotoxic. The complexing capacity of beta-Cyclodextrin based copolymer was determined using an antiviral drug, Acyclovir, as a model of poorly water-soluble drug. The antiviral activity of Acyclovir beta-CD/PAA polymer complex was evaluated against herpes simplex virus type I in cell cultures. The Acyclovir beta-CD/PAA complex exhibited a higher antiviral activity than the free drug.

Combinations of organic oligo- and polymers with inorganic nanoparticles

Jpn. Kokai Tokkyo Koho JP 2009209075 A 17 Sep 2009 describes titanium dioxide-apatite complex particles and cyclodextrins claimed as antibacterials for oral hygiene to remove virus and inflammation in the oral cavity and pharynx. The title antibacterials can be used as oral sustained-release preparations, buccal agents, and troches. The agent for oral hygiene aiming at the removal of the bacteria, which replace the hygienic mask or contain the virus in the oral cavity and the pharynx with use of the hygienic mask is provided concerning the agent for oral hygiene for making the prevention and therapy of the inflammatory disease in the removal of the bacteria containing the virus in the oral cavity and the pharynx. It is considered as the agent for oral hygiene containing titanium dioxide particles and cyclodextrin. Titanium dioxide particles are suitably used in complex forms with the apatite. By these actions, the inflammation in the removal of the bacteria containing the virus in the oral cavity and the pharynx is claimed.

DISCLOSURE OF THE INVENTION The object of present invention concerns the preparation of antiviral compositions based on stabilized metal- oxide dispersions in combination with different excipients and additives to prevent and control infections caused by herpes virus family.

These excipients ensure the long-term kinetic stability of the dispersed nanoparticles, eliminate incompatibility between dispersed nanoparticles and (2- hydroxy)propyl beta-cyclodextrin (HPBCD). The resulting gel forms also improve spreadability. The film-forming properties enable the antiviral components taking effect for extended time.

The object is reached in following way.

Variants offered:

Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxamer and auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio:

Titanium dioxide

or silicon dioxide 0.05-5.0

: or barium sulfate HPBCD 0.05-5

Exicipient: 0.1-20

Glycerol 10-20

Purified water up to 100

Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxomer, auxiliary additives selected from a group containing glycerol, propylene glycol, and paraffin oil in following per cent ratio:

Titanium dioxide

or silicon dioxide 0.05-5.0

or barium sulfate

HPBCD 0.05-50

Excipient 0.1 -20

Glycerol 10-20 Paraffin oil 1.0-2.0

Purified water up to 100

Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient of polymeric origin like; natural deoxyribonucleat or gelatin, auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio: Titanium dioxide

or silicon dioxide 0.05-5.0

or barium sulfate

HPBCD 0.05-50 Polymeric excipient 0.01 -20

Glycerol 10-20

Purified water up to 100

The object of present invention concerns the preparation and utilization of different nanosized metal- oxide dispersions in a combination with (2- hydroxy)propyl beta-cyclodextrin (HPBCD) in aqueous systems to prevent and control microbial infections.

Wang, W et al Archives of Virology, 154(4), 595-600 2009: Lipid rafts are involved in the life cycle of many viruses. In this study, the authors investigated the role of lipids in the life cycle of vesicular stomatitis virus. Cholesterol depletion by pretreatment of BHK cells or VSV particles with methyl-beta-cyclodextrin a cholesterol-sequestering agent, inhibited the production of VSV dramatically. This effect was reversible, and virus production was restored by the addition of cholesterol back to the cells, indicating that the reduction was caused by the loss of cholesterol in the cell membrane and virus. Cholesterol depletion at the adsorption stage also reduced the production of VSV significantly, but in contrast, only had a limited effect on virus production at the post-entry stage. Moreover reduction of cholesterol and sphingomyelin at the same time dramatically reduces VSV production, showing a significant synergistic effect. These results suggest that lipid rafts play an important role in the life cycle of viruses.

For the successful entry and infection of host cells, the enveloped viruses are dependent on their lipid envelopes. The role of cholesterol in the virus envelope was studied, using methyl-beta-cyclodextrin as a cholesterol sequestering agent. The pretreatment of virions with methylated-beta-cyclodextrin strongly removed envelope cholesterol from influenza virus and significantly reduced virus infectivity in a dose-dependent manner. A non-enveloped virus, simian virus 40, was not affected by methyl-beta-cyclodextrin treatment. In the case of influenza virus, infectivity could be partially rescued by the addition of exogenous cholesterol. Influenza virus morphology, binding, and internalization were not affected by methyl-beta-cyclodextrin depletion, whereas envelope cholesterol depletion markedly affected influenza virus fusion, as measured by a specific reduction in the infectivity of viruses induced to fuse at the cell surface and by fluorescence-dequenching assays. These data suggest that envelope cholesterol is a critical factor in the fusion process of influenza virus.

