Patent Description:
Improvement for restoring the physiological processes of cells and the body of certain nanoparticles alone and by UV-visible light, has been thoroughly studied, and is well known.

Cyclodextrins are enzyme-modified starch derivatives prepared from pre-hydrolyzed starch by the action of CTG-ase (cyclodextrin-glycosyl transferase) enzyme. (<NPL>) Cyclodextrins comprise glucose units arranged to a torus, by alpha-<NUM>,<NUM>-glycosidic linkages.

The most commonly used types of cyclodextrins are <NUM>-membered alpha-cyclodextrin, <NUM>-membered beta-cyclodextrin, and <NUM>-membered gamma-cyclodextrins, respectively. Also, cyclodextrin derivatives such as randomly methylated beta-cyclodextrin (abbr. : RAMEB), <NUM>-hydroxypropyl-beta-cyclodextrin (abbr. : HPBCD), sulfobutylated beta-cyclodextrin (abbr. : SBECD), 6A,6B,6C,6D,6E,7F,<NUM>,<NUM>-Octakis-S-(<NUM>-carboxyethyl)-6A,6B,6C,6D,6E,6F,<NUM>,<NUM>-octathio-gamma-cyclodextrin (INN/common name: sugammadex) or <NUM>-hydroxypropyl-gamma-cyclodextrin (abbr. : HPGCD) are widely used in healthcare products. Cyclodextrins have been disclosed as being useful for decreasing viral infections and against cancer alone and in combinations with antiviral/antineoplastic, cytostatic 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 ltraconazol and combinations are described as improved aqueous solubility and better bioavailable forms of the antifungal drug. <NPL>; <NPL>
<CIT> invention 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 drugs in vivo.

<CIT> discloses the preparation and use of azidothimydine-cyclodextrin combinations as potent antiviral agent. The said antiviral composition comprise an effective amount of alpha-cyclodextrin-sulfate a pharmacologically acceptable carrier. The antiviral composition may also contain an additional other known antiviral agent, e.g. AZT, glucocorticoid. Infection with retroviruses (particularly with HIV) can be treated by administering to a patient an effective amount of the said composition alone or in combination with other known antiviral agents. The preparation (by a modified known procedure), the viral inhibition effectiveness and toxicity of alpha-cyclodextrin-sulfate, as well as the comparison and enhancement of the viral inhibition effectiveness of alpha-cyclodextrin sulfate with other antiviral agents are disclosed.

Cyclodextrin complexed form of gancyclovir has been used to provide enhanced bioavailability of the antiviral agent.

Use of <NUM>-hydroxypropylated beta-cyclodextrin HPBCD itself to control viral infections has already been described in a number of previous publications. (see for instance papers in <NPL>; <NPL>.

Vaginal transmission of cell-associated HIV-<NUM> in the mouse is blocked by beta-cyclodextrin, a topical, membrane-modifying agent. Topical application of beta-cyclodextrin, a cholesterol-sequestering agent that interferes with cell migration and budding of virus from lipid rafts, blocks transmission of cell-associated HIV-<NUM>. (see <NPL>.

It has also been published that cholesterol in HIV virions is strictly required for fusion and viral infectivity. ) These observations in combination with those of past studies indicate beta-cyclodextrin to be an excellent candidate for use as a chemical barrier for AIDS prophylaxis. The cholesterol-binding methyl-beta-cyclodextrin was found to reduce SARS-Cov-<NUM> viral infection in cell test in vitro, and positive correlation was found between recipient cells cholesterol status and the virus infectivity (<NPL>.

Among the suitable organic components of the antimicrobial compositions according to the present invention, are natural and (ionic and non-ionic) synthetic mono-, di-, and oligosaccharides. Such compounds are for instance pentosan-polysulfate, dextrose-sulfate, heparinoids, natural heparin, e. known to have potent antimicrobial antiviral effects. ) Sulfated alpha- and beta-cyclodextrins in combination with known antiviral drug actives were found to have synergistic viricide effect.

Other types of sulfated macromolecules also exhibit antiviral effect. Three of these products PRO2000, Carraguard and cellulose-sulfate are anionic polymers and inhibit HIV-<NUM> infection by preventing virus-cell fusion predominantly through charged based interactions. In addition, Viva Gel (SPL7013, a sulphated dendrimer) thought to work by a similar mechanism has entered in early phase I safety trials. Another antimicrobial product in phase III trials is a buffer gel (Buffergel) containing polyanionic carbopol. These agents inhibit both HIV and HSV in cell culture and animal models.

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-,sulfoalkylated and carboxyalkylated negatively charged types of cyclic oligosaccharides are known to exert such a microbial potency.

<CIT> discloses the use of sulfobutyl ether cyclodextrin as a preservative. The method includes the step of including a derivatized cyclodextrin in a formulation capable of sustaining microbial growth. One embodiment of the formulation employs a sulfoalkyl ether cyclodextrin as a preservative and optionally as a solubilizing and complexing agent. A suitable cyclodextrin is the Dexolve brand cyclodextrin (sulfobutyl ether beta-cyclodextrin). Whether or not the formulation includes a conventional preservative, the formulation will remain preserved for at least a minimum predetermined period. Specific embodiments of the invention include a carrier, a derivatized cyclodextrin and optionally one or more active agents, one or more water activity-reducing agents, and/or one or more complexation-enhancing agents. The derivatized cyclodextrin reduces the water activity of the formulation. A liquid formulation can be lyophilized or otherwise dried to yield a solid formulation that is optionally reconstitutable.

Combinations of organic oligo- and polymens with inorganic nanoparticles Jpn. Kokai Tokkyo Koho <CIT> 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, the oral cavity, and the pharynx. It is considered as the agent for oral hygiene containing titanium dioxide particles and cyclodextrin. Titanium dioxide particles suitably form complex particles with the apatite. By these actions, the inflammation in the removal of the bacteria containing the virus in the oral cavity and the pharynx, the oral cavity, and the pharynx is claimed.

<NPL> describes the use of Ribavirin (RBV) a water-soluble synthetic nucleoside with broad spectrum antiviral properties. However, it is ineffective against major viral encephalitis because of a failure to cross the blood-brain barrier (BBB). The antiviral activity of the complexed drug the ribavirin/alpha-cyclodextrin complex was previously demonstrated to be stronger than free ribavirin, in an in vivo model of measles virus (MV) encephalitis in mice. The role of cyclodextrin on ribavirin uptake into the brain needs to be defined. Ribavirin specific extraction from brain tissue was developed, based on a solid phase extraction. It was quantified by high performance liquid chromatography at different time points after i. injection of single or multiple doses of free ribavirin or of the complex ribavirin/alpha-cyclodextrin. Whatever the tested dose (<NUM> or <NUM>/kg), the amount of ribavirin in the brain was significantly higher (p < <NUM>) when the drug was injected as a complex with alpha-cyclodextrin, in healthy or measles virus-infected mice.

<CIT> :This invention relates to method of reducing human immunodeficiency virus (HIV) infective events by applying cyclodextrin sulfate-<NUM> (terygyn) and a suitable excipient formulated for topical administration to the vaginal, anal, urethral or penile glans mucosa of an individual prior to or subsequent to infection by human immunodeficiency virus.

<CIT>: The present invention 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, <NUM>/mL (S)-<NUM>-(<NUM>-fluorophenyl)-<NUM>-(<NUM>-oxo-<NUM>-phenyl-<NUM>,<NUM>-dihydro-<NUM>-benzo[e][<NUM>,<NUM>]diazepin-<NUM>-yl)urea (free base equiv. ) was dissolved in <NUM>% hydroxypropyl beta-cyclodextrin, with addition of <NUM> phosphate buffer, at pH <NUM>. The lyophilized cake of this solution was reconstituted with <NUM> of <NUM>% dextrose solution to obtain <NUM> of <NUM>/mL (S)-<NUM>-(<NUM>-fluorophenyl)-<NUM>-(<NUM>- oxo-<NUM>-phenyl-<NUM>,<NUM>-dihydro-<NUM>-benzo[e][<NUM>,<NUM>]diazepin-<NUM>-yl)urea in <NUM>% HPBCD.

