SA113340430B1 - New benzene polycarboxylic acid compounds - Google Patents

Abstract

The present invention relates to new benzene polycarboxylic acids compound, which is prepared by alkaline oxidation of hydrolyzed lignin. The present invention also relates to the use of the new benzene polycarboxylic acids compound as part of a composite substance, where the composite substance is prepared by complexing or encapsulating the new benzene polycarboxylic acid compounds with a metal cation. The present invention also relates to a method for preparing the new benzene polycarboxylic acids compound and for its use in cosmetic, nutraceutical and pharmaceutical compositions. Figure 1.

Description

— \ — New benzene polycarboxylic acid compounds FULL DESCRIPTION BACKGROUND BACKGROUND The present invention relates to “new benzene polycarboxylic acid 6”; which are prepared by alkaline oxidation for aqueous lignin. The present invention also relates to the use of new 860 polycarboxylic compounds 0602806 as part of a © composite material 0001005116; Where the composite material is prepared by complexing or encapsulating new benzene polycarboxylic acid compounds with 081100 metal cation. The present invention also relates to a method for preparing a new compound, benzene polycarboxylic acid, and using it in cosmetically + pharmaceutically nutraceutical formulations. One of the drugs most studied for cancer treatment is Cisplatin .platinum | 0 Cisplatin is a broad spectrum drug effective in the treatment of sarcomas; Carcinomas and some lymphomas. At the same time, this property is accompanied by a number of significant disadvantages. Thus dag's rapid metabolism with the formation of compounds that bind to inactive protein in the drug denatures both normal and cancerous cells, exhibiting Ale toxicity, particularly nephrotoxic. To overcome these problems a substantial effort has been invested in searching for ways to reduce the toxicity of Yo 61501810 by means of developing new organometallic complexes based on low molecular weight organic ligands (US Patents 5,114,847 and 187,477). With this «a pail», the use of polymeric compounds as clamping agents or encapsulations represents in itself a possible effective solution to this problem. Patent application 00101/17977497 describes a new type of formation of the organic platonic compound Ye; It contains at least one platonic organic compound, a polymer soluble in

at least one associative water; Where the aforementioned polymer is produced by polymerization for Hemimaleate Urethane monomers ((Meth)acrylic acid monomers monomers and a compound ¢ggunae platonic selected from the group formed “Cisplatin; carboplatin and oxaliplatin specifically, then The invention makes it possible to obtain an enteric preparation of the drug in the form of syrup or granule form.The present invention differs from the inventions mentioned above by using a Polymer of benzene polycarboxylic acids as a water soluble polymer to produce an organometallic compound preferably For application other than the intestinal route; intestinal and topical.Another 8,176,420 patent describes a drug preparation - Cis— polymer diammineplatinum (Il) dichloride 0 showing antitumor effect.The purpose of the aforementioned invention is to fix (encapsulate) a platinum compound on the surface of the (6-carboxycellulose) The resulting drug preparation is used for brain implants in neurosurgery to prevent recurrence of malignant tumors. The mentioned biosoluble drug—polymer of 0181107-015 exhibits moderate dae toxicity and enhanced cytostatic effect. Yo varies The present invention for the described invention In 876420 in that the water-soluble polymer of benzene polycarboxylic acids shows its biological effect and a drug preparation - polymer depending on the mentioned polymer can be used for application other than the intestinal route; Intestinal and topical. In the Russian patent YVAYEAY a process for the preparation of a 0-anticancer agent based on tetrachloroplatinate (001855010) is disclosed. The said patent discloses a method in which potassium tetrachloroplatinate reacts with humic compounds. In this method the solution is treated aqueous of humic material with a solution of potassium tetrachloroplatinate. Curing is irradiated with ultrasound with a power density of You [ly 506] and a frequency of YY kHz per 4 to +4 minutes.The product of the present invention differs from the product

p

Described in Russian Patent 70874487 by selecting a flat-square coordination compound of platinum (11) as a platinum agent. In addition to this, the product of the present invention is produced using a method that differs in terms of the different conditions of exposure to radiation and the adjustment of the radiation strength according to the size of the product Irradiated The irradiation is carried out until the amount of non© platinum reacted with the polymer is less than or equal to 775 of the initial amount and further the temperature is regulated until the amount of water soluble platinum is less than or equal to .701 Thus we get a different product.The complex resulting from the present invention is characterized by high stability of the bonds

Intrinsically low toxicity. In EP 183747977 and Russian Patent 7771487179 platinum is described as another anticancer agent that is also produced by the reaction of a coordination compound of 0 with a humic compound that preparatively undergoes acoustic cavitation that occurs by undergoing ultrasonic (I) 176 waves. to 18 to © watt/cm? Ultrasonic frequency of 0.5 with an intensity of 58 by 58 kHz. The anticancer agent thus produced is characterized by a content of a high molecular weight fraction of a humic compound of less than or equal to 75. The product of the present invention differs from the product

0 described in European Patent 1874797 and Russian Patent 771487179 in exposure to radiation until the amount of platinum unreacted with the polymer reaches less than or equal to 775 of the initial quantity and additionally the temperature is regulated until the amount of platinum reaches Dissolvable Like to less than or equal to LTV so we get a different product. The complex obtained from the present invention is characterized by high bond stability and intrinsically low toxicity.

0 In Russian Patent 4 718717 a method for producing a means of protecting a living organism against ionizing radiation is disclosed; Specifically, a material with radial protective properties from natural materials Land. According to this method, humic materials are derived from natural raw materials, and Sle solution of these humic materials is treated with @ammonium molybdate. The mentioned treatment is done with ammonium molybdate at a temperature of 46 + #* 56 W/Vou

Lignin minutes. The method uses humic materials produced from A kHz for ; to YY with a frequency of Yo

Oxidized Wood The product of the present invention differs from the invention described in Russian Patent 4 718717 in selecting the molybdenum salt from a wide range of compounds. In addition to this, the product of the present invention is produced using a different method in terms of the different conditions of exposure to radiation, and the radiation strength is adjusted according to the size of the product exposed to radiation, and exposure to radiation is © until the amount of unreacted molybdenum with the polymer reaches less than or equal to AY From the initial quantity and further regulated to the temperature, Sa, the amount of water-soluble molybdenum is less than or equal to .7010, thus obtaining a different product. The resulting complex is characterized

of the present invention with high bond stability and intrinsically low toxicity. In European Patent 183747974 and Russian Patent 77507573 0 another method of producing an agent to protect an organism against ionizing radiation is disclosed. This agent is prepared by treating a Sle solution containing humic substances and ammonium molybdate with wave radiation. The content of ammonium molybdate picks a range of up to 0.4 parts by weight per part of humic material; Processing is carried out until the high molecular weight fraction of humic substances reaches a level less than or equal to 75. The product of the present invention differs from the invention described in 10 European Patent 1874314 and Russian Patent ?780757? In the selection of Molybdenum salt from a wide range of compounds. In addition to this, the product of the present invention is produced using a different method in terms of the different conditions of exposure to radiation, and exposure to radiation is carried out until the amount of molybdenum not interacting with the polymer reaches less than or equal to 7725 of the initial quantity, and in addition, the temperature is regulated until the amount of molybdenum is 0 to less than or equal to .7000 so we get a different product. The resulting complex is characterized by the invention

The current has a high ligand stability and intrinsically low toxicity. Besides the benefits; The combinations described in Russian Patent 7,187,547, European Patent 1,874,397 and Russian Patent 187,174? and Russian Patent 4 718717 and European Patent 18714774 and Russian Patent YO 73007507 have a number of defects resulting from the fact that organic ligands; that

-- include; Features a formula; variable safety and biological activity and; as a result; They cannot be used to develop stable complexes or composite materials suitable for the preparation of drug formulations; nutritional and cosmetic. GENERAL DESCRIPTION OF THE INVENTION He fide the present invention surprisingly finds that a new water soluble polymer © of benzene polycarboxylic acids characterized by low metal content, low molecular weight impurities and biological activity can be used to develop stable organometallic complexes; Safe and effective. The stability of the bonds between the polymer and the metal cation in these complexes is improved through the introduction of (polymerization) processes, purification, temperature control, and the use of ultrasonic exposure conditions 0 when the strength is adjusted for each volume, and the treatment continues until a complex is formed with more than 7975 of the metal compound The present invention also discloses composite materials based on a new water-soluble polymer compound of polycarboxylic acids 0602806, in which said polymer compound acts as a complexing agent and/or encapsulation forming highly complexed Low toxic activity with high binding stability 1. Also at low concentrations, these new composite materials show high activity. These composite materials include, for example, “JUN platinum complexes 7/5061017a000” that clearly show promising properties. platinum as effective anti-cancer agents and experimental results clearly show its improved ability to kill cancer cells compared to primary types and known anti-cancer agents such as Cisplatin and (Carboplatin) molybdenum Yu complexes act as effective agents for the prevention or treatment of diseases JIA-induced cell cycle; resulting; JU) from radiation exposure; Cell senescence or immune disorders. Pharmaceutical formulations of the present invention can also be used to reduce side effects (HEY) resulting from radiotherapy or conventional chemotherapy.

The chemical properties of the new water-soluble polymer compound of benzene polycarboxylic acids make it possible to obtain a wide range of highly stable complexes; In addition to pharmaceutical formulations; Food and cosmetics for administration other than the enteral and topical route Cred and animals.

In a first aspect, the present invention relates to a new water-soluble polymer compound of “benzene polycarboxylic acids” having an elemental composition of 77-7176; Z£.Y-Y.A A 234-74© and less than 70.7 JIN dry weight and where the sum of the other elements is not more than 71 each dry weight.

In a second aspect, the present invention relates to a method for preparing a polymer compound soluble in

0 The water is new from “benzene polycarboxylic acids” in which the starting raw material containing lignin is subjected to an alkaline treatment; Then a graded acid density treatment to obtain a crude water-soluble polymer compound of (benzene polycarboxylic acids) and finally subjecting the crude compound to purification.

In a third aspect the present invention relates to a new water soluble polymer compound

1 For use in the prevention of; treatment or modification of human and animal diseases and drug formulations comprising a new water-soluble polymer compound for use in the prevention of; Treatment and modification of human and animal diseases.

In a fourth aspect, the present invention relates to a cosmetic formulation or a food formulation comprising a new water-soluble polymer compound.

0 In a fifth aspect, the present invention relates to a composite material that includes a new water-soluble polymer compound of benzene polycarboxylic acids, a metal cation, and optionally an anti-cancer agent, and its use in a drug formulation for the prevention of; Treating or modifying a human or animal disease.

A — — In a sixth aspect the present invention relates to a process for preparing a composite material comprising a new water-soluble polymer compound of benzene polycarboxylic acids and a flat-square coordination compound platinum (Il) In a seventh aspect the present invention relates to a material A compound comprising a new water-soluble polymer © of benzene polycarboxylic acids and a square-flat format compound Platinum (11) for use as a drug or for use in the preparation of a drug formulation. In an eighth aspect, the present invention relates to the use of a drug or a pharmaceutical composition comprising a composite material comprising a new water-soluble polymer compound of benzene polycarboxylic and a square-flat coordination compound Platinum (Il) in the prevention of “treatment or palliative care” 0 for pain or to correct disease in mammals; For example cancer. In a ninth aspect, the present invention relates to a composite material that includes a new water-soluble polymer compound of polycarboxylic acids 561126176 and a “molybdenum” compound where the polymer compound of benzene polycarboxylic acids is encapsulated or forms a complex with a molybdenum compound. mentioned. Vo In a tenth aspect the present invention relates to a process for preparing a composite material comprising a new water soluble polymer compound of benzene polycarboxylic acids and a molybdenum compound. In an eleventh aspect the present invention relates to a composite material comprising a polymer composite A new water soluble form of benzene polycarboxylic acids and molybdenum 0 A for use as a drug or for use in the preparation of a medicinal formulation. In a twelfth aspect, the present invention relates to the use of the drug or pharmacological composition (dla dal) on a composite material that includes a new water-soluble polymer compound of benzene polycarboxylic acids and a molybdenum compound for the prevention of “treatment or care.”

q —_ _ Alleviating the pain of a mammal suffering from a disease, for example a cell cycle dysplasia, or to modify said disease. In a thirteenth aspect, the present invention relates to pharmaceutical formulations for use in reducing / minimizing the side effects resulting from radiotherapy or conventional chemotherapy. lo} Brief explanation of the drawings Fig. 1. 13C NMR spectrum of humic acids according to the initial type Russian patent 17 Fig.?. IR cada of the polycarboxylic acids polymer 56112616 of the present invention. appearance ?. 13C NMR spectrum of the benzene polycarboxylic polymer of the present invention. Fig. 4. Dimeric homo- or heteronuclear spectra of the polymer compound of polycarboxylic acids 06028606 of the present invention. .o Ki yo FTICR MS spectrum of benzene polycarboxylic polymer 5 of the present invention. FIG. 1 A microstructure extended (M) X-ray absorption spectra of a composite material comprising benzene polycarboxylic acids polymer of the present invention cis—diammineplatinum(ll) dichloride “cis—diammineplatinum(ll) dichloride 4 Yo Inorganic (symbolized as cis—diammine(cyclobutane~ , (“Cisplatin 1,1-dicarboxylate—-O,O0”platinum(ll)) (“Carboplatin”). ”