Huang H, et al J Gen Virol. 2006 87(2):277-85.: Human herpesvirus 6 envelope cholesterol is required for virus entry. In this study, the role of cholesterol in the envelope of human herpesvirus 6 (HHV-6) was examined by using methyl-beta-cyclodextrin (MbetaCD) depletion. When cholesterol was removed from HHV-6 virions with MbetaCD, infectivity was abolished, but it could be restored by the addition of exogenous cholesterol. HHV-6 binding was affected slightly by MbetaCD treatment. In contrast, envelope cholesterol depletion markedly affected HHV-6 infectivity and HHV-6-induced cell fusion. These results suggest that the cholesterol present in the HHV-6 envelope plays a prominent role in the fusion process and is a key component in viral entry.

US Patent 6835717 titled β-cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases, discloses the use of beta- cyclodextrins as chemical barriers to prevent and treat viral inferctions. The invention is based on the cholesterol status alteration of the virus envelope, via a reversible non-covalent inclusion complex formation between the used cyclodextrin and the surface lipids. The application of beta-cyclodextrin and its derivatives was found to effectively deplete cholesterol from the virus surface on the other hand also from the cell membrane of locally treated surfaces.

(2-hydroxy)propyl beta-cyclodextrin (HPBCD) in combination with metal and metalloid oxides nanodispersions demonstrates stronger antiviral effect in comparison to beta-cyclodextrins. High potency of antiviral effect is explained through a high exhaustive action of (2-hydroxy)propyl beta-cyclodextrin to cholesterol. In this case the effect is observed when there is no link (either covalent or absorption) between nanoparticles and cyclodextrin because of excpients present in the formulation.

IINVENTION REALIZING VARIANTS

Example 1

0.1-20 g Carbopol (sodium polyacrylate) was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water at room temprerature. 100 g of titanium dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred gently (50-100 RPM) until homogenous suspension was obtained. The pH of the solution was adjusted to the range of 6.0-8.0 by triethanolamine solution which resulted a homogenous soft, semi-transparent nanocomposite gel.

The in vitro assessment of the antiviral effect of composition according to Examnple 1. was preformed by using a one- and a six-hour incubation runs of Herpes simplex virus strain. The evaluation of viral infections were done after 3, 4 and 5 days, respectively.

Vera cells were infected for one hour in a serum-free culture media (preventing the misleading results caused by the presence of cyclodextrin components of the tested compositions according to the present invention). The control plates indicated a pfu-number (pfu stands for plaque forming units) to be 1000 (thousand) pfu. The treatment of cells with composition under Example 1 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu.

Example 2

0.1-20 g Methylcellulose was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g glycerol and 100 g of titanium dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred gently (50-100 RPM) until homogenous suspension was obtained. The coarse dispersion was heated to 80-95 °C. Having the liquid cooled to room temperature homogenous nanocomposite consistent gel was obtained.

Test conditions are the same as described in Example 1. The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 2 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu. Example 3

0.1-20 g Ethylcellulose was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g glycerol and 100 g of silicon dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred until gently (50- 100 RPM) homogenous suspension was obtained. The coarse dispersion was heated to 80-95 °C. Having the liquid cooled to room temperature homogenous nanocomposite consistent gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 3 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu.

Example 4

1-20 g Hydroxyethyl cellulose was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g propylene glycol and 100 g of barium sulfate nanosuspension of 0.05-5 % was added to the liquid and stirred vigorously (120-200 RPM) until homogenous homogenous nanocomposite soft gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 4 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu.

Example 5

0.01-20 g Gelatine was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g glycerol and 100 g of silicon dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred gently (50-100 RPM) until homogenous suspension was obtained. The coarse dispersion was heated to 80-95 °C. Having the liquid cooled to room temperature homogenous nanocomposite consistent gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 5 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu

Example 6

0.1-20 g Hydroxyethyl cellulose was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g propylene glycol and 100 g of barium sulfate nanosuspension of 0.05-5 % was added to the liquid and stirred vigorously (120-200 RPM) until homogenous homogenous nanocomposite soft gel was obtained.

The in vitro assessment of the antiviral effect of composition according to Examnple 6. was preformed by using a one- and a six-hour incubation runs of Herpe simplex virus strain. The evaluation of viral infections were done after 3, 4 and 5 days, respectively.