<NPL> described preparation and use of poly(amidoamine) (PAA) copolymer with beta-cyclodextrin, by reacting <NUM>-deoxy-<NUM>-amino-beta-cyclodextrin and <NUM>-methylpiperazine to2,<NUM>-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.

<CIT> This invention relates to cholesterol-sequestering agents and methods of using cholesterol-sequestering agents to prevent viral infection. The compounds of the invention can be used to decontaminate skin and environmental surfaces that are contacted with microorganisms such as envelope viruses.

<CIT> <CIT> <CIT> relates to compositions including a liquid medium, a cyclodextrin component and a preservative component, which has a reduced tendency to being complexed with the cyclodextrin component. In one embodiment, the preservative component is a chlorite component. Active drug components are included in the compositions. In the composition NaCl, KCI, CaCl2.2H2O, MgCl2.6H2O, Carboxymethyl-cellulose-sodium salt, boric acid, sodium borate decahydrate, brimodine tartrate, sulfobutyl ether beta-cyclodextrin and water, stabilized ClO2 <NUM> ppm. The presence of a cyclodextrin component does not have any detrimental effect on the preservative efficacy of stabilized chlorine dioxide. The stabilized chlorine dioxide remains free and effective as a preservative rather than being complexed by the cyclodextrin component. The composition is ophthalmically acceptable. <CIT> discloses an antiviral composition used as e.g. personal care or pharmaceutical products comprises titanium dioxide, silicon dioxide or barium sulfate nanoparticles of specific size, (<NUM>-hydroxy)propyl beta-cyclodextrin. <CIT> discloses a medical nano antibacterial gel comprises agarose, gamma-cyclodextrin, polyethylene glycol, boric acid, nano titanium dioxide, nano zirconium dioxide, and water. <NPL>, discloses a cellulose/TiO2/β-CD hydrogel with high photocatalytic antibacterial activity and sustained release of drug. <NPL> discloses the antibacterial effect of synthesized sulfated β-cyclodextrin crosslinked cotton fabric and its improved antibacterial activities in the presence of ZnO, TiO2 and Ag nanoparticles.

The object of present invention concerns the preparation and utilization of different nanosized metal- oxide dispersions in a combination with cyclodextrins and cyclodextrins derivatives in aqueous systems to prevent and control microbial infections.

<CIT> entitled 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 infections. 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.

Because of their physical-chemical characteristics nanoparticles become highly useful in different fields: treatment of different diseases, for example, infectious, bacterial or viral infections, cancer therapy, wounds healing, anemia treatment etc..

From the technical field the <CIT> <CIT> (PCT <CIT>) is known(Compositions of magnetic nanoparticles and their use).

The disclosure relates to use of biocompatible nanoparticle or nanoparticles aggregate in combination with external non-oscillating magnetic field, where said nanoparticle includes: a) a core containing magnetic material; b) biocompatible cover, surrounding the core; and, optionally, c) a marking agent, where the external diameter of the cover is less than about <NUM>, for preparation of composition, where said composition does not contain any other means for targeting on the cell. The present invention also relates to obtained compositions and their use in the health care area, for cancer treatment or in diagnostics (for example, visualization), for monitoring of the tumor development.

Ferromagnetic material is chosen from the group consisting of iron, nickel, cobalt, gadolinium, samarium, neodymium, boron, aluminium and any mixture of them. Material of ferromagnetic core is in form of oxide, hydroxide or metal.

Compositions may exist in solid or liquid form (suspended nanoparticles), for example, in the form of paste or aerosol.

The invention is destined for creation of pharmaceutical compositions, ensuring restoring the physiological processes of cells and all the organism, as a whole, at the expense of generation of reactive species of oxygen (ROS) in an organism.

Pharmaceutical composition on the base of which the medical agent is claimed is characterized by the fact that it ensures therapeutically significant effect for restoration of the physiological processes and cells of an organism.

Pharmaceutical composition for restoring the physiological processes and the cells of an organism is characterized by presence of cyclic maltooligosaccharides (cyclodextrins) chosen from the group of cyclomaltooligosaccharides, namely, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, randomly methylated beta-cyclodextrins, <NUM>-hydroxypropyl-beta-cyclodextrins, sulfobutylated beta-cyclodextrins, <NUM>-hydroxypropyl-gamma-cyclodextrins or their appropriate mixtures and sugammadex (6A,6B,6C,6D,6E,7F,<NUM>,<NUM>-octakis-S-(<NUM>-carboxyethyl)-6A,6B,6C,6D,6E,6F,<NUM>,<NUM>-octathio-gamma-cyclodextrin), used in amount <NUM>-<NUM> mass% in combination with aqueous solution of stable suspension of heterocrystals of titanium dioxide or silicon dioxide particles with size no less than <NUM> and content of titanium dioxide or silicon dioxide in amount of <NUM> - <NUM>% mass, having on the surface of crystals and particles in the energy centers electronically-excited triplet oxygen <NUM>O<NUM>.

Stable aqueous suspension according to the present invention is chosen in such a way that combined use in presence of components of cyclodextrin preferably have decreased toxicity, more preferably, in essence, non-toxicity at administration of compositions to a human or an animal.

The method of obtaining stable suspension of heterocrystals of titanium dioxide or silicon dioxide particles with size less than <NUM> having on the surface of crystals and particles in the energy centers electronically-excited triplet oxygen <NUM>O<NUM> is in detail described in application <CIT> "Method of obtaining stable suspensions of heterocrystals of titanium dioxide and particles of silicon dioxide and stable suspension obtained by this method for initiation of active form of oxygen in human body at use in medical forms".

The pharmaceutical composition additionally comprises active pharmaceutical ingredients (API) and pharmaceutically acceptable additives (PAA).

Used at present time active pharmaceutical ingredients and pharmaceutically acceptable additives are preferably chosen in the way to obtain benefit from presence of cyclodextrin components.

Usually active ingredients and pharmaceutically permitted additives have increased solubility in water, due to presence of cyclodextrin components.

Pharmaceutical composition is characterized by the fact that in aqueous solution of suspension heterocrystals of titanium dioxide have the following distribution: up to <NUM> is <NUM> vol%, up to <NUM> is <NUM>-<NUM> vol%, particles up to <NUM> are <NUM>-<NUM> vol%, particles up to <NUM> are <NUM>-<NUM> vol%, particles up to <NUM> are <NUM>-<NUM> vol%, particles with a size of more than <NUM> are not more than <NUM> vol%, and the distribution of finely dispersed particles of silicon dioxide with a size of <NUM>-<NUM> is <NUM>-<NUM> %, particles with a size of <NUM>-<NUM> are <NUM>-<NUM> %, particles with a size of <NUM>- <NUM> is less than <NUM> %, particles larger than <NUM> - no more than <NUM>%.

Data obtaining stable suspension of heterocrystal of titanium dioxide or particles of silicon dioxide with size less than <NUM>, in the analysis with the photon correlation spectroscopy instrument Malvern Zetasizer Nano ZS.

Presence on the crystal surface of oxygen O2 in the ruptures of the developed surface of crystals lattices of a great number of ionic groups of ligands ensures formation of excitonic structures, ionic bonds and zones of local energy overheating, i.e. the quantum dots, where O2 is in metastable electronically-excited triplet condition (2T3+) with unique characteristics of conversion into biological activity - singlet condition (S-<NUM>-<NUM>).

Illustration of pharmacological study of measuring quantity of electronically-excited triplet oxygen (2T3+), on particles surface. Executed as follows. Researches executed on a rabbit, male with <NUM> weight (without injuries).