=« \ — Fig. 7. Photographs of PBMC cells on day 11 and incubation in medium without the addition of benzene polycarboxylic acids polymer (denoted as “conjugate-(a)”) with poly from poly y A stands for Rn-(a)) and in a medium containing a benzene polycarboxylic acids “polymer” of the present invention at a concentration of 701 µg/L of medium (denoted as “compound —polymer 9 ( b) ; 111 μg/L'). gd Human after treatment with compounds of the present invention. le human WA “SKOV-3” Fig. VY showing LDH activity for IA (MCF=7) human breast cancer after Vo treatment with compounds of the present invention. Fig. 11 showing LDH activity For WA (T4T-D) human breast cancer after treatment with compounds of the present invention. Detailed Description 1: Yo relates to sister The current consideration is a new water soluble polymer compound of polycarboxylic acids 0602806 which has the following elemental formula: 717-717 C 4.-7. 74 no 774-74©0; Less than 70.7 JIN dry weight and the sum of the elements

-11- Others (inorganic impurities) less than 77 per dry weight. This new compound has its own pharmacological activity; and an improved degree of purity as well as an improved ability to form stable complexes or various encapsulating agents. cpolymer as used herein means 'water soluble polycarboxylic acids'. ALE many basic aromatic carbonic acids «13C NMR water soluble using new polymer methods may additionally feature FTICR-MS IR. The detected CHn aliphatic from carbon groups, the amount of ¢ (13C NMR according to 01 aromatic carbon LS; 777-11 in the range from zero-/; ppm constitutes

LS 7; 67-71 ppm Pg1 49-018 detected in the CAR range

YAV=310 detected in a range ranging from ester COO ycarboxylic from 007 groups detected in the range of 0-0 ketonic to carbon groups ppm forming 7917-5 and the amount of the total amount of impurities is low LAY ppm forming YY am VAY ranges from VO (part in VV) ((carbonate-anion) ppm 1608.5 molecular weight detected at 11-087 ppm and ( oxalate—anion) ppm 11777 million (10001816-20100);

JY is less than one million (acetate-anion) as is (low-molecular impurity) low molecular weight ALE The term is a Dalton; Which does not occur to Yer less than Aa used here means a compound with a weight of 0. Asymmetric polymerization ionized with COO The remarkable special expansion oscillations of the groups we see polymer absorption range for IR can Visible on 1-ms VEY spectra + peaks at -19500 in a wide complex range of aromatic and aliphatic carbonic acids against a mixture of

“yy also contains a very large amount of polymer containing carboxylic acids with a ratio of 1-ms 0. This is evidenced by the presence of hydrogen bands linked to each other by bonds of phenolic compounds -1700 (C=O ) 1-ms 0151 (OH) 1-ms ?0001-"' 46560 Absorption in the following regions: Contains absorption band with peaks 1-ms Tov om YA The (OH) region is 10 -00 ms in CH groups vs. 10-ms YAOY 5-ms 1-ms YAYA groups equivalent vibrations at © 1-ms 1786 more than or less than the apparent absorption peaks identified at LCH2 5 3 .-0 corresponds to the vibrations of groups New from the invention Polymer Dalton from compound 10501 It can be seen a part of its value

AY < XI where ((C3H20)x1(C2H20)x2(CH2)x3) is the current of the following aggregate formula: 1 < say “a >2x2 0” specified mostly on caromatic (components Benzene polycarboxylic acids The main monomers are (benzene polycarboxylic acids “methyl esters” they are benzene polycarboxylic acids polymer In addition to that. Polymer for saturated aliphatic includes; aliphatic carboxylic 80105 as monomers Unsaturated hydroxycarboxylic acids 0 aliphatic hydroxycarboxylic acids «Lal» Unsaturated aliphatic carboxylic acids are not polyunsaturated. Unsaturated monounsaturated aliphatic carboxylic acids dua corresponds to the general formula 600112002 - aliphatic carboxylic acids. Saturated corresponds to the formula aliphatic hydroxycarboxylic acids to 7 ?. The 1" is from 7 aliphatic carboxylic acids en .Y1 to 11 en year = 00112003 where 00 is -; CnH2n- 202 Monosaturate corresponds to the following formulas hydroxycarboxylic acids to 8?.N 14 where “7” is from “(CnH2n-205) (CnH2n-204 (CnH2n-203) The polymeric compounds The above sufa is responsible for the surface-active properties of 6Z, 13-015-18610016 acid which is polyunsaturated represented by aliphatic carboxylic acids cis,cis,cis—6,9,12-octadecatrienoic (9Z,12Z,15Z-octadecatetraenoicacid Yo £ 4Y4 ype 95- ((9R,13R)-2-oxo-5-pentyl-3—cyclopentene—]-octanoic acid «acid

C13(S)- <hydroperoxy—10E,12Z,15Z-octadecatrienoic acid 10S,11S—-epoxy—9S-hydroxy— <hydroxyoctadeca-9Z,11E-dienoic acid 0S,12S,13S~trihydroxy—-10E,15Z- < 12Z-octadecenoic acid 15(S)-hydroxy- , 5,6-dehydroarachidonic acid octadecadienoic acid © The antitumor effects of (52,82,112,13E,17Z)-eicosapentaenoic acid 13- and the antioxidant of many compounds that This last series belongs (eg

C13(S)-Hydroxyoctadeca-9Z,1 1E-dienoic (cis-Retinoic (Isotretinoin) of this invention. Polymer in (5,6-Dehydroarachidonic acid «acid] comprising aromatic (components) monomers The basic group of AD “3—-benzyloxy—4,5-dihydroxy—-benzoic acid methyl ester are the following: monomers 5-(furan-2-carbonyloxy)—2-methyl-benzofuran-3-carboxylic acid methyl 2,6—dimethyl-benzo(1,2-b,4,5-b"\difuran-3,7-dicarboxylic acid «ester 5-(furan-2-carbonyloxy)-2-methyl-benzofuran-3- « dimethyl ester methyl ((4-methyl-6-oxo-6h- rhamnetin (carboxylic acid ethyl ester 00 bis(2- «benzo(c)chromen—3-yl)oxy)acetate hydrate 2,6-diacetyl-7,9 - sulochrin ((methoxycarbonyl)phenyl) carbonate

O- «dihydroxy—-8,9b—dimethyldibenzofuran-1,3(2H,9bH)-dione acetylsalicylic anhydride, 4-ho-3—((6-ho-benzo(1,3)dioxol-5-yl)— (3~ 2,3-bis-benzoyloxy-succinic «methoxy-phenyl)-methyl)-5h—furan-2-one 0 methyl 5-hydroxy-7,8-dimethoxy-1,3-dioxo-1,3, 10,11- «acid (1- tetrahydrobenzol[5,6]cycloocta[l,2 —c]furan—-4-carboxylate methoxycarbonylmethoxy-6-oxo—-6h-benzo(c)chromen-3-yloxy)-acetic The -phenylpropanoid is substituted with epicatechins ; atranorin « acid methyl ester Many of the compounds belonging to this group exhibit antibiotic and antitumor effects. YO

-?1- The present invention also relates to a method for preparing a water-soluble polymer compound from benzene polycarboxylic acids. The new polymer compound of the present invention may be prepared according to the method mentioned below. In the first step of the method, a sale containing lignin is available as a starting raw material. © Examples of lignin-containing materials include “coxidized lignin”; peat; plant remains; pulp mill waste. The most preferred 19010-containing starter raw material is produced from coniferous trees and is characterized by having a pH from ©.5 to oF, a moisture content of 50 to IV, and containing not more than 777 polysaccharides and not less than 717 polysaccharides. lignin and not more than 77 water-soluble compounds. IK In the second step of the method, a water suspension of raw material containing lignin is subjected to treatment with an alkaline substance at pH 11 + 0.0 and pressure 7.7 + 1.7 MPa. Examples of alkalis that may be used include alkaline metal hydroxides, alkaline earths, and/or 38. The preferred alkaline substance; With this it is hydroxide 5001000. By this alkaline treatment we obtain a solution of benzene polycarboxylic acids sodium salts as a result of hydrolysis and oxidation in the third step of the method; The solution is reduced from sodium salts of benzene polycarboxylic acids for a graded acid density treatment. in this step; The solution of 0 salts of benzene polycarboxylic acids is treated with mineral acid and subjected to 398 centrifuge treatment. as a result; A density gradient and polymerization is performed, 0 for benzene polycarboxylic acids. Examples of mineral acids that may be used include those soluble sulphuric Jie nitric <orthophosphoric and 0116A01000/A0. The preferred mineral acid.” With this is hydrochloric acid

A \ — The fourth step is the AAT step where the purification is carried out with one or more purification processes Jie extraction; floatation; distillation; filtration; sedimentation; centrifugation; decanting and/or dialysis to remove Low-Weight Impurities (Aad) Purification continues until the amount of low-molecular-weight impurities detected with 13C NMR or another representative method (eg; © gas chromatography) drops to less than 71% of the dry weight of the polymer The best method for making a polymer is shown in Example 1. The results of comparison of the polymer of this invention and the resulting humic acids according to the Russian patent “YYAYEAY” will also be described in Example 1. The present invention also relates to composite materials including a compound ( New LE polymer water soluble 0 of benzene polycarboxylic acids, a metal cation and optionally an anticancer agent.In preferred composite materials the water soluble polymer compound of benzene polycarboxylic acids acts as a complexing agent and/or encapsulation. The term “water-soluble polymer” as used herein means polymer soluble in water at a neutral or alkaline pH at a Ve concentration of ∼7 wt. The term “complexing agent” as used herein means an electron donor compound; It is able to form soluble ALE complexes with metal ions. These complexes may be coordination complexes and/or chelate complexes. In these complexes the Polymer portions of the present invention are ligands of the central metal ion. The metal ion could be a 55-25 00 or 50-30 metal. The resistance to metals 25-55 R 30-50 is platinum (ron (manganese (magnesium (potassium) «calcium lithium ¢molybdenum] palladium «silver (zinc) and copper. The term "encapsulation agent" (encapsulating agent) as used herein means a large molecule; capable of jassing small molecules and preventing them from colliding with the surrounding environment.

1- Encapsulation, in contrast to a complexing agent, does not form stable chemical bonds with the small molecules it holds. So; the term “(encapsulating) Alas” means “the process of confinement of small molecules within a larger molecule” ° in addition; The inventors of the current invention undertook the task of preparing pharmaceutical formulations; Food and cosmetic This new water-soluble polymer includes and optionally one or more additional excipients. Cosmetic formulations are made with a new water-soluble ALE polymer complex together with other ingredients typically found in these cosmetic formulations. Cosmetic formulations may additionally include other compounds containing; For example, it has bactericidal properties; dressing wounds; antioxidant. Thus, to obtain a bactericidal composition, silver cation is used as a metal that shows bactericidal activity. To obtain a formula that works on pal all, copper is used as a metal that shows wound healing activity. For an antioxidant formula; OAS lithium uses metal-organic complexes that exhibit antioxidant activity. Cosmetic formulations can be used to correct 1 skin or to treat such. Nutritional formulations are made from a new water-soluble polymer complex together with other ingredients typically found in these nutritional formulations. Food formulations may additionally include nutrients. as nutrients (important food minerals for living organisms); large items can be used; for example” magnesium calcium potassium dron and other materials 0 and/or these micron elements; For example in the article “copper” zinc silver dithium palladium (manganese) and other substances. Nutritional formulations can be used to restore nutritional balance. In some embodiments the drug formulations include a new water-soluble polymer compound; in other embodiments it Pharmaceutical formulations include a combined substance