Vero cells were infected for one hour in a serum-free culture media (preventing the misleading results caused by the presence of cyclodextrin components of the tested compositions according to the present invention). The control plates indicated a pfu-number to be 1000 (thousand) pfu. The treatment of cells with with 2 % w/v methyl -beta-cyclodextrin + 0.6 mg/mL BaS04 containing nano-dispersion as Example 6. of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu. The hunderfold reduction of Hepres virus infectivity by using the methyl-beta-cyclodextrin BaS04 nanodispersion composition indicated a practically useful efficacy.

Example 7

0.01-20 g Sodium deoxyribonucleate (DNA) was dispersed in 800 g 0.05- 50 % HPBCD solution prepared with purified water. 10-20 g glycerol and 100 g of _; silicon dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred gently (50-100 RPM) until homogenous suspension was obtained. The coarse dispersion was heated to 80-95 °C. Having the liquid cooled to room temperature homogenous nanocomposite consistent gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 7 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu.

Example 8

0.1-20 g Carboxymethylcellulose was dispersed in 800 g 0.05-50 % HPBCD solution prepared with purified water. 10-20 g glycerol, 1.0-3.0 g paraffin oil and 100 g of titanium dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred vigorously (120-200 RP ) until homogenous nanocomposite soft gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 8 of the present invention, < significantly reduced the number of pfu to be less or equal to 10 (ten) pfu.

Example 9 0.1-20 g Pluronic F127 (poloxamer) was dispersed in 800 g 0.05-50 %

HPBCD solution prepared with purified water. 10-20 g glycerol, 1.0-3.0 g paraffin oil and 100 g of titanium dioxide nanosuspension of 0.05-5 % was added to the liquid and stirred vigorously (120-200 RPM) until homogenous nanocomposite consistent gel was obtained.

Test conditions are the same as described in Example 1.

The control plates indicated a pfu-number to be 10000 (ten thousand) pfu. The treatment of cells with composition under Example 9 of the present invention, significantly reduced the number of pfu to be less or equal to 10 (ten) pfu. Example 10

0.01-20 g Sodium deoxyribonucleate (DNA) was dispersed in 800 g 0.05- 50 % HPBCD solution prepared with purified water. 10-20 g glycerol and 100 g of barium sulfate nanosuspension of 0.05-5 % was added to the liquid and stirred gently (50-100 RPM) until homogenous suspension was obtained. The coarse dispersion was heated to 80-120 °C applying counterpressure. Having the liquid cooled to room temperature homogenous nanocomposite consistent gel was obtained.

The obtained nanocomposite gel containing Sodium DNA and HPBCD was a composition intended to topical application and suitable for homogenous distribution over the skin surface and as a mucoadvasive topical gel to prevent and control sexual transmission of viral, fungal, bacterial infections.

Experimental results obtained demonstrated that the morphology of Vero cells was changed indicating the occurrence of some dysfunctional properties (cytoplasmic granulation, improved contrasts) . The control, untreated infected cells had an average of 10.000 (ten thousand) pfu units.

The same Veros cells treated with 2-hydroxypropyl beta-cyclodextrin had an extent of Hepres virus infection by two orders of magnitude less:only 100 pfu. In general it can be concluded that the cyclodextrin nanoparticle combinations according to the present invention reduced the viral infection by a factor of 100, in vitro.

Claims

1. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy) propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxamer and auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio:

Titanium dioxide

or silicon dioxide 0.05-5.0

or barium sulfate

HPBCD 0.05-50

Excipient 0.1-20

Glycerol 10-20

Purified water up to 100

2. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient selected from a group containing sodium polyacrylate, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, poloxamer, auxiliary additives selected from a group containing glycerol, propylene glycol, and paraffin oil in following per cent ratio:

Titanium dioxide

or silicon dioxide 0.05-5.0

or barium sulfate HPBCD 0.05-50

Excipient 0.1-20

Glycerol 10-20

Paraffin oil 1.0-2.0

Purified water up to 100

3. Antiviral composition is characterized in that the titanium dioxide, silicon dioxide or barium sulfate nanoparticles sized to max. 200 nm, (2-hydroxy)propyl beta-cyclodextrin (HPBCD) aqueous solution, an excipient of polymeric origin selected from a group containing natural Sodium deoxyribonucleate (DNA) or gelatin and auxiliary additives selected from a group containing glycerol, propylene glycol in following per cent ratio:

Titanium dioxide

or silicon dioxide 0.05-5.0 or barium sulfate

HPBCD 0.05-50

Polymeric excipient 0.01 -20

Glycerol 10-20

Purified water up to 100