Through the needle <NUM> of suspension was injected, where <NUM> is injection water and <NUM> TiO2, at the entry inside the needle opening there was a light guide for feeding laser photons and supplying injection suspension simultaneously.

The photonic-thermic procedure was executed with the laser IR <NUM> with <NUM> Wt power, dose <NUM> J regulating synchronously.

In the local treated part of the examined rabbit, with a help of an additional needle the sensor for measuring O<NUM> was installed, and the analyser of automatic chemiluminiscent gas analyser of singlet oxygen <NUM>O<NUM> (the model FOMS - <NUM> OXYGEN, made in FRG).

Presence of conversion of triplet oxygen with presence in oxygen structure n metastable electronically-excited condition into singlet condition (S-<NUM>-<NUM>) was fixed.

The surface of heterocrystals of titanium dioxide and silicon dioxide particles has sorption ability, that is an important factor for use in the medical forms.

Doxorubicin is a known cytostatic drug applied via intravenous route. Those skilled in the art have a concept that doxorubicin may not be applied intramuscularly due to its necrotic effect. We have surprisingly found that a particulate composition containing doxorubicin (in an amount of <NUM> to <NUM>/mL) besides the nanoparticles and cyclodextrin according to present invention is suitable for intramuscular injection whereas the therapeutic function of the drug is manifested, without unwanted necrotic side-effect.

Said pharmaceutical compositions may be used intravenously, intramuscularly, orally, nasally, vaginally, rectally, ENT administration or topically and in the form of ointments, creams, lotions, solutions, powders, patches and aerosols.

Pharmaceutical composition is used, in particular, in the form of medical articles of topical use in the form of hydrocolloidal medical plasters, impregnation for tampons, absorbent pads, diapers, tapes, bandages etc., having antimicrobial and antiseptic influence, anti-inflammatory action, immunomodulatory and adsorbing action, depending on form and method of their use.

Mechanism of action in composition of a medical agent or gel is that in interaction of electronically-excited O<NUM> on the surface of crystals or particles with membrane cellular enzyme complex NADFH ROS is formed.

Present invention directs to novel pharmaceutical compositions for restoring the physiological processes of cells and the body by combining cyclodextrins selected from the group of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, randomly methylated beta-cyclodextrin, <NUM>-hydroxypropyl-beta-cyclodextrin, sulfobutylated beta-cyclodextrin, sugammadex or <NUM>-hydroxypropyl-gamma-cyclodextrin. Cyclodextrins (CDs) are a class of highly water-soluble and biocompatible cyclic oligosaccharides. Cyclodextrins tend to bind other molecules in their quasi-cylindrical interiors. This inclusion (and release) behaviour leads to applications in medicine. The compound is of wide interest because it exhibits host-guest properties, forming inclusion compounds. Cyclodextrins differ by size, for example, alpha-cyclodextrin composed of <NUM> glucose subunits, beta-cyclodextrin: <NUM> glucose subunits, gamma-cyclodextrin: <NUM> glucose subunits. Methyl-β-cyclodextrin (Methyl-beta-cyclodextrin) is a cyclic heptasaccharide used to deliver hydrophobic drugs based on its property of solubilizing non-polar substances. Methyl-β-cyclodextrin is also extensively used as a cholesterol-depleting reagent, <NUM>-Hydroxypropyl-β-cyclodextrin is a cyclic oligosaccharide that is widely used as an enabling excipient in pharmaceutical formulations, but also as a cholesterol modifier. Sulfobutyl ether beta-cyclodextrin is a highly water-soluble anionic derivative of cyclodextrin, which ensures solubility and stability of API and their properties. Sugammadex is a modified gamma-cyclodextrin, with a lipophilic core and a hydrophilic periphery. Sugammadex is used to reverse neuromuscular blockade after administration of the aminosteroid non-depolarizing neuromuscular-blocking agents such as vecuronium or rocuronium.

Representative examples of additives include API and pharmaceutically permitted additives taken in amount <NUM> - <NUM>% mass, such as Lenalidomide, nivolumab, Imbruvica, cytostatic agents: anthracyclines (doxorubicin, epirubicin, pegylated liposomal doxorubicin), Taxanes (paclitaxel, docetaxel, albumin nano-particle bound paclitaxel), <NUM>-fluorouracil (continuous infusion <NUM>-FU, capecitabine), Vinca alkaloids (vinorelbine, vinblastine), Gemcitabine, Platinum salts (cisplatin, carboplatin), cyclophosphamide, Etoposide and combinations of one or more of the above such as Cyclophosphamide/anthracycline+/-<NUM>-fluorouracil regimens (such as doxorubicin/cyclophosphamide (AC), epirubicin/cyclophosphamide, (EC) cyclophosphamide/epirubicin/<NUM>-fluorouracil (CEF), cyclophosphamide/doxorubicin/<NUM>-fluorouracil (CAF), <NUM>-fluorouracil / epirubicin / cyclophosphamide (FEC), cyclophosphamide/metothrexate/<NUM>-fluorouracil (CMF), anthracyclines/taxanes (such as doxorubicin/paclitaxel or doxorubicin / docetaxel), Docetaxel / capecitabine, Gemcitabine/paclitaxel, Taxane/platinum regimens (such as paclitaxel / carboplatin or docetaxel/carboplatin).

Representative examples of antiviral additives include: Abacavir, Acyclovir (Aciclovir), Adefovir, Amantadine, Ampligen, Amprenavir (Agenerase), Umifenovir (Arbidol), Atazanavir, Atripla, Baloxavir marboxil (Xofluza), Biktarvy, Boceprevir, Bulevirtide, Cidofovir, Cobicistat (Tybost), Combivir, Daclatasvir (Daklinza), Darunavir, Delavirdine, Descovy, Didanosine, Docosanol, Dolutegravir, Doravirine (Pifeltro), Edoxudine, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Ensitrelvir, Entecavir, Etravirine (Intelence), Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Ganciclovir (Cytovene), Ibacitabine, Ibalizumab (Trogarzo), Idoxuridine, Imiquimod, Imunovir, Indinavir, Lamivudine, Letermovir (Prevymis), Lopinavir, Loviride, Maraviroc, Methisazone, Moroxydine, Nelfinavir, Nevirapine, Nexavir formerly (Kutapressin), Nitazoxanide, Norvir, Oseltamivir (Tamiflu), Penciclovir, Peramivir, Penciclovir, Peramivir (Rapivab), Pleconaril, Podophyllotoxin, Raltegravir, Remdesivir, Ribavirin, Rilpivirine (Edurant), Rilpivirine, Rimantadine, Ritonavir, Saquinavir, Simeprevir (Olysio), Sofosbuvir, Stavudine, Taribavirin (Viramidine), Telaprevir, Telbivudine (Tyzeka), Tenofovir alafenamide, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Umifenovir, Valaciclovir (Valtrex), Valganciclovir (Valcyte), Vicriviroc, Vidarabine, Zalcitabine, Zanamivir (Relenza), Zidovudine.