-11- New water soluble and a metal cation. Compositions may include JLB polymer including a compound from the Lode penal pharmacokinetic classification system plus an anticancer agent; Which is selected from N (ATC) World Health Organization Anatomical Therapeutic Chemical “Cisplatin (Cyclophosphamide) good for anti-cancer agents These are [FEN] Filgrastim (Tamoxifen (Goserelin <Doxorubicin (Fluorouracil (Methotrexate)) © The drug combination can be used to treat Prevention or modification of interleukin interferon-alpha disease Examples of excipients that may be used in pharmaceutical formulations according to the present invention include compounds selected from the group consisting of anti-adhesives; binders; coating agents; disintegrants; materials Methylants; solvents/covalent solvents; flavorings; coloring agents; lubricating agents; lubricating agents; preservatives; absorption agents; sweeteners; 0 stabilizing agents API for protection of polymers Modified release API for polymers pH carriers; antioxidants; wetting agents; anti-foaming agents; thickening agents; wetting agents or mixtures thereof. Pharmaceutical compositions according to the present invention are preferably formulated so that they are administered by an enteral, mucosal, or my tongue. Thus the pharmaceutical compositions of the invention are preferably formulated as tablets; VO as lozenges; liquid viscous pastes; hard candies, lollipops, chewable candies, or jelly drops. Certain embodiments of the present invention relate to a composite material; comprising a new water-soluble compound and a metal cation. Among the above-mentioned types of composites, polymer or those platinum and polymer composites attract more attention (0.molybdenum-containing composites and polymer-containing compounds which themselves have a salsa structure) Bi-platinum It is known that the complexes in the construction have a central location and platinum compounds are placed square-flat; where the bonding ion occupies both sides of the square that lie on the same surface; They are the most anti-tumor compounds, precisely fit the distance, platinum equivalence angle, ion coordination, old, efficacy. In these compositions» Yo

m \ _ between adjacent guanine molecules of (DNA) which allows it to inhibit the synthesis of the latter by forming strand Jak aggregates. In a preferred embodiment of the present invention, potassium tetrachloroplatinate «cis—diammineplatinum(ll) dichloride is used. Or mixtures thereof as bivalent platinum complexes to synthesize a composite material.

o The present invention relates to a process for preparing a composite material according to the present invention. According to the invention; This composite material comprising a polymer composite of the present invention and a flat-square coordination composite (11) platinum may be produced by exposure to sald radiation and more specifically to ultrasonic curing with a force density of o—+., 0 W/cm Y and frequency from 18-1171 kHz for 1 to Ve min until unbound platinum content decreases

0 (i.e. “unreacted platinum with polymer) to Ji of 775 from its original amount. In the next step the composite material is subjected to temperature control (i.e. storage under specified temperature conditions aa) for 1 to A day at 1 *"residence to ra *"residence until a portion of the bound pe platinum is reduced to less than 701 of its original quantity and a complex is formed between a platinum coordination compound (11) square - flat and polymer Vo in the final step.The composite material undergoes purification to obtain a product suitable for a pharmaceutical application.Purification may include one or more purification processes such as sterile filtration, autoclave or irradiation.in sald)composite; platinum encapsulates or forms a complex with one of the following polymer constructions of benzene polycarboxylic acids Oo OH COOH 8 COOH od Ir 1( 7 A 11 - LL OH ~~ caoH [a Y 0 (a) (b) (€) (9) 5

q —_ \ _ where the constructions ba © and > represent parts of the aromatic components and the construction © comprises part of the aliphatic components mentioned above. The presence of these structures is evident in the characteristic IR absorption bands at 68 11-766 cm-3 Nia 1-6 (0-ms 011). cm- .1 where; The intensity of the peaks at 68 21-766 cm-01. Ah No Yoo mal 0 and YY mV You cm-1 is smaller than the intensity of the peaks of the polymer compound of benzene polycarboxylic acids as a result of the formation of Bonding between polymer and platinum Laws empirical formula for platinum-containing composite material using NMR 136 (total formula) and 2D NMR methods according to which it consists of a single repeating shal of Polymer L (CH2) ((C2H20) (C3H20) 0 Due to the fact that the polymer compound is present in solutions only in the form of a colloidal molecule it is difficult to determine its correct molecular mass. The exact molecular formula for the polymer has not yet been determined and so cannot Deducing the most specific coefficients in their total form According to the present invention, the composition of the platinum-containing composite material is represented by the following general formula: (C3H20)x1(C2H20)x2(CH2)x3(Pt (NH3)2)x4 0. Thus, the stoichiometric ratios estimate the following elements: at x354 2X2 017 2x1) = x4 JY > This overall formula describes a Yeeee—YO0 dalton fraction of the composite material. If a compound substance of greater or lesser molecular weight is obtained, the coefficients of X2 x] aie 0 are proportionally changed. x4 4 x3 it remains xf ad simple natural correct or fractions . 0 Describes in Example 2 the best method for preparing a composite material comprising a polymer and a platinum compound The present invention also relates to a drug comprising a polymer and a platinum compound 1 (£4Y4)

Cy. polymer The present invention also relates to a drug combination comprising a drug from a compound This drug combination may optionally include one or more platinum (I) substances and a compound of additional excipients from the additional excipient HAST. preferably Select one or the combination of anti-adhesives; binders; encapsulating agents; loosening agents; solvents/covalent solvents; flavourings; coloring agents; lubricants; © agents to release the polymers into the sled; preservatives; absorption agents; sweeteners; carriers; pH stabilizers; antioxidants; API for protecting polymers (APL) modified for wetting agents; anti-foaming agents; thickening agents; wetting agents or mixtures thereof. Cancers AB should treat various types of cancer including metastatic breast cancer.The 0 that can be treated with the drug combinations of the present invention include, but are not limited to, prostate cancer, colon cancer and head cancer ASB breast cancer pancreas; cancer

ASU and neck. The drug and the drug combination can also be used in the prevention or palliative care of a mammalian being suffering from cancer or in the treatment of said cancer. The term “modifying the cancer” as used here means the case in which (Modifying the said cancer) mentioned Vo does not guarantee the dose of the drug a direct anti-cancer effect; cp Uae DU Life for cancer patients The drug may be given by any usual method, enteral or topical, and in the case of administration (gsr) the method of administration is administration other than the intestinal route; intramuscular injection is preferred. To be treated are in one of the embodiments non-food-producing species. It is preferable to select the aforementioned non-food-producing species from among 0 humans » dogs, cats and horses. High inhibition of tumor growth in preclinical trials and clinical trials in humans (eg (3).

_— \ \ _ The inventors of the present invention also obtained a range of composite materials based on a water-soluble polymer compound of benzene polycarboxylic acids and a compound of .molybdenum preferably; The molybdenum compound is selected from among the molybdenum salts 0 as “ammonium molybdate tetrahydrate ammonium molybdate sodium molybdate di-hydrate (sodium molybdate (potassium molybdate) and mixtures thereof. In the composite material; Molybdenum or Forms a complex with one of the following structures of a polymer of benzene polycarboxylic acids OH © 9d COOH Cr COOH ou ir OH J 7 "' broon -- ~~ OH a 0 (a ) 2 (€) (d) 2 Ya where the constructs ba © and > are parts of the aromatic components and the construct © Jia is part of the aliphatic components mentioned above. The characteristic IR at 68 11-766 cm-3 nia 1-6) 0-ms 011. No Nam 100 Nam AH Vp 011 and 01 cm-01. Then the intensity The peaks at 6680 .-1 4 Va 2111-1 no cm- 10001 1 YT mV YOM gman 5 cm-1 are smaller than the intensity of the peaks of benzene “polymer (polycarboxylic acids) due to the formation of aki) , between polymer and .molybdenum according to the present invention “0” The composition of the composite material containing molybdenum can be represented by the general formula A Next: (C3H20)x1(C2H20)x2(CH2)x3(MoO3)x4 (H20)x5(NH4)x6 £4Y4.

— \ \ — then; The stoichiometric ratios estimate the following elements: at 2X2 7 2X1 0) = x4 .1 < x6 1 > x5 FY > X3 This overall formula describes a .r a 1.1 dalton fraction of the composite material. If a composite material of greater or lesser molecular weight is obtained; The parameters of XS x4 x3 2 x] and 6* are relatively variable. then; They remain simple whole numbers or fractions. The present invention also relates to a process for preparing the composite material according to the present invention. According to the invention; This composite material includes a polymer compound of the present invention and we may obtain a molybdenum compound by exposing the material to wave radiation and more specifically to an ultrasonic treatment with an intensity of 548 in the range of o—+.,0 W cm Y and a frequency in Sub kHz limits for 1 0 to ve min until the content of the unbound molybdenum (unreacted with the Polymer) decreases to less than 775 of its original quantity. In the next step the composite material is subjected to Adjust the temperature (i.e., store under special heat conditions) for 1 to yo day at a 5 1 to 4” bronchus until a portion of the unbound molybdenum is reduced to less than 701 of its quantity In the final step the composite material undergoes purification to yield a product suitable for a pharmaceutical application Purification may include one or more purification processes ie sterile filtration Autoclave Or exposure to radiation Describes in Example 4 the best method for preparing a composite material comprising a polymer 00 and a compound molybdenum .The present invention relates to a drug comprising a polymer r and .molybdenum compound The present invention also relates to a drug combination comprising the drug of a poluymer and a .molybdenum compound This drug combination may optionally include one or more additional excipients. preferably One or more additionally warranted items are selected from the collection

Ad —_ \ _ composed of anti-adhesives; binders; encapsulating agents; disintegrating agents; fillers; solvents/covalent solvents; flavorings; colored agents; lubricants; lubricating agents; preservatives; absorption agents; sweeteners; carrier material; modified-release polymers for polymers (AP) to protect “API pH-stabilizers”; antioxidants; “wetting agents”; anti-foaming agents; “thickening agents” and wetting agents. Mammalian suffering from a cell cycle defective disease eg radiation-induced carcinogenesis or caused by normal cell senescence The drug and drug combination may also be used in the palliative care of a mammal suffering from 0 cell cycle defective disease eg (Jd) carcinogenesis Radiation-induced or caused by normal cell aging or to modify the said disease. disease and/or alter the patient's quality of life. + The drug may be administered by the enteral route. The mammals to be treated are in one embodiment a non-Yo-producing species for food. It is preferable to select the mentioned non-food-producing species from among the humans; dogs; Cats and horses. Example 5 shows the results of combination studies involving a polymer and a cmolybdenum compound where said drug combination is used to induce a cell response. Examples Y. The invention is further illustrated by reference to the following examples; which are not considered to be limited in any way to the scope of the present invention. Comparative example 1A Method for producing humic acids as indicated in the Russian patent 7 7 ? and distinguish the aforementioned compound

— ¢ \ — For the purpose of comparison, humic acids known according to Example 1 of the Russian patent YIAYEAY are prepared and characterized as described below. The preparation uses dissolved lignin Like - an unspecified internal adsorbent (available under the trade name “Polyphepanum” © Scientek Ltd) as a starting material. A solution of 1 kg of starting material is treated; .001 g of sodium hydroxide and A.) kg of water for 1 hour in an oxidation reactor with a mechanical stirrer at a temperature of 1000*h; pressure of 0.¥ MPa and an oxygen supply of 0 L/min. The reaction mixture was then cooled to room temperature and the solid residue was removed by filtration.0 Adjust the pH of the filter material; alkaline solution containing humic materials; to -7?using sulphuric acid.The residue is isolated from humic acids using successive filtration and rinses with distilled water and a water-alcohol mixture until a pH of 1.9-7 is obtained The resulting product is then dried at a temperature of Ja iY vo obtaining the discriminant Yo The humic acids prepared as described above are characterized as follows. (mineral impurity): 71.5 Elemental composition: Jo YAO YN Zt HY Low molecular weight impurity: bound by peaks The following NMR 136: VIAL ppm 1771 ((carbonate-anion) 0 ppm 1777 ((formate—anion) ppm (Oxalate—anion) and 181-187 ppm (30661818-30100). The total amount of specific impurities constitutes 4.1 7 of the dry weight.

a J \ -

The humic acid structure is analyzed using NMR ©13. The result is shown in Table 1 below and Figure 1. Table 1: The result of the 13C NMR integrated tensile strength analysis; 7+ standard deviations 1 | | ] Example 18: A method for producing a water-soluble polymer compound from benzene

Polycarboxylic 8005 © of the present invention and identification of said compound

preparation

Dissolved Lignin Like Unspecified Internal Adsorbent (available under the trade name “Scientek Ltd” “Polyphepanum”) is used as a starting material.

This starting material has the following physical chemical discrimination: pH 1.0

0 Moisture content 77171.77 Polysaccharides content © 77 Lignin content equals 7.5 Water soluble compounds equals 70.5 per dry weight. Step 8: Put 490 + kg of Polyphephanum in a V0 liter container and add 1 kg of distilled water. Mix well. Step tb is added intermittently around ? L of sodium hydroxide solution 75 to 1 mixture from Step 8 to obtain a pH of NY The suspension is then subjected to alkaline treatment in a 01 L oxidative—hydrolytic destruction reactor. When the shall degree and pressure reach 10" and 1 MPa respectively; the air supply is reduced to 5 dm/min and the treatment continues for an additional 2 hours to ensure complete decomposition and oxidation.

_a \_ for soluble je lignin. The resulting product is then isolated; A solution of Cr Sodium benzene polycarboxylic acids from sald) solid residue using a press filter. Step ©: Then the solution of benzene polycarboxylic acids sodium salts obtained in step 0 is treated with a hydrochloric acid, obtaining a pH of (Y=) 5, and then subjected to the effect of centrifugal force for 11 minutes at Your rpm to induce polymerization for benzene polycarboxylic acids through the density gradient. This is how we obtain the crude polymer condensed from benzene polycarboxylic acids. Step 0: The crude polymer of benzene polycarboxylic acids is then placed in dialysis tubes with a capacity of Yoo kilodalton, and the dialysis is done against distilled water until the amount of impurities is low. molecular weight detected with NMR 136 or another representative method (eg; gas chromatography); To ZY from the dry weight of order “70016a00. We obtain the final purified polymer compound of benzene polycarboxylic acids. Yom dries the final purified polymer compound of benzene polycarboxylic acids for further differentiation. Yo Distinguishing The resulting polymer in step d is characterized as follows Description: black crystals Identity: absorption bands of the IR spectrum at: (C- 1 Te 1 vO “(OH) 1 Te v1 LR -Y ¢ ve (0; h 011 cm-(OH) 1) The .61h 0...cm-1 region contains a 0 absorption band with peaks at VATA cm-1 and 1887 cm -01 vs. equivalent vibrations of CH groups in LCH2 5 CH3 groups More than or less apparent absorption peaks specified at 1756 cm-1” correspond to oscillations of groups 0-0. The IR spectrum is represented by polymer in the form of l

A Solid residue: 797.75 Ash (metallic impurities): 70009 Chlorides less than ¥ Jv. Heavy metals: less than 720.001 H. Elemental composition: ©. ‏

Low Molecular Weight Impurities: Determined by the following NMR spectrum 130 peaks: VTA ppm (68+000816-30100); 1/17 ppm 177 ((formate-anion) ppm (Oxalate—anion) and 187-181 ppm (3081816-30101). The total amount of impurities identified makes up 70.8 per dry weight.

Ya polymer composite structure is analyzed using NMR ©13. Is the result in a table? Below (BS) table ?: 13C NMR analysis result

We further obtain a homogeneous and dimeric nuclear spectrum for 801/06 of the invention

current (Fig. 4). The results of peak determination are shown in the table below.

Vo Table ?: Homogeneous and Heterodimeric Nuclear Spectrum of the Polymer of the Present Invention F2 1h Structural Parts Description for" -

m \ _ ppm “(13C) ppm 1H,1H-COSY Y.A-YLY to dissolve —CHn- aliphatic alcohols CHnO-m —CHn—CHn- Y.Y -V.o Alkyl Cf substituted with aromatic rings or groups: Cf~CHn- has been dissolved by a carboxylic acid

CHn-Cf (aliphatic alcohols unsalted Y.¥-Y.Y substituents with -CHnO- rings or aromatic CHn—Cf carboxylic groups —CHNnO- HA H AH

Aliphatic alcohols

CHnO- 1H,1H-TOCSY —CHn—...— 0ah 7 mah Alkyl CHn— substituted with alkyl rings Cf-CHn-...— L4 L4 or aromatic groups 0110-0

q — \ — out —CHn-...— =v.CHnO- Aliphatic alcohols ~CHNO-...— ¥.4-v.4 CHnO- 1H 13C-HSQC Alkyl 7-7 1.11 substituted with aromatic CHn-Cf rings or carboxylic groups ¢.Y-Y oh but aliphatic alcohols, CHnO methoxyl according to the data obtained from (NMR) analysis The polymer of this invention can be characterized as AB 20756 substituted with the 8-hydroxy yalcohol imethoxy in addition to the carboxy groups in practically all positions. As it can be seen from the oF table that 5.5 To T atoms of aliphatic carbon corresponding to 6 carbon atoms of -aromatic carbon in cally the following structural © parts repeat: ¢((C2H20) ((C3H20) (0112). The molecular weight decomposes of the polymer determined using a gel filtration method. Thus the molecular weight of a fraction of the polymer stably determined Yoo is a kilodalton. The following Ast formula is calculated based on the molecular weight; data from elemental composition and NMR analysis (C3H20 )x1(C2H20)x2(CH2)x3, where x1<12, x2<9, x3<33

= “The polymer monomers of the present invention are also studied using

) 11 Ga Fourier Transform lon Cyclotron Resonance Mass Spectrometry

.4 (Table 0A (MS format)

Table ¢: 0100000615 is available in a highly specified degree in the polymer of the present invention

Mass DB Ab. light H/C | formula | the name

E total

aliphatic carboxylic acids and saturated hydroxycarboxylic acids

Tetracan | C14H2802 Y each [Yo from YYV.Y VY oic

hexadecan | C16H3202 Y has hopes YYLAYYTIT 14

oic.

(palmetic)

Heptadeca | C17H3402 High Price Yo 411 Noic

Hydroxyhex | C16H3203 Y CAAA Yo [TY ey Ladd YVY.YYVA adecanoic

Octadecan | C18H3602 Y AYY LMA AYATIVTE 7 oic (stearic)

Hydroxyoct | C18H3603 Y CATV LMA 117152411 1.07 adecanoic

£4Y4

EA] —_

Dihydroxyio | C18H3604 Y CYYY [Yoo | YAOYTNYY 15.7046 ctadecanoic

Hydroxyurea | C20H3903 Y Hope | Ma 11 77.756 osanoic

Trihydrohyo | C18H3605 Y High Y.o 414 77.4 ctadecanoic docosanoic | 7 C22H4402

Hydroxydoc | C22H4403 Y CATT H.A YY egao0oY Ldkn osanoic tetracosano | C24H4802 7 .ach 13775149 has the 0 ic (lignoceric) pentacosan | C25H5002 | The Yo |

Hydroxytetr 1 C24H4803 Y Money [Yio 407 YAY.YOY) 3005317016 hexacosan | C26H5202 7 M 7477 Alma to 6 634 oic

ITAL!

Hydroxypen 1 C25H5003 Y AY [Yoo| oovvavy FAV.YTAY tacosanoic monounsaturated hydroxycarboxylic acids aliphatic carboxylic acids

Hexadece| 161300 Y.AYe | v.AYo | Y.o 122111765 .ha noic 2

Heptadec | C17H320 | Y.AAY | «MYA| Wrap YoVAY ETT 117 enoic 2 octadecen| C18H340 | Y.AA | Takht 1 211594360 AA oic (oleic) 2

Hydroxyo | 0181340 | Y.AAA | +. ATV | Roll YéVooY A. 497.7 m ctadeceno 3 ic

Eicosenoi | C20H380 4 «NOY. YAY ££VAa)D 4 0 2

Dihydroxy 01813401 Y.AAQ | » Y.o IAH 4 71.106 octadecen 4 oic

Dihydroxy | C20H380 3 L Y.o| Y.ouAAoY 0.75 eicosenoi 4 lo}

A 0 A ARE ARS 0. Ed | Tetrahydr C18H340 | Y.AAQ oxyoctade 6 cenoic dihydroxy C22H420 | y.a +a | “YAY Y.o YY4¢YVYAQ 11.7 1 docosenoi 4 0 aliphatic carboxylic acids (highly available) non-polyunsaturated DAK. Isotretinoin ) ( 1 aq LA oon Stearidonic | CI8H28 | 0.1". 14431471 | Yvo.Y.\Y acid 021 av 6Z,92,122,15 —/ Octadecatetra enoic acid all-cis—6,9,12,15 Octadecatetra enoic acid FE, OH 5 by Mah Harry ITAL!

AVY | £.0] YIaVIYAS| YVYV.YIVY + at 01830 | y-Linolenic acid 021 1v cis,cis,cis—-6,9,12 Octadecatrien oic acid (OR,13R)-2—| CI18H30 | ).7 | +.V TY] f.0| YoodVill| 7 oxo—5-pentyl- 03 1 —3 cyclopentene- 1-octanoic acid JAP 5 oxo—5-pentyl- 03 for 10 a 0.10.1 1830 © 95 -1 1 gen hydroperoxy— -10,122,152 octadecatrieno ic acid C13(S)- CI8H32 | 011101011 y.o vee QAYY | 1.14 Hydroxyoctade 02 74 ca-9Z,11E-

Delicious dienoic acid 13(S)-HODE 10S,11S- CI8H32 | y.v | ".YYY Y.of 108 YYY.YYYA epoxy—-9S- 04 78 hydroxy—-12Z-octadecenoic acid ooyYoyo) | YYV.YVVY is not 0S,12S,13S—| CI8H32| Y.¥| +.YYA| 0 Dehydroarachi 02 donic acid 7 Dehydroarachi 1.0 15(S)- C20H30 | Y.o| of Hydroxy— 03 17213 21 ( E,17Z)-

#1 eicosapentaen oic acid (highly available) aromatic constituents, 3-benzyloxy—| CISH| +.aYY | 0d 4.0] YVYYoAe.d | a. 4,5-| 1405 dihydroxy- benzoic acid methyl ester

HO

bj( 5 0 HO be OCH,

A ho 5—(furan—-2- Cl6H Yo ada..‎ 105 YYAYOYAY | 44. carbonyloxy)-| 1206 2-methyl-benzofuran-3-carboxylic acid methyl ester

Dope 3 LOL 2,6—~dimethyl=| C16H | +.AYo | Led Yeo Mach | vis benzo(1,2-|1406 b,4,5- b"difuran-3,7- dicarboxylic £4Y4

except acid dimethyl ester EVAN a LLL when you run out S-(furan—2—| 6170 «AYE | .¥or[V).o| carbonyloxy)- 1406 2-methyl - benzofuran-3— carboxylic acid ethyl ester Uh a A 15.3201 C6 11.21 146 L | Rhamnetin | C16H Yo 1207 and OH OH methyl (4=|CITH| «.ag] | 17 | 00.01 | TYYNAVY[ 14 methyl-6-| 1606 oxo—6h- benzo(c)chrome en—-3- yl)oxy)acetate hydrate £4Y4

m with alo 0 g s oF y with | CITH| +. AYE] «VY | 0 YEAYZAYY -515)2 (methoxycarbo | 1407 nyl)phenyl) carbonate 2 Na RY u — l mm { = WMA 3 “AY | Yeo] YATWVEYA[ YYY.LAYY Let Sulochrin | CIT7TH|[ 1607 8 mm oa Wa “ala ] 1 HO fd HO n 1. Alacamat 011 H01 Ank Albhd.. 2,6-Diacetyl-| CI18H|1607|-7,9 dihydroxy—8,9b- dimethyldibenz ofuran—(2H : 9bH)-1,3 dione (+)-Usnic acid from Usnea dasypoga ZAK

q —_ since TH 8 TH H.C et A “oH, a ry tern p . Ho He 1.1 1101.7: | VEY.

TTY ak O—| CI8H| +.YYA|Acetylsalicylic | 1407 anhydride 2 9 mg MAM 6606 HP AYY d Amg 10. 111 Matthew.. CIOH-6))-4-00-3 7 1-benzo(1,3)diox -3)-(Al-01-5 methoxy—phenyl )- methyl)-5h- furan-2-one OH ha Ny o a a l p L 1 EN CHG 4 Sr 2,3-bis—| CI8H|[ +.YYA| «88s | 1.5 YeVYAVELA Yov.

Tt benzoyloxy--| 1408 succinic acid 7 B PN Our Ha L Ta Gap a7 ££Y4

It is not as good as for Hekla ‎methyl 5-1 CI8H| AAA vegetables | YY. of hydroxy-7,8-| 1608 dimethoxy- 1,3—dioxo- -1,3,10,11 tetrahydrobenz o[5,6]cycloocta [1,2—c]furan—4-carboxylate d a MG rr “gh A” no) 1-1 CIOH| ..mc|.;71|1.11 YOYY.£aT| methoxycarbo | 1608 nylmethoxy - 6-oxo—-6h- benzo(c)chrom en—-3-yloxy)- acetic acid me ester TO & Yvyr..ava for curling VY.o| to any CIOH| a and ha

_ \ —_

Phenylpropano | C24H AY TKD YEO D LAC id—Substituted | 2009

Epicatechins Experimental Data Lilia) benzene polycarboxylic acids (polymer) compound from the present invention is diluted with distilled water to produce different concentrations and tested on peripheral blood mononuclear cells (PBMCs) consisting of WIA lymphocytes (= (ZA) and mononuclear cells (0) (AF 0=Y) isolated from the blood of healthy donors by central Hb of Lymphoprep preparation. polymer of benzene polycarboxylic acids of the present invention, the latter exerts an effect on PBMCs (which is evident in the increased motility of lymphocytes in addition to the increased stability of mono-hal cells) as illustrated in Figure 1. 7187 487 Example 28: Method of preparation of an anti-cancer agent according to the Russian patent Ve and description of the said anti-cancer agent preparation The humic acids prepared in the example of TA are treated according to the method described in the Russian patent 70187477 with 75 800000018 solutions in the amount of Av milliliters per 1 10 grams of acid slo Lana filtered and mixed with cammonia water to remove excess from humic plea; Heat over 1 distilled potassium. In addition to that; The resulting solution is treated in the form of salts of humic acids with