Representative examples of additives include excipients, fillers, soloubilizers, co-solvents, surfactants, lubricants, gelling agents, colorants, sweeteners, taste modifiers, etc, such as cetyl pyridinium chloride, gelatin, casein, lecithin (phosphatides), dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol <NUM>), polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween <NUM>® and Tween <NUM>® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs <NUM>® and <NUM>®, and Carbopol <NUM>® (Union Carbide)), dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), <NUM>-(<NUM>,<NUM>,<NUM>,<NUM>-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol, superione, and triton), poloxamers (e.g., Pluronics F68® and F108®, which are block copolymers of ethylene oxide and propylene oxide); poloxamines (e.g., Tetronic <NUM>®, also known as Poloxamine <NUM>®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, N. )); a charged phospholipid such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS); Tetronic <NUM> (T-<NUM>) (BASF Wyandotte Corporation), dialkylesters of sodium sulfosuccinic acid (e.g., Aerosol OT®, which is a dioctyl ester of sodium sulfosuccinic acid (American Cyanamid)); Duponol P®, which is a sodium lauryl sulfate (DuPont); Tritons X-<NUM>®, which is an alkyl aryl polyether sulfonate (Rohm and Haas); Crodestas F-<NUM>®, which is a mixture of sucrose stearate and sucrose distearate (Croda Inc. ); p-isononylphenoxypoly-(glycidol), also known as Olin-<NUM>® or Surfactant <NUM>-G® (Olin Chemicals, Stamford, Conn. ); Crodestas SL-<NUM>® (Croda, Inc. ); and SA9OHCO, which is C <NUM> 37CH <NUM>(CON(CH <NUM>)CH <NUM>(CHOH) <NUM>(CH 2OH) <NUM> (Eastman Kodak Co. ); decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside; n-decyl β-D-maltopyranoside; n-dodecyl β-D-glucopyranoside; n-dodecyl β-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl β-D-thioglucoside; n-hexyl β-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl β-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-µ-D-glucopyranoside; octyl β-D-thioglucopyranoside; and the like. Tyloxapol is a particularly preferred additive for the pulmonary or intranasal delivery of steroids, even more so for nebulization therapies.

Representative examples of additives include Cacao Butter, Rose Oil Extract, Pumpkin Seed Oil Extract, Griffonia Simplicifolia Oil Extract, Celandine Oil Extract, Chamomile Extract, Liquorice Extract, Pure vanilla extract.

Stable suspension of heterocrystals of titanium dioxide and particles of silicon dioxide is characterized by presence on the lattice surface of electronically-excited triplet oxygen <NUM>O<NUM> in the energy centers, namely, in the quantum dots - zones of local overheating, ensuring catalytic activity for formation of active forms of oxygen in a living organism.

Polydispersity of obtained suspensions of heterocrystals of titanium dioxide and particles of silicon dioxide determines their unique properties at forming pharmaceutical compositions, that ensures not only targeted delivery into the area of pathological processes, but also unique mechanisms of action in their use.

As a result of the fact that the surface of crystals of titanium dioxide and particles of silicon dioxide contains the oxygen and presence in the ruptures of the developed surface of lattices of a great number of ionic groups of ligands formation of excitonic structures, ionic bonds and a range of zones of local energy overheating is ensured, all the types of sorption are possible, that determines detoxication possibilities of the obtained pharmaceutical compositions.

Presence on the crystal surface of oxygen O<NUM> presence in the ruptures of the developed surface of crystals lattices of a great number of ionic groups of ligands ensures formation of excitonic structures, ionic bonds and zones of local energy overheating, i.e. the quantum dots, where O<NUM> is in metastable electronically-excited triplet condition (<NUM>T<NUM>+) with unique characteristics of conversion into biological activity - singlet condition (S-<NUM>-<NUM>).

It has been earlier demonstrated that in one dose of the preparation <NUM>/ml including stable suspension of titanium dioxide crystals or silicon dioxide particles their sorption capacity as a result of said sorption properties of crystals and particles is multiply higher in comparison with the existing preparations.

Peculiarity of the crystals and particles is that O<NUM> on their surface and is initially in excited triplet condition, with regulated possibility of catalysis in ROS, even in the cases where the human body temperature <NUM> is sufficient, using in pharmaceutical compositions, which at the expense of synthesis of regulated active oxygen, ROS, firstly, selectively penetrate into the pathogenic cells of organism, targeting the areas of inflammation, with infectious and non-infectious nature, in particular, the cells using a ferment NADPH - for ROS formation, phagocytes and macrophages, causing in them numerous cytomorphological changes (vacuoles in cytoplasm, fragmentation of membrane, abnormality of mitosis), that launches apoptosis or necrosis type of death of pathogenic cells (because the pathogenic cells do not have effective antioxidant ferments).

NADFH - oxydases membrane-bound enzymatic complex, inversed into extracellular space of plasmatic membrane, and also in membranes of phagosomes, used by neutrophilic leukocytes (immune cells, white blood cells) for absorption of microorganisms is executed in the immune response.

Biocompatible TiO<NUM> crystals and SiO<NUM> particles are the only most indifferent in use in different forms of medical agents.

Laboratory and clinical researches, when oxygen, O<NUM>, on the crystal lattices is initially in excited condition <NUM>T<NUM> in the case of the crystals-sensitizers use in composition of medicines hydrogels (forms of use: topically, in nose, in throat, in mucous layer, vaginally, rectally, orally), and also medical articles of topical use in the form of hydrocolloidal medical plasters, impregnation for tampons, absorbent pads, diapers, tapes, bandages etc., having antimicrobial and antiseptic influence, anti-inflammatory action, immunomodulatory and adsorbing action, depending on form and method of their use.

Pharmaceutical composition is used as adjuvant therapy, both independently and in combination with oncotherapy, antiviral, vaccination, for orthopaedic use.

In adjuvant therapy pharmaceutical composition is used independently or with active pharmaceutical ingredients and pharmaceutically acceptable additions.

Absence of general and local toxicity is confirmed by the results of toxicological researches.

The side effects in examinations of toxicity and examination of the repeated doses were not revealed, and the results of researches also confirm absence of mutagenicity and clastogenicity. Parenteral tolerated dose for TiO<NUM> is <NUM>/kg bw per day, and for SiO<NUM> <NUM>/kg bw per day. Peroral tolerated dose for TiO<NUM> is <NUM>/kg bw per day, and for SiO<NUM> <NUM>/kg bw per day (Dossier No. <NUM>. <NUM>; <NUM>. <NUM> from <NUM>. <NUM>, TOXI COOP Zrt).

Stable suspension of titanium dioxide crystals and silicon dioxide particles ensures induction of immune response of a vertebrate by means of physical or chemical interaction with antigens.

Biological inertness of TiO<NUM> crystals and SiO<NUM> particles is well-known, and by their expressed and regulated biological activity they acquire in the course of a special method of their obtaining, as a result of which the local zones of energy overheating appear (de la <NPL>), ensuring catalytic activity for formation of active forms of oxygen in a living organism.

Regulated active oxygen, ROS has become first demanded in the pathologies in focus (respiratory explosion), where oxygen necessity is multiplied.

Catalytic properties of crystals and particles are unique in the field of preparing pharmaceutical compositions for medical agents used for influence on a wide range of pathogens.

Photocatalytic properties of titanium dioxide or silicon dioxide heterocrystals - mobilizing at immune reaction to pathogens and normalization of ROS production in a living organism.

Hereinafter we present the examples of obtaining pharmaceutical compositions for restoring the physiological processes and cells of organism on the base of different cyclodextrins, chosen from the group of cyclomaltooligosaccharides, namely alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, randomly methylated beta-cyclodextrins, <NUM>-hydropropyl-beta-cyclodextrins, sulfobutylated beta-cyclodextrins, <NUM>-hydropropyl-gamma-cyclodextrins or their appropriate mixtures and sugammadex, in combination with aqueous solution of stable suspension of heterocrystals of titanium dioxide or particles of silicon dioxide with size no less than <NUM> having on the surface of crystals and particles in the energy centers electronically-excited triplet oxygen <NUM>O<NUM>.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of methylated beta-cyclodextrin (CD) and titanium dioxide or silicon dioxide.

Different amounts of randomly methylated beta-cyclodextrin (RAMEB, Wacker Chemie, Munich, Germany, CAVASOL® W7 M <NUM> with molar substitution of <NUM> methyl group per a glucopyranose unit) were dissolved in <NUM> of purified water at room temperature at slow, from <NUM> rotation/minute mixing. Obtained solutions were transparent and had pH between <NUM>-<NUM>.