— \ ¢ — tetrachloroplatinate in an amount of ”.717 mass# per 1 gram of humic acid salts and subjected to an acoustic cavity at $v W/cm Y and Yy kHz for 4 minutes. Use p to set the volume of the solution to 100 milliliters. Experiment 1-/2

2 The resulting anticancer agent was administered subcutaneously in an amount of 17.28 mg/kg body weight to inoculated Ehrlich tumor-infected mice. The tumor is inoculated under the skin in an amount of 701 cells. Treatment begins approximately 4 hours after tumor inoculation. Injections are given in an amount of 0.00000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000 and 2/4 weeks (total 4 injections). A comparison group of an isotonic sodium 6 solution is given according to the same dosing regimen. Recorded in the experiment 7060 on ad life) 1

001 of 01 animals) and 86 inhibited tumor growth compared to the untreated control group. The cause of animal mortality is the toxicity of the unbound platinum compound with humic acids. Example 28: Method for producing the composite material comprising (11) platinum of the present invention and description of said composite material (Yo) Preparation Step 8: Dilute 5.5795 grams of the dry polymer obtained by the method described in Example 8 in 1 liter of water Distilled and pH adjusted to 9.7 using 701 Solution 328. +.AYYY g of cis—diammineplatinum(ll) dichloride is added to the solution.The resulting solution is subjected to ultrasonic treatment at 7.5 W/cm?5 YY 0 kHz until the content of unbound platinum is reduced to less than 775 of the original amount Unbound platinum method (ais) Completeness of platinum complex formation is controlled using cellulose dialysis membranes with standard 0001-0 pores Dalton The size of the pores makes it possible for the platinum compound to permeate through

— ¢ — membrane; While this prevents the specific polymer with a weight of 1501 Daltons and its complex with ope platinum from permeating the membrane. To perform the test calcine dialysis tubes with samples A milliliter of composite material collected during the ultrasonic treatment and immerse them in vessels filled with distilled water sAD; Hours to suit this dialysis. AYVY Caddy + g of cis—diammineplatinum(Il) dichloride in 1 liter distilled water to produce a sample solution (contrast solution). The amount of platinum transferred from the sample solution to the humus is JV The concentration of all platinum measured in the humus from the sample solution comprises YT mg/L (ZY 0) 0 while its concentration in the humus from the composite material comprises of This invention is from YA mg/L Y¢ (%) step:b addition |cia The reaction mixture comprises a polymer rN of benzene polycarboxylic acids and undergoes cis—diammineplatinum(ll) dichloride to adjust the Shall Point at 0 5" rest for YE hr to suit the completion of formation of the desired complex. Yo continues to adjust the temperature until the concentration of unbound platinum decreases (fixed with the method described above) to less than 701 of the amount added to step 8. © step: In addition, the raw composite material from step b is purified from mechanical inclusions using a 0 µm polypropylene filter and then used to prepare a drug formulation as described in Example 3 Yo. Experiment 28-1 The resulting compound is administered subcutaneously in an amount of 17.8 mg/kg body weight to animals with inoculated Ehrlich's tumor The tumor is inoculated subcutaneously in a quantity of 701 cells. fas a to process after 8; hour of tumor inoculation. Injections are given in an amount of 1ml/mouse three times

_ _ per week for? weeks (required 4 injections). A comparison group of isotonic sodium chloride solution is given according to the same dosing regimen. 70,000 scores survival (ad 0 (of 01 animals) and ay slowed down tumor growth compared with the untreated control group in the experiment.

° The better safety and efficacy of the composite material compared to the anticancer agent of the Russian patent “YYAYEAY” is due to the better complexation of the platinum compound within the specific composite material. Discrimination

The formation of the new complex from a polymer complex of benzene polycarboxylic acids 0 with cis—diammineplatinum (11) dichloride is further verified using Extended X-ray Absorption Fine Structure (EXAFS) analysis (see Fig. 1). In the EXAFS spectrum we can see significant differences between the specified composite material comprising a polymer compound of polycarboxylic acids 6 of the present invention and -15e cis—diammineplatinum(ll) dichloride “diammineplatinum(Il) dichloride” 15 The organic oligosaccharide fragment has a spectrum that is “Cisplatin” and cis-diammine(cyclobutane~-1,1-dicarboxylate—O,0"platinum(ll) (indicated in the figure as “Carboplatin”). The composite material of the present invention is characterized by the following characteristic absorption bands in the IR spectrum: 2-6 Nam v1 0 1 0 Te 1 1 0 Nam 1 7 0 -1 Ou Nam 791 0 . Yo D +1 mah 01.01 cm-1 and 01 cm-A where the intensity of the bands is 60: 60h cm-A 16 no Y= am 000 Y= am and Yam AAA REX of the composite material is smaller than that of the polymer compound of .benzene polycarboxylic acids ‎£4Y4

C ¢ — Based on data derived with EXAFS methods, 130 NMR computes the following aggregate formula of the composite material: “(C3H20)x1(C2H20)x2(CH2)x3(Pt (NH3)2)x4 where x3 x2 “x1 and gala are the coefficients that represent any rational or positive natural integer number. Example 3: Description and identification of non-clinical and clinical data supporting the use of a drug formulation based on © Compound material comprising 007/006 water-soluble benzene polycarboxylic acids and Pt compound Preparation uses 70.5 sald) Compound prepared according to For Example 28 as a base for the production of a medicinal composition (Lilia) includes these excipients as a solvent in the form of an isotonic sodium chloride solution, Yo, for the production of SH 1... z, and a pH-stabilizing agent in the form of hydrochloric acid to produce pH 1 to A We obtain a drug formulation through mechanical stirring of the compound and excipients at constant pH monitoring. Further purify the drug formulation using a sterile filtration. The resulting drug composition is used for parenteral (subcutaneous or intramuscular) administration. Yo Discrimination The drug composition is distinguished by the methods described in the 6th edition of the European “(Pharmacopoeia) as follows: Description: transparent; dark brown liquid pH: Y.YY Yo Symmetry: absorption bands Distinctive IR at 6668 01 AH 10-ms 1111-1 cm-F 15.76 cm-A ARAN cm-A 06 Ah Yeo 10-ms 01 cm-A with intensity

— A ¢ — peaks at 6,001 Vp YWeemYo uw 10-ms 117-766 cm- or oh 101 cm- 1 is smaller than the .benzene polycarboxylic acids polymer content of platinum 494 ... 723 Sterilization: sterile Toxicity: non-toxic at 0.1 mg per mouse Febrile: non-pyrogenic at icp. 3 mg/kg body weight intramuscularly (rabbit test) Antitumor effect of specific drug formulation is evaluated In mammary tumors of autologous origin in Ve, many HER=-2/neu females are characterized by a high level of expression of an oncogene (HER=-2/neu human growth factor) and a high potential for spontaneous development of multiple breast tumors. According to For the design chosen, when the diameter of the mammary tumors increased to at least ¾ millimeters, the animals were randomly assigned between control and experimental groups The specified drug formulation was injected subcutaneously in two doses (17.0 mg/kg body weight and 1 mg/kg body weight) y times in Vo week until the animals die. The estrous ratio is 1-?1 day after alleviation of disease in animals treated with 8 mg/kg body weight or ? Fame kg body weight of the given drug combination is 7297 to 797 respectively (results are statistically significant) versus zero in the comparison groups. Y. This is a good indicator of the efficacy of the selected drug combination in treating tumors (Adil) that can be elicited in humans and non-dietary producer animal species. Clinical data

A clinical study of phase Ib of the specified drug is carried out in A patients with breast cancer (SEY). Patients are given an injection of the drug once Leg for YY day. The evaluated cumulative dose consists of 41 mg/kg body weight to mg/kg body Cs. We obtain the following results using the specific drug combination: one complete response© (disappearance of all metastases); 1 partial response (greater than 775 reduction in metastasis size); 0 Fixed diseases (change in the size of metastases between -775 and 775) and progressive diseases (a greater increase in the size of metastases). These results are a good indicator of the clinical efficacy of this specific drug combination in the treatment of metastatic breast cancer. Ya The total YA score is an adverse event in the study. None of the reported adverse events are serious. The adverse event was mainly mild or moderate and only 77 of the adverse event YA related to the specific drug formulation. beside that; A reduction in the number of side effects is observed in response to an increase in the treatment dose of the specific drug combination. These data would be a good indication of the apparent safety of the given drug combination1 and its potential benefit in analgesic therapy; For example; for terminal patients. It is additionally proven that the specific drug combination helps normalize blood parameters. Thus, at the end of the follow-up period, blood parameters become normal. hemoglobin in 1 of ; sick red blood cells in 1 of? Patients; clot in 1 who? patients with mononucleosis in? from 0 patients; Neuploid cells in Y from patients Y and lymphocytes in patient alg 1 compared with 9y levels recorded on examination. These data are a good indication that the specific drug combination can be used effectively to modify

M ¢ — Example 4: Method for producing a composite material comprising a water-soluble polymer of benzene polycarboxylic acids and a molybdenum compound and description of said composite material Step 8: Dilute V0 g of dry polymer produced by the method described in Example 18 in 1 liter plac ele Adjust the pH to 9.7 using approximately 708 Vo milliliters of .ammonia solution. In addition, the solution is heated to 10 pH and stirred for an hour and a half. AY 38 Excess. © g of ammonium molybdate tetrahydrate is added and the resulting solution is subjected to ultrasonic treatment at 7.0 W/cm? and 7? kHz until the unbound molybdenum content drops below 775 of the original amount. molybdenum method (unrelated ais: AD) Completeness of molybdenum complex formation is controlled using 061101058 dialysis membranes with standard pores 0001-8.0 Daltons. This pore size enables the molybdenum complex to leave through the membrane ; while the specific polymer whose weight is YOu Dalton and according to its complex SUA with molybdenum of Jad prevents this.To perform the test, dialysis tubes are filled with samples of A milliliters of composite material collected 0 during treatment Ultrasound and immersed in vessels filled with distilled water for hours to suit dialysis Dilute © g of ammonium molybdate tetrahydrate in 1 liter of distilled water to produce a sample solution (comparator solution).The amount of molybdenum transferred from sample solution to The humus is J 0 0 0 The concentration of free/unbound molybdenum in the humus from the OY form solution is mg/l) A 0 4 while its concentration in dla constitutes the composite material of this invention AR mg/l (7%).

q —_ _ step tb in addition to that; The sal all composite comprising a polymer of ammonium molybdate tetrahydrate benzene polycarboxylic acids from step 8 is subjected to temperature adjustment at A900 for a period of YE hours to suit the completion of formation of the desired complex. Temperature adjustment continues Sa The concentration of unbound molybdenum (fixed with method 0 described above) drops below 701 of the amount added to step 8. Step ©: The raw composite material from step 0 is purified from mechanical inclusions using ‎ 01 μm polypropylene filter and used to prepare a pharmaceutical composition as described in Example 5. Discrimination The composite material has the following characteristic absorption bands from 1-6060 IR 0 Na 1 0 Patek 791 0 cm-A 1 791 =) Yo 0 CARP 1 ¢ 1 0 CA Pew 1 7 0 =) Ou cm-1 and 1510 cm-1 ¢ where the intensity of the bands is 6:0a ch cm-01 vw s d cm-1 1-1" man VEY cm-11 of the composite material is smaller than it is in a polymer compound of benzene polycarboxylic acids. Depending on the derived data 13C NMR, the following general formula is calculated from B with: Eh from 1 Composite material: “(C3H20)x1(C2H20)x2(CH2)x3(MoO3)x4(H2O)X5(NH4)X6 where X5 x4 x3 x2 x] and 6 are the coefficients of any rational number or both positive Example 5: Describe the empirical data that support the clinical use of a drug-based formulation that includes a A water-soluble polymer compound of benzene polycarboxylic acids 0 and a molybdenum compound, and their distinction in preparation

R - sald) The compound prepared according to Example 4 is used as a base for the production of a medicinal composition further comprising distilled water as a solvent. For this, 50 0.5 7 of the composite material is mixed with distilled water in a ratio of 50:1 and stirred mechanically. The resulting drug formulation can thus be used for oral administration. Discrimination o The drug composition is characterized by the methods described in the 6th edition of the European WLS Pharmacopoeia as follows: Description: opaque; Dark brown liquid pH: AYY Symmetry: Distinctive IR absorption bands at regions: NADs A Cm-6 “YA -1 6 Nam 10 Yo No Nam 100 Nam Nal Las Da Nam 01 0 and Vp with intensity ranges at -1 6 Na 16660 No -\Yo 0 and Va 100 CARP 0 cm-1 smaller than the polymer compound of benzene polycarboxylic acids. Bio-load: Less than 10 g [cfu] Toxicity: Non-toxic in 0 A ie mg per rat Yo Feverogenic: Non-pyrogenic in icp. a mg/kg bw 3 intramuscularly (rabbit test) Data The experimental drug formula based on the composite material comprising a water-soluble polymer compound of polycarboxylic acids 0602806 and a compound Molybdenum 0 is further diluted with distilled water to produce different concentrations and tested on peripheral blood mononuclear cells (PBMCs) consisting of From lymphocytes (7/50-170) and mononuclear cells (0) (ZY = X) isolated from blood of healthy donors with central kh of Lymphoprep.

_— \ g It has been proven that after 11 days of incubation of the cell culture containing YV0 5 Vo μg/L of the drug combination, the latter that exerts an effect on PBMCs is evident in the increased ability to move lymphocytes in addition to the increased stability For mononuclear cells The effect of the drug combination on the set of cytokines produced by peripheral blood mononuclear cells (PBMCs) is evaluated in the same series of experiments It has been shown that after 11 days of incubation of the cell culture the production of INF-gamma increases From 0 VO pg/mL in the control group to Fev a= Yon pg/mL in the combination drug-treated groups, TNF-alfa production grew from 0 in the control group to 060;-150 pg/mL in Groups treated with the combination drug.01 These data are a good indication that the combination drug can be used effectively for the prevention and treatment of diseases associated with cell cycle disruption (eg, radiation-induced carcinogenesis or normal aging of cells).Example 6: Describe the experimental data that support the clinical use of the formulation Composite material-based pharmacokinetics comprising a water-soluble polymer of benzenepolycarboxylic acids 10 and a molybdenum compound in reduced/minimalized side effects associated with radiotherapy or conventional chemotherapy Patient characteristics: The patient in this study is a woman. Elderly TE year old with a long history of gastrointestinal problems. Diagnosed with colon cancer with local metastases to 0 lymph nodes in May 7007 and surgery was recommended and performed in June of the same year. due to different circumstances; She had to repeat the operation twice. The patient was evaluated for the first SPE since the beginning of chemotherapy from the end of August. results and procedure

— \g Laboratory findings related to first evaluation revealing significantly reduced serum albumin in association with hemoglobin erythrocyte coagulation co Lian ad neuploid cells and few lymphocytes; In addition to that; Laboratory analysis reveals ASAT (ALAT (Eosinophil) and reduced Alkaline Phosphatases (© table*). Responsible tumors avoid initiation of chemotherapy © and a new evaluation is carried out within 2 weeks. During this idl) the patient is given daily Alle 01 of Pharmaceutical formulation comprising the new benzene polycarboxylic acids complex with .molybdenum The formulation is administered by the intestinal route. Laboratory results taken at the second evaluation show an equivalent in calbumin A significant increase in the level of hemoglobin, erythrocytes, coagulation, leukocytes Neutral WAN and Eosinophil 5 lymphocytes In addition to that Increased levels of both 0 and ASAT Chemotherapy begins immediately Chemotherapy The patient is given twice daily injections 11 times with a two-week rest period between each Chemotherapy treatment Blood samples are taken for laboratory analysis after each treatment In addition, the patient fills out a quality questionnaire (QoL) form 6-30 in the middle part of some resting moments Vo Patient Yoo is given milliliters of the formula given by route enteric of the present invention (i.e., the composite material comprising compound p A water-soluble polymer of benzenepolycarboxylic acids and compound (molybdenum) for two weeks before and in the first week after the first two days of injection. Before and one week after the second injection period (candy) no combination of the present invention is available. 0 Treatment with the formulation of the present invention is restarted one week after the second injection period and given daily before and after the next three injection periods. 1 week before the sixth injection period; The patient again uses a combination of the present invention. This additional treatment is started again just before the seventh treatment period and outside the remaining part of the duodenal chemotherapy treatment period.

Ad —_ gm Say Patient QOL Survey Form 6-30 3.58 hours after first treatment and second treatment period. In addition to that; Slay the survey form after the fifth processing period; Six and seven. RESULTS Laboratory variant: There was a decreased serum albumin at the start of chemotherapy treatment. © MbDTHIA is found as low as YA (Table 0) but increases to 4 after 10 days of treatment with the formulation of the present invention. This value is also maintained during the treatment period with the first chemotherapy with additional treatment with the formulation of the present invention. Reduced albumin in a slight degree during both the second and sixth chemotherapy treatments without additional treatment with the combination of the present invention compared with the treatment before and after in which the patient was also treated with the combination of the present invention.

a A similar pattern is detected for hemoglobin ab So blood op Lean granulocytes; Lymphocytes WA|1M505100. All of these variants are low before chemotherapy begins; But it increases substantially with additional enteral route treatment with the formulation of the present invention in 10 days. These resulting levels exist almost unchanged during treatment with the first chemotherapy with additional treatment with the formulation of the present invention.

VO Table 20 Evolution of some laboratory variables during the first seven chemotherapy treatment periods. The column in black indicates the state without further processing with the combination of the present invention variables before | period of chemotherapy treatment

‎IB

_ g Yea WL pa edh ods] at th lect or l 3 granulocytes blood cells|1 10| 16 1 "7 | vax | a0 for rubbing 011 lymph 0 0 *additional treatment denotes whether the combination of the present invention is administered together with chemotherapy; "yes" denotes that the combination of the present invention is administered in this “yall” where Jas is “for” not to give the formulation of the present invention in this period. A second period of chemotherapy treatment is conducted without giving the formulation of the present invention and there are 0. All the variables described above are again low. Three periods of chemotherapy are given with the administration of Addition to the combination of the present invention and 11860109A0517. Leukocytes, granulocytes and lymphocytes are increased again to previous levels. Almost a similar pattern is also detected for Eosinophil except for the third treatment period. 3538 The sixth treatment with chemotherapy is the same as the second. Also without additional administration of the combination of the present invention and approximately similarly occurring again 0. ALAT and ASAT are measured only before the onset and during the first two periods of chemotherapy treatment. However the same pattern as described for the hematology variables above is indicated.

Quality of Life Survey 06-30: It was found that the 0-30 score decreased by 7257 from the remainder of the period after the first chemotherapy treatment with additional administration of the formulation of the present invention for the remaining period after the second chemotherapy without additional administration of the formulation of the present invention. A similar pattern is also detected in the remaining period after the fifth chemotherapy treatment; sixth © and seventh. From the fifth treatment with additional administration of the combination of the present invention to the sixth treatment without additional I administration the total C-30 is decreased by 7 oA and increased by 7 oA from the sixth to seventh treatment with additional administration of the combination of the present invention. Conclusion: Although this study was only an unconstructed case report; They clearly indicate the beneficial effect of the combination of the present invention as a possible complementary treatment to chemotherapy treatment. Yo Example 7: Studying the vitality of cancer cells when treated with compounds of the present invention The cells studied in this study are: {MCF-7 human gd cancer cells (very different) T47-D human breast cancer cells ( Low grade) Human pancreatic cells (low grade) Yo 124 Bladder cancer = (low grade) SKOV Human ovarian cancer cells (low grade) 6 Human colorectal cancer cells Fadu Human head and neck cancer cells Cells treated with: 00 water-soluble polymer compound of benzenepolycarboxylic acids (referred to in Figures 1-8 as “compound 2”)

h — g composite material comprising water-soluble compound 007/016 of benzenepolycarboxylic acids and compound platinum (referred to in Figures - YY as “compound 1 and composite material; comprising compound 00/006” Soluble in water of 0e benzenepolycarboxylic acids and molybdenum compound (in Figures M-YY denoted as “compound 3”) in various amounts 01-0000 (μg/eye) for YY h. Cells Cells are placed in dishes of 976 wells (5,501 x 501 cells/mL), On the second day 0, the medium is replaced with medium containing different concentrations of compounds/composites After YY and 57 hours, cell viability is determined using a test XTT according to the protocol accompanying the treatment group.The results are shown in AVA figures.The results show that all three compound(s) affect the viability of all cell lines.1 The viability decreases from 7400 to 7980 depending on the cell line studied. The most effective lethal effect was observed in human head and neck cancer cell lines and human colon cancer, and the least lethal effect was observed by test subjects in ovarian and liver cancer cell lines. . See Table 1 below. Table a 1: 1050 estimated platinum-containing composite cell line Fad| 1 PL45 | Skov3 | 1240 06 MCF | 1471 al) D 2 (bladder | (ovary | (pancreas | 6 u : : liver colon) | (vertebral head (fe (colon) |) and neck ( £4Y4

— 7 g 1C50 approx. | about | about a about | about | about | About me) 86 micrograms Ah Ah, You Yo.

Owe 101 Ou/mL) Cytotoxic activity measured by (LDH) lactate dehydrogenase The integrity of the plasma membrane is determined by measuring the activity of released LDH in the culture medium. LDH activity is monitored after oxidation for NADH and the absorbance decreases at FYE nm. The percentage for absolute LDH is determined as the ratio of LDH activity in the supernatant (A) the sum of the amount of absolute LDH plus measured activity in the ADA cell. The results are shown in Figures 13-117. The results show no Presence of signs of cellular damage This releases LDH from the control WAN and also from cells treated with test materials i.e. the substances are non-toxic Cellular damage such as necroptosis causes an increase in the concentration of LDH in the medium The integrity of the plasma membrane is determined After treatment - by measuring the activity of LDH released in the culture medium.The enzyme activity is measured using the spectrophotometric method (Moran and Schnellmann 1996).

Claims (1)