In another vessel suspension of activated crystals or particles TiO<NUM> or SiO<NUM> quantum dots (QD), PCT/IB2022/<NUM> was mixed in water for injection (WFI) in concentration up to <NUM>% TiO<NUM> or in WFI in concentration up to <NUM>% SiO<NUM>, dispersed in <NUM> of purified water (WFI) in the hydrodynamical cavitational homogenizer, for obtaining stable suspension of TiO<NUM> heterocrystals or SiO<NUM> particles in specified concentration.

Process of treatment in the hydrodynamical cavitational homogenizer lasts from <NUM> minutes depending on specified indices required for suspension.

According to the results of readiness of preliminary mixing in two separate vessels the CD solution and suspension of heterocrystals or particles, which were enough homogenous for subsequent homogenizing by the hydrodynamical cavitational homogenizer, PCT/IB2022/<NUM>, where the process of homogenization is executed simultaneously with delivery from two vessels, one vessel as basic and one as dosed.

At the final phase the obtained pharmaceutical composition is filled into package from <NUM> to <NUM>.

In the examples <NUM>-<NUM> the process of preparation of aqueous nanodispersion of cyclodextrins (<NUM>-Hydroxypropyl beta-cyclodextrin, Sulfobutylated beta-cyclodextrin sodium salt) and titanium dioxide or silicon dioxide or their mixture is analogous.

The variants of pharmaceutical compositions according to the examples <NUM>-<NUM> and their characteristic is shown in the Tables <NUM>-<NUM>, the Tables <NUM>-<NUM> show suspensions of TiO<NUM> heterocrystals and SiO<NUM> particles, and the Table <NUM> shows variants of pharmaceutical compositions containing suspension of mixture of TiO<NUM> heterocrystals and SiO<NUM> particles in declared amount.

From the Tables <NUM>-<NUM> it is evident that the pharmaceutical compositions containing the above-listed CD and suspensions of activated SiO<NUM> or/and TiO<NUM> particles ensure ROS production in all the declared quantitative values.

Measuring of active forms of oxygen (ROS) in the pharmaceutical compositions were executed by means of determination of stationary levels of prooxidants (hydroperoxides) at the cells HT-<NUM> of fibrosarcoma using sensitive to oxidation <NUM>,<NUM>-carboxi-<NUM>,<NUM>-dichlordihydrofluorescein diacetate (CDCFH<NUM>) <NUM>/ml. Its reactive-capable product fluorescent coloring agent was detected by the fluorescent microscope Zeiss or measured at the fluorescent device using bandpass filter with λ ex = <NUM> and λ em = <NUM>. Using Fluoroscan Ascent. Florida, Labsystems.

Results of researches are shown at the <FIG>, where dependence of ROS amount on the tested example of pharmaceutical composition is shown. On the x-axis - % amount of ROS on the y-axis - numbers of examples.

The results of measurements in the presented samples demonstrate a stable dependence on the amount and concentration of nanoparticles and cyclodextrins. The composition of TiO2, SiO2 with SBECD demonstrates a greater significance of ROS formation. Nevertheless, the formation of ROS in different amounts was confirmed in all samples.

The results of researches show that ROS production occurs in significant amount in comparison with a control sample (methylated beta-cyclodextrin).

Hereinafter we present the examples of obtaining compositions of medical agents characterized by therapeutically significant effect for restoring the physiological processes and cells of organism.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropylbeta-cyclodextrin and silicon dioxide in the form of hydrogel as pharmaceutical means for prophylaxis and therapy of ENT and viral diseases.

Composition of ingredients listed in the Table <NUM> in each phase of preliminary mixing was placed in three tank mixers and mixing was executed simultaneously.

According to the results of readiness of preliminary mixing in three tanks, the compositions that were enough homogenous for subsequent homogenizing were used for obtaining stable suspensions (hydrogel), by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery from three tank mixers.

At the final phase the obtained mass of hydrogel, composition of medical agents is filled into package from <NUM> up to <NUM>.

Medical agent of the Example <NUM> was characterized by the following methods:
Content of silicon dioxide in products was determined by ICP-analysis.

Average size of dispersed nanoparticles of silicon dioxide was in the range of <NUM>-<NUM>, as determined by Malvern Zetasizer Nano ZS.

Content of <NUM>-hydroxypropyl-beta-cyclodextrin in the products was determined by HPLC.

Characteristic of the obtained ready composition has the following indices: - pH <NUM>, transparent.

The final structure of hydrogel is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropylbeta-cyclodextrin, and particles of titanium dioxide with obtaining gel for pharmaceutical medical agent for obtaining hydrogel, as pharmaceutical medical agent for prophylaxis and therapy of orthopedic, gynecological, urological, endocrinological, autoimmune, gastroenterological, neurologic, cardiological, oncological, dermatological, viral and ENT diseases.

Composition of ingredients listed in the Table <NUM> in each phase of preliminary mixing the ingredients was placed in three tank mixers and mixing was executed simultaneously.

According to the results of readiness of preliminary mixing in three tanks, the compositions that were adequately homogenous for subsequent homogenizing were used for obtaining stable suspensions (hydrogel), by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery from three tank mixers.

At the second phase the obtained mass of hydrogel, composition of medical agents is filled into package from <NUM> up to <NUM>.

Compositions of the Example <NUM> were characterized by the following methods:
Content of silicon dioxide in products was determined by ICP-analysis.

Characteristic of the obtained ready composition has the following indices: pH <NUM>, transparent.

The final structure of hydrogel is: cyclodextrins <NUM> mass%, crystals of titanium dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropylbeta-cyclodextrin, and particles of titanium dioxide in the form of hydrogel as pharmaceutical medical agent for rejuvenation, prophylaxis and therapy of orthopaedic and cosmodermatological diseases.

Composition of ingredients listed in the Table <NUM> in the first phase of preliminary mixing was placed in two tank mixers and mixing was executed simultaneously.

According to the results of readiness of preliminary mixing in two tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used for obtaining stable suspensions (hydrogel), by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery from two tank mixers, one mixture as basic and the second as dosed one.

At the second phase the obtained homogenous substance of the Example <NUM> is filled into package from <NUM> up to <NUM>.

Average size of dispersed nanoparticles of titanium dioxide was in the range of <NUM>-<NUM>, as determined by Malvern Zetasizer Nano ZS
Content of <NUM>-hydroxypropyl-beta-cyclodextrin and Sulfobutylated beta-cyclodextrin in the products was determined by HPLC.

The final structure of hydrogel is: cyclodextrins <NUM> mass%, particles of titanium dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of sulfobutylated beta-cyclodextrin and the particles of silicon dioxide in the form of hydrogel, as pharmaceutical medical agent for prophylaxis and therapy of autoimmune, neurological, oncological and ENT diseases.

According to the results of readiness of preliminary mixing in two tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used for obtaining stable suspensions (hydrogel), by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture as basic from one tank mixer, and the second as dosed one.

Content Sulfobutylated beta-cyclodextrin in the products was determined by HPLC.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropylbeta-cyclodextrin and silicon dioxide in the form of oil-water mixture, as pharmaceutical medical agent for prophylaxis and therapy of gynaecological, urological, orthopaedic, endocrinological, gastroenterological and viral diseases.

In the first phase mixing of oil extracts and oil was executed, until obtaining enough homogenous mixture, for better homogeneity the homogenizer was used.

According to the results of readiness of preliminary mixing in tree tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used for obtaining stable suspensions (aqueous-oil mixture), by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank mixer, as basic one, and from two mixers as dosed ones.

At the second phase the obtained aqueous-oil mixture, composition of medical agents, is filled into package from <NUM> up to <NUM>.

The final structure of hydrogel is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, pharmaceutically admissible additive <NUM> mass%, water for injections up to <NUM> mass%.

The final structure of aqueous-oil mixture is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropyl beta-cyclodextrin and silicon dioxide particles with obtaining lyophilized powder for pharmaceutical agent in the form of tablets, powders, capsules for prophylaxis ant therapy of orthopedic, gynecological, endocrinological, autoimmune, gastroenterological, neurological and viral diseases.