Mg protection elements - 1 A water-soluble polymer compound of “benzene polycarboxylic acids”, which is characterized by having an elemental formula of 717-717 6 M.71-7. 74 (H 5-74 77©; and less than 70.7 No per dry weight and where the sum of the other elements is not more than 71 per dry weight. 0 ?- the compound of claim 1; which is additionally characterized as having characteristic 13C NMR peaks at 1-27 in the range zero-</; ppm” 747-700 in the YEO A range ppm” ©-71 in the range 1715-187 ppm and 7-78 in the YY em AY range ppm *- compounded according to any of the preceding claims; which is further characterized by the inclusion of no more than 71 low molecular weight impurities defined by characteristic NMR peaks of 136 at AVY velocity no. 087-181 ppm. — the compound of which of the foregoing claims is additionally characterized as having IR Yo absorption bands at 60 6a? Nam 1 ls a sam-0) a ls a Nam ARAN Nam a los red char sam-1 and 101 cm A 0— compound according to any of the preceding claims; Which is further distinguished by the fact that it contains at least a monomer alg from the groups: aliphatic carboxylic acids saturated aliphatic carboxylic acids (ix ill aliphatic hydroxycarboxylic acids 0 unsaturated aliphatic hydroxycarboxylic acids «Lala! monounsaturated and aliphatic Unsaturated carboxylic acids and .aromatic components = the compound according to the claim ©; where at least one of the saturated aliphatic carboxylic Yo 8005 is selected from the group consisting of <hexadecanoic acid tetradecanoic acid -4e- docosanoic <eicosanoic acid (octadecanoic acid heptadecanoic acid “acid pentacosanoic acid” tetracosanoic acid “tricosanoic acid” and “hexacosanoic acid”) .acid o -1 compound according to any of claims 7-5; Where at least one of the saturated aliphatic hydroxycarboxylic acids is selected from the group consisting of <hydroxyoctadecanoic acid <hydroxyhexadecanoic acid <hydroxyeicosanoic acid «dihydroxyoctadecanoic acid <hydroxydocosanoic acid »trihydroxyoctadecanoic acid 00 hydroxytetracosanoic acid and hydroxypentacosanoic acid. 4- The compound according to any of claims 7-5; Where at least one of the monounsaturated aliphatic carboxylic acids is selected from the group consisting of acid Vo 660016 from octadecenoic acid heptadecenoic acid and eicosenoic acid .acid 4- Compound according to any of claims 8-5; Where at least one of the monounsaturated aliphatic hydroxycarboxylic acids is selected from the group consisting of “dihydroxyoctadecenoic acid < hydroxyoctadecenoic acid Y. tetrahydroxyoctadecenoic acid “dihydroxyeicosenoic acid .dihydroxydocosenoic acid -0 compounded according to any of Claims 9-5; Where at least one of the unsaturated aliphatic carboxylic acids Yo is selected from the group consisting of -13-015 «6Z, 97,127,15Z—-octadecatetraenoic acid «retinoic acid -5,015,05-6,9,12© £4Y4 qm (9R,13R)-2-oxo-5-pentyl-3—-cyclopentene—]1- .octadecatrienoic acid «9S—-hydroperoxy-10E,12Z,15Z-octadecatrienoic acid octanoic acid 10S,11S-epoxy -9S-:C13(S)-hydroxyoctadeca—-9Z,11E-dienoic 0 0S,12S,13S~trihydroxy-10E,15Z- <hydroxy-12Z-octadecenoic acid 15(S)-hydroxy-, 5,6—dehydroarachidonic coctadecadienoic acid ©(52,82,112,13E,17Z)-eicosapentaenoic acid wherein at least one of the 0) emo compounds is selected according to any of the claimants from -11 3-benzyloxy—4,5-dihydroxy— benzoic ingredients 8701713116 of the group consisting of 5-(furan-2-carbonyloxy)-2-methyl-benzofuran-3- “acid methyl ester 0 2,6—dimethyl-benzo(1,2-b,4,5- b")difuran— «carboxylic acid methyl ester 5—(furan-2-carbonyloxy)—-2-methyl- (3,7-dicarboxylic acid dimethyl ester methyl ((4-methyl- rhamnetin :benzofuran-3-carboxylic acid ethyl ester bis(2- «6—oxo-6h-benzo(c)chromen-3-yl)oxy)acetate hydrate 2,6-diacetyl-7,9- sulochrin ((methoxycarbonyl)phenyl) carbonate 10 O- «dihydroxy— -8,9b—dimethyldibenzofuran-1,3(2H,9bH)-dione 4-ho-3~((6-ho-benzo(1,3)dioxol-5-yl)-(3~ «acetylsalicylic anhydride 2, 3-bis—benzoyloxy-succinic «methoxy-phenyl)-methyl)—5h—furan—-2—-one methyl 5-hydroxy—7,8—dimethoxy—-1,3-dioxo-1,3,10,11 - «acid (1- tetrahydrobenzol[5,6]cycloocta[l,2 —c]furan-4—-carboxylate 0 methoxycarbonylmethoxy-6-oxo—-6h-benzo(c)chromen-3-yloxy)-acetic .phenylpropanoid —substituted epicatechins and atranorin acid methyl ester benzene polycarboxylic water soluble from polymer Process to prepare compound 1- comprising steps: 1-11 according to any of the claims of 8005 Yo dignin ( A) Providing a starter raw material that contains — \ a — (b) Subjecting the starting raw material containing lignin: step 0 to an alkaline treatment to obtain a solution of 0 salts of “benzene polycarboxylic acids” (c) subjecting the solution of benzene polycarboxylic acids sodium salts from step (b) to an acid density gradient treatment to obtain a crude polymer of s«benzene polycarboxylicacids© (3) Purification of the crude polymer of benzene polycarboxylic acids from step (c) by removing low molecular weight impurities to obtain the water-soluble polymer compound Sal from the crude benzene polycarboxylic acids lignin-containing starter. on sald) where the OY of the process of claim YY Yo Ov from step (a) is produced from coniferous trees and has a pH of 0.0 to 7; Moisture content of not less than 717 polysaccharides and comprising not more than 777 Ive to not more than 77 water soluble compounds. lignin Vo? At pH 11 + 8.5 and pressure 7.7 + 0.7 MPa. 1- The process according to any of the VEY safeguards where the processing takes place 0 graded WES the acid from step (c) by subjecting the solution of sodium salts of benzene polycarboxylic acids from step (b) to treatment with a mineral acid to obtain a pH of (Yo) and respectively to the effect of the centrifugal force centrally. 7- The process according to any of the claims 11-15, where the purification takes place in step (d). Yo by subjecting the crude polymer of benzene polycarboxylic acids from step (c) to one or more purification processes selected from the extraction; quenching; distillation; filtration; sedimentation — \ a — centrifuge; Dialysis Lally-1" composed according to any of the claims from 11-1 for use in the prevention, treatment and modification of human and animal disease; Jie immune diseases; viral diseases; bacterial diseases; fungal and inflammatory diseases .—Y A pharmaceutical composition includes the compound according to any of the claims of AVY -11 0 0 Wh pharmaceutical composition of the claim OA where the compound is present according to any of the claims Protection from 11-1 as a starting raw material; as an excipient or as a drug 0 Pharmaceutical composition according to any of the claims 18 ge 5 to V4 where the method of administration is Is the enteral administration; in the mucous membrane or under the tongue.- 1 Pharmaceutical composition according to any of the protection elements from “YA” to “Yo” where the drug composition is formulated as a tablet 3 as a lozenge “alle viscous paste Liquid 3 Y 0 hard candy, lollipop, chewable candy, or gel-drop.” “- a cosmetic composition comprising Apply according to any of the protective ingredients of IVY Yo ??- Wh cosmetic composition of the protective ingredient (YY) where the formulation is in the form of a cream or gel. a ; >- Wh cosmetic composition of any protectant from Yy to YY in which the compound Wl of protectants 11-1 is present in the form of an anti-inflammatory agent and/or an antioxidant agent. | ©?- a nutraceutical composition that includes the compound according to any element of IVY Protectants - Wa nutraceutical composition of protectant (Yo) where the said composition additionally includes nutrients. 7" -71 is a composite substance comprising a water soluble polymer of benzene polycarboxylic acids according to any of the protection elements of -1 11 and a metal cation. Vo /?- Wh composite substance of the protectant (YY) where the water-soluble Jal polymer of benzene polycarboxylic acids acts as a complexing agent and/or an encapsulating agent. 4?- The lula composite substance of any pale of the protection elements of “YY.” YAY where cation Jl 0101018 is selected from the group of 0-25-55 or 30-elements. -©0 The composite substance according to the claim element (YA), where the metal cation is selected from the group of elements consisting of platinum ron (manganese (magnesium (potassium potassium) “calcium lithium” “nasil dance” yo .copper and palladium “silver (zinc) — A — -1 a pharmaceutical composition comprising a substance compounded according to any of the claims of Nem VY 7?- the pharmaceutical composition 60010051100 pharmaceutical composition according to the claim (FY where © the pharmaceutical composition includes Additional-mentioned pharmaceutical composition contains anti-agent YY — the pharmaceutical composition according to any of the Claims of 7-17?; where the additional-mentioned pharmaceutical composition 0 includes one or more of excipients; Flavorings Coloring agents Lubricating agents Lubricating agents Preservatives Absorbing agents Sweeteners Carriers Modified-release polymers for API protection pH-stabilizing agents Antioxidants Wetness factors anti-foaming; thickening agents; Moisturizing materials and mixtures thereof. Yo #*?-kh pharmaceutical composition of any TET protectant for use in the prevention of; Treating or modifying a human or animal disease. sale -7 a composite substance comprising a water-soluble polymer of benzene polycarboxylic acids according to any of the elements of protection from 1-11 YO and a flat-square coordination compound platinum (Il) Where the polymer compound of benzene polycarboxylic acids is encapsulated or forms a complex with the aforementioned (11) platinum compound. They are YY — the composite substance pursuant to claim 7?; Which is characterized by having distinctive IR absorption bands die 10-76668? Sama Toe m YA Smada 0966 F 1401 Oman Sm-A 1786-13 Sm and 1510 man where the intensity of the peaks at 0-7266 Sm is 117 -15.3 Sm10; Smw*75 JAR © cm-1 is smaller than the peak strength of the .benzene polycarboxylic acids polymer /-_composite Wl. The composite substance of any alc of the protective elements, A) YS TT ge, is further characterized by having a molecular formula of “(C3H20)x1(C2H20)x2(CH2)x3 (Pt (NH3)2)x4, where x2 x1 3 and gala are coefficients representing any natural number.”; cage is integer or fractional. A 4- The composite substance according to the claim (FA where AY 2x] x3 4 <2 > 7 and N= - the composite substance according to any An element of protection from “V1 Sheva oe” is further distinguished by whether it encapsulates the platinum compound by or forms a complex with one of the following constructions of benzene polycarboxylic acids (polymer OH © COOH COOH OH © OH ~ CL OH CL COOH CLC, | LA A 0 (© (4) (©) (®) (3) where structures 8; cb © and do not represent parts of the aromatic components mentioned in the claim 11 The construction © is part of the acids mentioned in claims 01-17 901 1 ?- Process for preparing compound sald according to any claim of £417 comprising the steps: a) ))1) provide a starting raw material containing 00 waa; qt to alkaline treatment) 1) the starting raw material containing 9010| From step A) Lad) 1 (b) “benzene polycarboxylic acids sodium” to obtain a solution of benzene polycarboxylic acids “sodium” salts subjecting the solution of salts (1) (c) crude from polymer From step (b (1)) to a gradient acid density treatment to obtain “benzene polycarboxylic acids © 1 (c) step (crude benzene polycarboxylic acids from polymer purification) 1 (d)” benzene polycarboxylic acids from dwpolymer to obtain the product in step benzene polycarboxylic acids purified from reaction polymer (1) (e) to obtain a reaction mixture; 018101177 (Il) with coordination compound square-flat )1(d) temperature adjustment of the reaction mixture from step (e(1)) to obtain a composite feedstock; and (1)f)0 purification of the feedstock from step (f (1)) to obtain the composite material.(1)(g) of lignin: containing Bald where the raw material of) is produced by the process according to claim 7-500 step (a)1 )) of coniferous trees and having a pH of 9.5 to ; moisture content of not less than 717 polysaccharides and comprising not more than 777 Ive to 1 and not more than 77 water soluble compounds. lignin and 7?; Where the alkaline treatment of 41 takes place? and a pressure of 7.7 + 0.7 MPa. 1.8 + 11 at a pH of 0 where the stepwise treatment ($Y) of the protection elements from pale is carried out; of salts (Va) shall of acid density from step (b (1)) of treatment with mineral acid to obtain benzene polycarboxylic acids and respectively to the effect of centrifugal force.(Yo) at a pH of 5 5- The process according to any of the elements of protection from (£48) where the purification takes place in step (D (1)) by subjecting the crude polymer of benzene polycarboxylic acids from step (C (1)) to one process or More than selective purification processes from extraction, quenching, distillation, filtration, sedimentation, centrifugation, decanting, and dialysis. 