Compositions of ingredients listed in the Table <NUM> in the first phase of preliminary mixing was placed in two tank mixers and mixing was executed simultaneously.

According to the results of readiness of preliminary mixing in two tanks, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank as basic, and from another tank as dosed one.

At the second phase the obtained homogenous substance of the Example <NUM> was lyophilized in the vessel until total dehydration. Lyophilizing was executed at the expense of soft drying without use of high temperatures.

The obtained lyophilizate, composition (substance) in the form of powder for subsequent formation of medical agents in the form of tablets and capsules is filled into package from <NUM> up to <NUM>.

Compositions of the Example <NUM> were characterized by the following methods:
Content of titanium dioxide in products was determined by ICP-analysis.

Characteristic of the obtained ready composition has the following indices: white color powder.

The final structure of lyophilizate is: cyclodextrins <NUM> mass%, particles of titanium dioxide <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropylbeta-cyclodextrin and silicon dioxide, sulfobutylcyclodextrine and titanium dioxide particles in the form of lyophilized powder for pharmaceutical medical agent in the form of tablets, powders, capsules for prophylaxis ant therapy of orthopaedic, gynaecological, endocrinological, autoimmune, gastroenterological, neurological and viral diseases.

Compositions of ingredients listed in the Table <NUM> in the first phase of preliminary mixing was placed in three tank mixers and mixing was executed simultaneously.

According to the results of readiness of preliminary mixing in three tanks, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank as basic, and from two tanks as dosed ones.

Content of <NUM>-hydroxypropyl-beta-cyclodextrin and Sulfobutylated beta-cyclodextrin in the products was determined by HPLC.

The final structure of lyophilizate is: cyclodextrins <NUM> mass%, crystals of titanium dioxide <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of Sulfobutylated beta-cyclodextrin and silicon dioxide particles in the form of lyophilized powder for pharmaceutical medical agent - tablets, powders, capsules for prophylaxis ant therapy of orthopaedic, gynaecological, endocrinological, autoimmune, gastroenterological, neurological and viral diseases.

According to the results of readiness of preliminary mixing in two tanks, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank as basic, and another as dosed one.

The obtained lyophilizate (substance) in the form of powder for subsequent formation of medical agents in the form of powders, tablets and capsules is filled into package from <NUM> up to <NUM>.

Content of sulfobutyl-beta-cyclodextrin in the products was determined by HPLC.

The final structure of lyophilizate is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropyl beta-cyclodextrin and silicon dioxide particles in the form of stable suspension as pharmaceutical medical agent for prophylaxis and therapy of endocrinological diseases.

According to the results of readiness of preliminary mixing in two tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions, by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank mixer as basic and another as dosed one.

At the second phase the obtained quasistable suspension, composition of medical agents is filled into package from <NUM> up to <NUM>.

Characteristic of the obtained ready composition has the following indices: pH <NUM>, whitish color.

The final structure of suspension is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of <NUM>-hydroxypropyl beta-cyclodextrin and titanium dioxide crystals in the form of stable suspension as pharmaceutical medical agent for prophylaxis ant therapy of orthopedic, urological, gynecological, endocrinological, autoimmune, gastroenterological, neurological, viral and dermatological diseases.

According to the results of readiness of preliminary mixing in two tanks, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank as basic and another as dosed one.

Average size of dispersed nanoparticles of titanium dioxide was in the range of <NUM>-<NUM>, as determined by Malvern Zetasizer Nano ZS.

The final structure of suspension is: cyclodextrins <NUM> mass%, crystals of titanium dioxide <NUM> mass%, pharmaceutically admissible additives <NUM> mass%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of sulfobutylether beta-cyclodextrin and silicon dioxide particles in the form of stable suspension as pharmaceutical medical agent for rejuvenation, prophylaxis and therapy of orthopedic, cosmodermatological, dermatological diseases.

According to the results of readiness of preliminary mixing in two tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank mixers as basic composition and from another as dosed one.

Content of Sulfobutylated beta-cyclodextrin in the products was determined by HPLC.

Characteristic of the obtained ready composition has the following indices: pH <NUM>, whitish suspension.

Example <NUM>. Obtaining and properties of aqueous nanodispersion of sulfobutylether beta-cyclodextrin, silicon dioxide particles and Doxorubicin in the form of suspension as pharmaceutical medical agent of therapy of oncological diseases.

According to the results of readiness of preliminary mixing in two tank mixers, the compositions that were enough homogenous for subsequent homogenizing were used, in particular, for obtaining stable suspensions by hydrodynamical cavitational homogenizer, where the homogenizing process was executed simultaneously with delivery of mixture from one tank as basic and another as dosed one.

The final structure of suspension is: cyclodextrins <NUM> mass%, particles of silicon dioxide <NUM> mass%, pharmaceutically admissible additives <NUM>%, water for injections up to <NUM> mass%.

Example <NUM>. Obtaining and properties of Pharmaceutical composition (<NUM>) in the form of hydrogel or hydrocolloidal medical products, having in their structure cyclodextrins SBECD, HPBCD <NUM>/g, and TiO<NUM> crystals or SiO<NUM> particles, QD, <NUM> in <NUM> gram of hydrogel or hydrocolloidal composition.

Starting material of different necessary components ChinMed Technologies are submerged in the mixer, the mass is heated at the temperature from <NUM>, after homogenizing a pharmaceutical composition is injected, comprising stable suspension of TiO<NUM> crystals or SiO<NUM> particles taken in concentration <NUM> - <NUM>% and cyclodextrins SBECD or HPBCD taken in concentration <NUM> - <NUM>%. After mixing sterilization occurred. At the output the obtained soft homogenous mass was reprocessed into a roll band from two sides, wound into a roll paper adding in the surface part a polyurethane (PU) adhesive for isolation of stickiness, and then it was delivered to the final forming and package.

Used pharmaceutical composition in the form of articles has antimicrobial and antiseptic influence, anti-inflammatory action, immunomodulatory and adsorbing action, depending on form and way of use.

Pharmaceutical composition in the structure of hydrocolloidal mass of a medical product, plaster, is in quasi-stable condition of crystals and particles, mechanism of action is that at the moment of contact with skin or mucous a thermal reaction occurs, resulting in accumulation of energy, obtained from superficially saturated with energy reactogenic centers crystals and particles of a special class of oxides (TiO<NUM>, SiO<NUM>), being semiconductors, the active molecules of oxygen are produced. Demonstration of oxygen activity promotes energy appearance and, correspondingly, transfer of reverse energy onto specified body areas, and as a result additional energy promotes enzyme complex NADPH, in conditions of increased need, initiation of additional ROS production in pathogenic focuses with therapeutic purposes, and also promotes normalization of functioning of neuromediator receptors of organism. So, on the example of key monoamine neuromediator serotonin, regulation of inhibition of reverse capture of serotonin occurs by the way of selective blocking of serotonin absorption by a membrane of presynaptic cell. Due to elimination of disbalance of neuromediator in synaptic gap neurotransmission intensifies in serotoninergic synapses.

Ensuring of balanced level of neuromediators in an organism has evident positive effect on the state of health of a human and promotes elimination of symptoms of different pathological conditions. And healthy functioning of serotonin receptors in an organism also assists to restore homeostasis quickly, promotes general health improvement and improvement of activity of the principal organs and systems of organism.

Formation of active form of oxygen is detected by the system shown at the <FIG>, where:.

The pharmaceutical composition (<NUM>) in the form of hydrogel in the structure of medical product containing cyclodextrins SBECD, HPBCD in quantity of <NUM>/g and TiO<NUM> crystals or SiO<NUM> particles, QD, in quantity of <NUM> in <NUM> gram of hydrogel or hydrocolloidal mass, is placed in a medium to which the sensor for registration (<NUM>) transmitting the signals to the analyzer (<NUM>) and PC (<NUM>), source of thermal influence (<NUM>) in the radiation spectrum of IR-laser with wavelength of <NUM>, or IR-laser, (<NUM>) heater with circulation of warm water (stably <NUM>) are connected.

Peculiarity of the pharmaceutical composition is that regulated catalysis in ROS occurs at human body temperature <NUM>, by means of photo- or thermo- catalytic induction of O<NUM> on the surface of crystals or particles of the pharmaceutical composition.

Examination of onco-biological effects of pharmaceutical compositions: cyclodextrins and TiO<NUM> and SiO<NUM> suspensions.

From the data of literature is known, that TiO<NUM> and SiO<NUM> have ability to reduce tumours volume in vivo (<NPL>), and cyclodextrins have ability to improve effect of a therapeutical agent (<NPL>).

The results stated below demonstrate improvement of antitumoral activity of pharmaceutical compositions due to compositions of cyclodextrins and stable dispersions ADAM QD/T, TiO<NUM> and ADAM QD/S, which modulate protective mechanism of tumour cells.

A range of the experimental data showed a critical role of active forms of oxygen (ROS) and accompanying metabolic processes, including activation of signalling pathways, in cytotoxic action of titanium dioxide and silicon dioxide.

Demonstration of antitumoral effect of pharmaceutical compositions consisting of cyclodextrins and stable dispersion ADAM QD/T, TiO<NUM> and ADAM QD/S, SiO<NUM> in local administration.

A range of the experimental data on used pharmaceutical compositions shows at a critical role of active forms of oxygen (ROS) and accompanying metabolic processes, including activation of signalling pathways, in cytotoxic action of titanium dioxide and silicon dioxide. Therefore, importance of the mechanism of cellular response to generated ROS was proposed as a basic element in this research.

In these studies cells (<NUM>×<NUM><NUM>) were seeded in <NUM>-well plates and cultured in RPMI-<NUM> medium containing <NUM> % fetal bovine serum. The cultures were incubated for <NUM> hours in CO<NUM> thermostate at <NUM>. After the preincubation period the medium was removed, the cells were washed with physiological saline (<NUM> × <NUM> <NUM>% NaCl) and exposed to testing samples applying various concentrations for <NUM>. After removing the test compounds fresh RPMI <NUM> medium containing <NUM> % FBS was added and the cultures were incubated for further <NUM> hours at <NUM> in humidified thermostate (<NUM>% CO<NUM>). At the end of the posttreatment period the medium as supernatants of the cultures, containing released cells was removed and saved for cell counting.

Fragments of adenocarcinoma of murine large intestine were transplanted subcutaneously to male mice of the line C57BL. Treatments were executed <NUM>-<NUM> days after transplantation, when the tumour mass was about <NUM>-<NUM>. Skin above the tumour was shaved and the tested compounds were administered immediately into the tumours. Treatment in aforesaid doses in calculation of mass mcg/tumour was executed intratumorally.

Changes in tumour growth were estimated controlling the tumour volume and measuring tumours mass at the moment of finishing the experiments. For evaluation of growth speed the tumour volume <NUM>-<NUM> days after transplantation was divided by the tumour volume measured during the first treatment (Vt/V<NUM>). In this period tumours were in quickly growing condition.

The tumour cells HT1080 and ZR-<NUM>, obtained from the cell cultures, were transplanted orthotopically in amount of <NUM>×<NUM><NUM> to naked mice. The tumours volumes were measured as described above. The test substances were administered inside the tumour, as indicated at the experimental area.

The data was expressed as average +/- standard deviation.

In this research the cytotoxic effects of TiO<NUM> (CYL-<NUM>), SiO<NUM> (CYL-<NUM>), HPBCD (CYL-<NUM>); TiO<NUM> - HPBCD (CYL-<NUM>) were compared. The cells of medulloblastoma revealed high sensitivity to the test substances at indicated concentrations. Different cytomorphological changes were observed: Arrows indicate changes as a result of the impact of tests on samples, particles near vacuolization of cytoplasm on <FIG>, appearance of multinuclear and giant cells on <FIG>, death of cells in the form of apoptotic corpuscles on <FIG>. The test substances TiO<NUM> (CYL-<NUM>), TiO<NUM> - HPBCD (CYL-<NUM>) themselves caused sharp damage of cells (<FIG>).

In subsequent experiments compounds of Doxorubicin (CYL-<NUM>) and - SiO<NUM> - Doxorubicin (CYL-<NUM>), SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>), TiO<NUM> (C YL- <NUM>) and TiO<NUM> - HPBCD were examined in different compounds in order to make clear whether is possible to eliminate toxicity from Doxorubicin with saving cytotoxic action associated with SBECD, HPBCD, TiO<NUM>, SiO<NUM>. In administering of Doxorubicin only, i.e. without other components, evident cytotoxicity of Doxorubicin was observed at starting concentration.

In administering of compositions TiO<NUM> - HPBCD, when TiO<NUM> concentration was <NUM> mcg/ml, and cyclodextrin <NUM> mcg/ml, cytotoxicity was noted.

In administering of SiO<NUM> (CYL-<NUM>), evident cytotoxicity was observed at concentration of <NUM> mcg/ml. Moreover, Doxorubicin in concentration <NUM> mcg/ml showed significant cytotoxicity. In use of SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>) it is necessary to note increase of efficiency of compound at SiO<NUM> concentration <NUM> mcg/ml, SBECD <NUM><NUM> mcg/ml and Doxorubicin in concentration <NUM> mcg/ml and caused more evident and specific cytotoxicity (<FIG>).

The research results confirmed antitumoral efficiency of pharmaceutical compositions SiO<NUM> - Doxorubicin (CYL-<NUM>), SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>) for transformed tumoral lines of cells, at the <FIG> structural morphological changes in comparison with the control <FIG> are evident, when the normal human fibroblasts were not affected (see: <FIG>.

Critical metabolic processes for cytotoxic efficiency of pharmaceutical compositions TiO<NUM> (CYL- <NUM>); SiO<NUM> (CYL-<NUM>); - Doxorubicin (CYL-<NUM>); SiO<NUM> - Doxorubicin (CYL-<NUM>); HPBCD (CYL-<NUM>); TiO<NUM> - HPBCD (CYL-<NUM>); SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>) were studied.

Taking into account a conception that a better understanding of the mechanism of antitumoral action of examined samples could give recommendations for creation of efficient new therapeutic protocol, it was decided to characterize active forms of oxygen as supposed target for TiO<NUM> and SiO<NUM> in tumour cells. Therefore, antitumoral efficiency of TiO<NUM> and SiO<NUM> may be expected from revealing the cell processes determining whether treatment will result in death or survival of tumour cells.

In this research reinforced ROS formation showed dependence on combinations of test substances. So, SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>) produced greater amount of ROS in comparison with the test sample SiO<NUM> - Doxorubicin <FIG> control, <FIG> SiO<NUM> - Doxorubicin, <FIG> SiO<NUM> - SBECD - Doxorubicin.

Taking into account significant, expressed antitumoral activity of TiO<NUM> and SiO<NUM> nanoparticles in vivo, it is necessary to understand the optimal conditions for its efficiency.

The role of speed of tumour growth in antitumoral action of pharmaceutical compositions.

Since a size of transplanted fragment of tumour defines speed of the tumour growth, efficiency of TiO<NUM> - HPBCD (CYL-<NUM>) and SiO<NUM> - SBECD - Doxorubicin were compared in two experimental groups with transplanted tumour fragments Colon <NUM> with small or big size. During therapy it was a significant difference in tumours volume (V<NUM>) between two experimental groups. Speed of growth during subsequent <NUM> days was <NUM> times higher for animals with transplanted small tumour fragments, in comparison with the animals with transplanted big tumour fragments. Estimation of changes in tumour volume showed enough convincing proofs of depending on speed of growth efficiency of administered tested substances, since TiO<NUM> - HPBCD (CYL-<NUM>) and SiO<NUM> - SBECD - Doxorubicin (CYL-<NUM>) inhibit tumours with high speed of growth. The experiment showed that TiO<NUM> - HPBCD and SiO<NUM> - SBECD - Doxorubicin by <NUM>% and <NUM>% correspondingly suppress growth of transformed cells in culture Colon <NUM> in comparison with control.