7- Process Wh of any claimant from 20-8 where the platinum square-flat coordination compound is cis—diammineplatinum (Il) dichloride, potassium tetrachloroplatinate, or a mixture thereof. YL 7;- process according to any of the claims of (£14) in which the reaction from step (e(1)) is carried out by subjecting the reactants to wave radiation, more specifically to ultrasonic treatment; with a power density of 0000 W / cm?, and a frequency ranging from 11-18 kHz and within a period of time ranging from 1 to 10 minutes until the unbound platinum content decreases to less than 775 of the amount originally added. Vo, where the process temperature of 41-47 is set according to any element of protection from –€A free in the raw compound platinum reaction mixture in step (f (1)) until the content of . (1(e) added in step platinum (a1) from the amount of 70 to less than 0 0 9?;- The process according to any of the claims of 1408-4, wherein the purification from step (g (1)) is carried out by subjecting the raw composite material from step (f (1)) to a purification process one or more selected from the nomination; Autoclave and irradiate. -*0 A drug that includes the composite material according to GY element of protection from 40-176 Yo for use in the prevention of; Treat or modify a disease. “A for use in the prevention of” treatment or palliative care 0 0 drug 01119 of claim —o) of a mammalian organism suffering from cancer or modification of said cancer; For example, YSU's prostate cancer; Colon cancer and breast cancer ABR; Pancreas cancer; cancer and neck —oY drug 00119 of claim 0 0 for use in the prevention, treatment, palliative care, or modification of disease in a mammal; Where the method of giving is to give by other than the intestinal route; enteral administration; topical administration; oral administration; Administration into the mucous membrane or under the tongue. ye to 57 for use in preventing 00 element of protection from GY according to drug —o¥ from cancer or modifying cancer; where ley from; Treatment or palliative care of a mammal, cat or horse. (IS all) The said mammal is of a non-food producing species. Preferably Vo #4 - a pharmaceutical composition comprising the drug according to any of the Claims 5-?5. —oo The Wh pharmaceutical composition of claim additionally includes one or more excipients 0 According to claim 00 where the pharmaceutical composition is selected - Ex. 670101601 from the group consisting of anti-adhesive binders; solvent agents/covalent solvents; flavourings; Agents AA Encapsulation; disintegrating agents; Sweetening materials; (palatal) colouring; lubricants; lubricating agents; preservatives; factors Yo Materials Ileal polymers Modified release for API polymers To protect (API) pH stabilizing agents Antioxidants Wetting agents Anti-foaming agents Thickening agents Materials — a q — Moisturizing and blends le <1” pharmaceutical composition according to any of the claims 01-54 for use in the prevention of; Palliative treatment or care for a suffering mammal oo cancer or cancer modification; For example, breast cancer; Pancreas cancer; Bladder Cancer; Prostate cancer, colon cancer, and head and neck cancer. —o A pharmaceutical composition according to any of the claims 01-4 for use in the prevention of; treatment or care palliative to pain or to modify a disease in an organism (a 001) where the method of administration is administration other than the enteral route; enteral administration or topical administration. 4- The pharmaceutical composition according to any of the protection elements from 21-54; For use in the prevention of; Palliative or disease-modifying treatment or care in Yo as gynecomastia; Where the method of administration is enteral administration; in the mucosa or Caan The tongue. dus 09 For the protection element, Wa pharmaceutical composition -0 The formulation is presented as a tablet; as a lozenge; gum; liquid viscous paste; Hard candy, Yo Lollipop, chewable candy, or jelly drop. ) = the pharmaceutical composition according to any of the claims ?07-5 for use in the prevention of; Palliative treatment or care for a suffering mammal cancer or modifying cancer; Where the aforementioned mammal is a non-food-producing species; Yo Adam prefers 3 dogs; cat or horse. Vm -17 A composite substance that includes a polymer compound that is soluble in Water from benzene polycarboxylic acids according to any of the protection elements from -1 11 And the molybdenum compound is in the form of a salt “molybdenum acids”, where the compound is encapsulated molybdenum or forms a complex with benzene polycarboxylic acids polymer © mentioned. -0 A composite substance according to the claim HY is characterized by having 0966 Samada Toe m YA 10-76668? Sama die distinctive IR absorption bands P 1401 Oman cm-A 1786-13 sama and 1510 man where the intensity of 0 peaks at 0-7266 sama is 117 -15.3 10 sama; A sama*75 JAR cm-1 is smaller than the peak strength of the .benzene polycarboxylic acids polymer 4- The composite substance of any of the elements of protection from TY arg which Woh is also pa format . Molecular of “(C3H20)x1(C2H20)x2(CH2)x3(MoO3)x4(H2O)x5(NH4)x6 0 where x2 x1 3d bin X6 5X5 are JS parameters any natural number; positive; true or fractional. 5+- the composite substance according to any of the elements of protection from 14-77 which is further characterized by either encapsulating the molybdenum compound by or forming a complex with 0 one of the following constructions of a compound: benzene polycarboxylic acids polymer Q OH COOH 001 OH © OH CL OH CL COOH CL. | LA AN lo} (3) (®) (©) (4) (©) mentioned in an aromatic element and do not represent parts of the components © cb since structures 8; .01-17 and the © structure represents a part Of the acids mentioned in the elements of protection from 11 protection “vy 7- A process for preparing (sald) the vehicle according to any of Claims 77-19 including On the steps: (a) “) provide raw sale prefix containing 00waa; (b(7)) lad) prefix raw material containing 9010| From step (a) to © alkaline treatment to obtain a solution of “benzene polycarboxylic acids sodium” salts (C (7)) Subjecting a solution of benzene polycarboxylic acids sodium salts from Step (b(7)) to a gradient acid density treatment to obtain 0017/0161 ore from Benzene polycarboxylic acids ((Y)=) step (crude benzene polycarboxylic acids from polymer (D (7)) purification benzene polycarboxylic acids from swpolymer to obtain 0 ((Y)”) Reaction of the polymer purified from benzene polycarboxylic acids produced in the step (d(7)) with compound 7710175081010 to obtain a reaction mixture; (f (vii)) adjusting the temperature of the reaction mixture from step (e (vii)) to obtain a composite feedstock; (g(”)) Purification of the raw composite material from step (f (7)) to obtain the composite material. yo lignin where the starting raw material containing the process TT is produced according to protection element -71 pH from 0.0 to; Moisture content of leds from step (a(7)) of coniferous trees 717 and not less than (polysaccharides to 7970 and comprising not more than 777 of 0 of lignin and not more than 77 water-soluble compounds. 0 Wherein, alkaline treatment of (TY 5 676 process under any element of protection from —TA oxygen Step 7) with lignin: Step (B (7)) is carried out by reaction of an alkaline suspension of a material containing At a pH of 1.5 + 11 and a pressure of 7.7 + 0.7 MPa. 4- Operation according to any of the protection elements 18-775; Where the density-graded Yo acid treatment from step (c (7)) is carried out by subjecting the solution of sodium salts of benzene polycarboxylic acids from step (b (1)) to treatment with a mineral acid and on 1 \ — respectively to the effect of the centrifugal force. -700 The process is according to any of the elements of protection from 11-19 (Cua) The purification is carried out in step (D (7)) by subjecting the crude polymer of benzene polycarboxylic acids from step ((Y)=) © to one or more purification processes selected from extraction, flotation, distillation, filtration, sedimentation, centrifugation, decanting, and dialysis 17-_process ale GY Ed of claims 70-715 where salt is ammonium molybdate “ammonium molybdate” is molybdenum acids sodium molybdate (sodium molybdate (potassium molybdate tetrahydrate 00 dihydrate) or a mixture thereof. VY The process is according to any of the claims 71-75 where the reaction from step ( E(7)) by subjecting the reactants to ase radiation and more specifically to ultrasonic treatment, VO with a power density of 07000 W/cm2 and a frequency of 11-18 kHz and a time period of 1 to “1 minute until the unbound molybdenum content decreases to Jil from 775 of the amount originally added. 7- The process is according to any element of protection from 77-77 where the degree of Sha is set Ye. the reaction mixture in step (f (?)) until the content of free molybdenum in the crude composite material decreases to Ji from 701 of the amount of molybdenum added in step (e (7)). (vii) The process according to any of Claims 75-77 wherein the purification from step (g(vii)) is carried out by subjecting the crude compound sald to one or more purification processes selected from the filtrate; YO Place in autoclave and irradiate. SL 5- A drug comprising the combined substance according to any of Claims 59-77 for use in the prevention of; Treat or modify a disease. -1 Drug 00119 of claim Vo is for use in the prevention, treatment, or palliative care of a mammalian organism suffering from a cell cycle-disrupting disease, or for the modification of said disease. except- drug 00110 of claim VT for use in the prevention, treatment, palliative care, or modification of disease in an organism where the method of administration is enteral administration; Administration into the mucous membrane or under the tongue. ye For use in the prevention of “treatment or palliative care” drug VT 01110 according to claim —VA for pain of a mammal suffering from a cell cycle-dysfunctional disease or modification of said disease where said mammal is a non-food-producing species” preferred human; dog; cat or horse. Vo 24- a pharmaceutical composition comprising the drug according to any of the claims NA-Yo - the pharmaceutical composition according to claim 179 additionally comprising one or more excipients excipients 0 Where (Av) is selected according to the claim pharmaceutical composition Pharmaceutical composition — AY Ex. 670101601 From the group consisting of anti-adhesives; binders; solvents/covalent solvents; flavorings; agents; AA; packaging; disintegrating agents; coloring materials; lubricating agents; lubricating agents; preservatives; absorption agents; sweeteners; Yo Materials Ileal polymers Modified release for API polymers To protect (API) pH stabilizing agents Antioxidants Wetting agents Anti-foaming agents Thickening agents Materials Moisturizers and mixtures 7- kh pharmaceutical composition of any element of protection from 81-79 for use in the prevention of; Treatment or palliative care of a mammal suffering from a disease of cell cycle dysfunction or to modify said disease. —AY pharmaceutical composition according to any Claim 81-4 for use in the prevention of; Palliative or disease-modifying treatment or care in SIE (ad where the method of administration is enteral administration; administration into the mucosa or tongue A Caan—A¢ Wa pharmaceutical composition of an ingredient Protection dus (AY) The pharmaceutical composition is formulated as a tablet; Protection 79-81 for use in the prevention, treatment, or palliative care of a mammal suffering from a cell cycle-dysfunctional disease or modification of said disease, where said mammal is a non-food-producing species “preferably” = “dog”; cat or horse. Y. - the pharmaceutical composition wh pharmaceutical composition of any protective element of AO=VA 5 11-54 2-71 11-18 for use in the treatment of disease in an experimental organism. —AY Pharmaceutical formulation 6007100511010 pharmaceutical pursuant to claim AT for use in the dialled YO or palliative care of a mammalian organism suffering from a cell cycle-dysfunctional or disease-modifying disease. A 1 AA — wh pharmaceutical composition of any protective ingredient of AY=AT is prepared for administration by any number; other than the intestinal route; intestinally or topically. 4 M8 - Pharmaceutical composition 0017005111010 pharmaceutical according to any of the elements protection from AAAT where al is a non-food-producing species” preferred human; dog; a cat or a horse. 6- Pharmaceutical compositions, wh pharmaceutical composition for any of the elements 0 Protection from Ae-VA 5 11-54 8-731 1-18 For use in reducing/reducing side effects from radiation therapy or conventional chemotherapy. 1- The pharmaceutical composition according to the protection element, de, where Uae, the composition is enteric. Vo for any of the protective elements kh pharmaceutical composition -7 from 90 and 99; The drug or combination is given enterally before, during, and/or after conventional chemotherapy or radiation therapy. Yo? Where the drug formulation (a aS) is formulated as a sucking lozenge » alle a sticky paste liquid, a hard candy, a lollipop, a chewable candy, or a gelatinous drop. 4- The drug formulation according to any of the protection elements from (You) 11-54 5 and Cla-Blood to be used to reduce/reduce side effects resulting from radiotherapy or conventional chemotherapy in the mammalian organism. 1 fig.] : ) 0 1 § 0 § N 4 1 A 1 aoa AYR NS a PO ya a ayr 2 ا ا ا ا ا ا ا ا ا 1 0 3 REET LIN LEE HEN 1 Fa 0 5 You A [= falcon form ? ty RE 0 touches H 0 : to 1 0 3 + 0 oy i 1 i 3 i »,04 1 1 for 3 { A if 0 m 3 1 1 the J vo JEN Ta Sav fag i l 1 a 1 Pol Y 1 Ye 1 \ 08 a l pe / Ne ] i bY and «1 i N\ 1 (WE ARCS Ba | A BR > 1 ™ Led Ba vr, A x 3 CD A FR a3 SS Suss Tacisp Yellow [ERE Town Yuen Yvon (oe) Wave No. + Ka | LA RAH A A 1 8 5 A WL WR MY LAT i H Bade adie © i i WY Sr ki 8 Aya Abi Nyay 1 1 i J 0 0 Jz 8 in A Te 1 B " [33 os 0 zero {Tl} for 1 figure; ny! | ev wn, ri l z SEN BRA CA = TT Nu a million SE EE EE EE 4 for sa sa l a i a a as EERE and for bhi 5 A A L R by R A A as Ot SU | SU Se SN dragged it into the libttttq '! got wet ag? ? +4 TAN Te million | 9 Teg? 10017 sdm aaa sss cm a ppm_”< PSY, hk A aa (--Tl A 8: — > 2 . | 0 1 = RL 7 Lo { A — tL 3 aa 77 zero?© 4 5 FAVA 17-017 ]0-0 | ANG VR KHAL STR ROE TR NU BE L A SA ARE A A JES FFT FI FA L Eg A db YT Fragment in YY TY psd 1 27 1 70090 Hama- o KE i “4 Be La A 4st gillian g [ Y CE EE 4 1 i La A Bh Vis + LIP » 4 1 EH Moh: A iid 8 Caf bE position * YY. * ee ed BEER for Teor RE SEH ' RARER 0 no ram la la aaa aaa la ma aaa ak ada la la la la la la la la la la la la la la la la la la la la pa] rd m Yor fee Gea Ars Vase form + YA a H [| > Yi 3] Vi ' Ed | - the # 1 3 13 VY 8 0 fd 1 3 a : : ) Ye i 3 $3441 CH x + JEN kJ e e yi ITS YJ $ 3 no 2 < + Ei 1 1 # 0 7 3 : b rv > i 1 < } 7 0 A 10 Py a ¢ 233 ¥ RY! : : do dn 1 : yk 0 + 1 | # zm 1 RAE AN 1 l 1 21 hrs EWE WR STAR WL AA AA HL ¥ Ni 5 EM 3 "BL TE Line B Abn MAVEN i Wo 5 1 + a af 4 Ww, HA AE 1 ; « 1 3 + alpha 7 p $ m : and IY yah " and a #* 1 + 0 3 LE 3 1 a | H +7 [ l : A 1 no x : ht A sqr 3 KA cisplatin ss carboplatin .> “ » - the specified composite form m «from ا - ا ڪنڪ ڪ ا 0 7 0 BEET } muskiya at 1 ol | mI | BE 3 ERNE EFT DF — SN) | | 0" | wr | ml Be Yur YO jb Ya Ta Ss concentration µg/eye form ? mm termo a a 1 a le - Ca nn |B 3 p ie EFETE 0 0 ?© ?: * Bi FF Yo + Ao Yen Yo. Focus (micro fa) eye) 01 Fig. be ss sss EE EHH rs 0 Ne ae ee a IM man Eee Tre BE | . zs aaa | oh oh no | — = 000 LL (μg/eye) YO) Concentration 11 Fig. 1 LA 7 Spr =— P a no EXT dha ER, BN rr "™ Daas 1 NE The Bh T24F wat Al Ain fal as Sue Ve “I EAR A !1 0 on yer Ta FEB 1 The validity period of this patent is twenty years from the date of filing the application, provided that the annual financial fee is paid for the patent and that it is not invalid or forfeited for violating any of the provisions of the patent system, layout designs of integrated circuits, plant varieties, and industrial designs, or its executive regulations issued by King Abdulaziz City for Science and Technology; Saudi Patent Office P.O. Box TAT Riyadh 57??11 ¢ Kingdom of Saudi Arabia Email: Patents @kacst.edu.sa