In was a big problem to examine action of TiO<NUM> - HPBCD (CYL-<NUM>) and SiO<NUM> - SBECD - Doxorubicin in vivo on tumours ZR. <NUM> and HT1080, which showed remarkable sensitivity in cellular cultures. It was marked that in intratumoural administering in concentrations causing cytotoxicity in the cell cultures, changes in growth of the same tumour in the model of human xenotransplantant were not registered.

The new pharmaceutical compositions TiO<NUM> - HPBCD, SiO<NUM> - SBECD - Doxorubicin in presented form demonstrate additional advantages over initial tested substances considering cytomorphological changes. Therefore, the indicated pharmaceutical compositions may be used for ensuring antitumoral activity as an adjuvant.

The presented experiments gave the additional data on variability of antitumoral efficiency of the pharmaceutical compositions depending on biological analysis, i.e. in vitro or in vivo, type of cellular population and presence of biological substrates.

The pharmaceutical compositions presented in the examples ensure ROS formation in damaged cells. ROS induce both physiological processes and molecular mechanisms, resulting in death of pathogenic cells.

Influence of pharmaceutical compositions on restoration of physiological processes, rejuvenation and life duration of Caenorhabditis Elegans.

The results of the research stated below demonstrate ability of used pharmaceutical compositions to restore the physiological processes in an organism, and also rejuvenation and prolongation of life of the tested animal.

The literary base of C. elegans correspondence as a model for researches.

Nematode Caenorhabditis elegans is multicellular genetic model for researching fundamental questions in biology. Its reproductive cycle is relatively short and an animal which may be easily kept in laboratory conditions. As a human organism, C. elegans grows, develops (from mature single-cell oocyte into multicellular adult organism), breeds, has a sensation, moves, learns, has a behaviour, grows old, falls ill, dies etc. - i.e. it shows the basic biological traits which characterize the highest living systems. Its genetic material (DNA) and duration of cells development are well-known, that allows to study with effect functioning of genes and proteins at the level of a single cell. About <NUM>% of genes C. elegans have human homology. Functional analysis of these genes resulted in discovery of several evolutionary significant biological lows, for example, genetics of apoptosis (programmed death of cells) and differentiation of the cell destiny by means of the cellular signals. These important discoveries were awarded with Nobel prize in <NUM> and <NUM>. Our purpose is to present C. elegans in industrial, clinical and biological research application.

elegans is a microscopic organism with <NUM> length. The term of its reproduction is relatively short (<NUM> days at <NUM>) and, as all the microorganisms, it may be kept in great amount on a plastic plate. The kinds of nematode may be also kept during indefinite time in liquid nitrogen. elegans exists in two sexual forms: self-matured hermaphrodites are a source of pure genetic colonies, at that the males make possible mating between different genetic colonies. An animal consists of about <NUM> somatic cells, with the term of development (cellular age) is invariative and totally determined. <NUM>-dimensional anatomical structure of the nervous system of a worm (contains <NUM> neurons) and a network of its nerves are well-known. Since under the light microscope a body of C. elegans is transparent, at the level of single cell it is possible to easily determine both normal and pathological events in development.

Genome of C. elegans is decoded and counts about <NUM> genes, the functional analysis of which already contains very detailed data. <NUM> genes of a worm are for the present characterized concerning mutation, but the attempts to generate perfectly functioning form of potentially every gene continue (Gene Knockout Project). Simultaneously, the scientific method on the base of the sequence of genes allowed to inactivate a code potential of primary genome of a worm (Gene Knockout Project). Now the program of protein-protein interaction and a map of systematic expression of genes are revealed. A vast potential of combination of genetics, cellular biology and molecular biology made C. elegans an attractive system model in researching biology. Thanks to presence of a great amount of genic conformity between a worm and a human system C. Elegans became one of the most popular models of examination of serious human diseases. (See <NPL> and <NPL>, also<NPL> Measurements of the Age-related Changes of Physiological Processes that Predict Lifespan of C.

In the researches the compositions containing SBECD and ADAM QD suspension of SiO<NUM> and TiO<NUM> activated particles were used.

Composition of NGM plates (all the chemical compounds and reagents of analytical class); NaCl, agar, peptone, <NUM>/ml cholesterol in ethanol, non-autoclaved, <NUM> K<NUM>PO<NUM> buffer pH <NUM> (<NUM> KH<NUM>PO<NUM>, <NUM> K<NUM>HPO<NUM>, H<NUM>O for <NUM> liter), <NUM> MgSO<NUM>, Petri dishes, peristaltic pump.

The results present average of three parallel, independent definitions, research cycles of C.

The effect of ADAM QD/T, TiO<NUM> on life duration of C. elegans:
Heterocrystalline suspension TiO<NUM> in concentration <NUM>/ml, used in a standard cultural medium (NGM), showed significant improvement of life duration and prolongation of youth during a term of life.

The animals treated by TiO<NUM> suspension remained young and, correspondingly, kept "life quality" for a longer time.

Analogous tendencies were marked on a wild kind of C elegans, treated by SiO<NUM> suspension in analogous conditions.

Combination of TiO<NUM>, SiO<NUM> nanodispersions, with concentration <NUM>/ml with SBECD <NUM>/ml still more enlarged life duration and breeding of animals.

Besides registration of a number of animals, survival factor of C. elegans was determined as a time function, moreover, examination of C. elegans gave possibility to reveal the process of aging with a help of fluorescent microscopic research of animals histology. Since the process of aging always correlates with forming fluorescent senile pigment (generally, lipofuscin) in interstitial tissues of C. elegans, use of appropriate microscopy immediately gives a real picture of animals life in the course of their aging.

In the result of executed microscopy, using the light microscope Nomarski, C. elegans fluorescent image of a young adult animal, in <NUM> days age, does not show senile fluorescence in interstitial tissues.

In the result of executed microscopy, using the light microscope Nomarski, fluorescent image of a young adult animal, in <NUM> days age, C. elegans shows self-luminous senile pigment in interstitial tissues (often lipofuscin accumulation).

As the Table <NUM> shows, a positive effect of treatment by suspensions ADAM QD/T TiO<NUM>, ADAM QD/S, SiO<NUM> and SBECD <NUM>/ml on life duration of C. elegans was noted. In the result of administration of TiO<NUM> in the medium to C. elegans, life duration of animals enlarged by <NUM>% in comparison with a control group, and by <NUM>% using TiO<NUM>+ SBECD.

Combined administration of polydisperse suspensions, taken in amount <NUM>/ml, and SBECD taken in amount <NUM>/ml, into the matrix of a cultural medium NGM showed extension of life duration of an animal, and also rejuvenating effect on wild kind of C.

Claim 1:
Pharmaceutical composition for restoring the physiological processes and the cells of an organism, characterized by presence of cyclodextrins - cyclic maltooligosaccharides chosen from, alpha-cyclodextrins, beta-cyclodextrins, gamma-cyclodextrins, randomly methylated beta-cyclodextrins, <NUM>-hydroxypropyl-beta-cyclodextrins, sulfobutylated beta-cyclodextrins, <NUM>-hydroxypropyl-gamma-cyclodextrins or their mixtures and sugammadex, used in amount <NUM>-<NUM> mass% in combination with aqueous stable suspension of heterocrystals of titanium dioxide or silicon dioxide particles with size not less than <NUM> and content in amount of <NUM> - <NUM>% mass, having on the surface of crystals and particles in the energy centers electronically-excited triplet oxygen <NUM>O<NUM>.