Title of Invention

"BENZAMIDE DERIVATIVE-CONTAINING PHARMACEUTICAL FORMULATION "

Abstract

A pharmaceutical formulation comprising, (i) a benzamide derivative represented by formula (I): wherein A represents a structure represented by any one of the following in formula (2): or a pharmaceutically acceptable salt thereof, and (ii) one or more than one selected from the group consisting of (1) a mixture of a polyethylene glycol and a surfactant as herein described, (2) a salt of an amino acid as herein described and a mineral acid as herein described, and (3) propylene carbonate, at a weight ratio of (i) : (ii) is 0.2:1.35 - 24.14.

Full Text

DESCRIPTION BEN2AMIDE DERIVATIVE-CONTAINING PHARMACEUTICAL FORMULATION HAVING IMPROVED SOLUBILITY AND ORAL ABSORPTIVITY Field of the Invention The present invention relates a pharmaceutical formulation with increased solubility containing benzamide derivative or a pharmaceutically acceptable salt thereof, which are useful as drugs, and especially anticancer drugs. In particular, it relates to a pharmaceutical formulation containing high concentration of active ingredient with improved oral absorptivity, that may also be used as injection. Background Art The benzamide .derivatives used for the invention and their pharmaceutically acceptable salts have histone deacetylase inhibitory action, and are useful as therapeutic and/or ameliorating agents for disease connected with cellular growth, as effect enhancers for gene therapy, and as immunosuppressants. They exhibit particularly powerful effects as anticancer agents, and are effective for hematopoietic tissue tumors and solid tumors (Japanese Unexamined Patent Publication HEI No. 10-152462 ) . However, while the benzamide derivatives used for the invention have very satisfactory absorptivity when orally administered to mice and rats, some cases of low absorptivity have been found in dogs. Some cases of low absorptivity with oral administration have also been found even when the formulations are prepared using common additives such as lactose, corn starch, carboxymethyl cellulose, light anhydrous silicic acid, magnesium aluminometasilicate, magnesium stearate and titanium oxide. It has therefore been considered difficult to achieve stable blood concentration only with formulation for oral administration containing benzamide derivative or salt thereof as an active ingredient. It has also been attempted to dissolve benzamide derivatives or their pharmaceutically acceptable salts in water, phosphate buffer solution and the like to make liquid drugs or injections, but their low solubility has made it impossible to obtain formulations of sufficient concentration. Thus, injections containing benzamide derivatives or their salts as active ingredients must have very large volumes because of the poor solubility of the active ingredients, and it has therefore been difficult to provide them as drugs. Disclosure of the Invention It is an object of the present invention to provide formulations with increased solubility and improved oral absorptivity for benzamide derivatives and their pharmaceutically acceptable salts that are useful as histone deacetylase inhibitors, and to provide injections containing the active ingredient at high concentration. In order to overcome the problems described above, the present inventors have conducted diligent research on addition of various additives to benzamide derivatives and their pharmaceutically acceptable salts to improve solubility and absorptivity, and as a result the present inventors have completed the present invention upon finding that this object can be achieved by using certain types of additives. In other words, the present invention provides: [1] A pharmaceutical formulation comprising a benzamide derivative represented by formula (1): (Figure Remove) wherein A represents a structure represented by any one of the following in formula (2): ) H or a pharmaceutically acceptable salt thereof, and one or more than one selected from the group consisting of surfactants, acidic substances, organic solvents and polyethylene glycols; [2] The pharmaceutical formulation according to [1] further comprising water; [3] The pharmaceutical formulation according to [1] or [2] wherein the benzamide derivative is represented by formula ( 3 ) : (Figure Remove) [4] The pharmaceutical formulation according to any one of [1] to [3] wherein the surfactant is one or two selected from anionic surfactants and nonionic surfactants; |5] The pharmaceutical formulation according to any one of [1] to [4] wherein the acidic substance is one or more than one selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids, acidic polysaccharides, acidic amino acids, and salts of an amino acid and a mineral acid; [6] The pharmaceutical formulation according to any one of [1] to [5] wherein the organic solvent is one or more than one selected from the group consisting of methanol, ethanol, propylene glycol, glycerin, propylene carbonate and dimethylacetamide; [7] The pharmaceutical formulation according to any one of [1] to [6] wherein the molecular weight of the polyethylene glycol is from 200 to 20,000; [8] The pharmaceutical formulation according to any one of [4] to [7] wherein the anionic surfactant is sodium lauryl sulfate; [9] The pharmaceutical formulation according to any one of [4] to [8] wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester or a sugar ester; [10] The pharmaceutical formulation according to [9] wherein the polyethylene sorbitan fatty acid ester is polysorbate 80; [11] The pharmaceutical formulation according to [9] wherein the sugar ester is a sucrose ester of fatty acid; [12] The pharmaceutical formulation according to any one of [5] to [11] wherein the mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid; [13] The pharmaceutical formulation according to any one of [5] to [11] wherein the carboxylic acid is citric acid, fumaric acid, adipic acid, tartaric acid, malic acid or acetic acid; [14] The pharmaceutical formulation according to any one of [5] to [11] wherein the sulfonic acid is aminoethylsulfonic acid; [15] The pharmaceutical formulation according to any one of [5] to [11] wherein the acidic polysaccharide is alginic acid; [16] The pharmaceutical formulation according to any one of [5] to [11] wherein the acidic amino acid is aspartic acid or glutamic acid; [17] The pharmaceutical formulation according to any one of [5] to [11] wherein the salt of an amino acid and a mineral acid is glycine hydrochloride, aspartic acid hydrochloride or glutamic acid hydrochloride. BRIEF DESCRIPTION OF THE DRAWING Fig. 1 shows serial changes in plasma concentrations upon oral administration of the formulations obtained in Examples 2 to 4 and Comparative Example 1 to fasted male beagles with 20 ml of water. Embodiment for Carrying Out the Invention The present invention will now be explained in greater detail. Formulations are generally produced by including one or more additives to the active ingredient. The benzamide derivatives as active ingredients for formulations, as represented by formula (1) according to the invention, are exemplified in Table 1, and these compounds may be produced by the process described in, for example, Japanese Unexamined Patent Publication HEI No. 10-152462. Surfactants to be used for the invention include anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants and the like without particular restrictions; and sodium lauryl sulfate, polysorbate 80, sucrose ester of fatty acid and the like are preferably used alone or in combination. Acidic substances to be used for the invention include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of an amino acid and a mineral acid, such as glycine hydrochloride, aspartic acid hydrochloride and glutamic acid hydrochloride. One or more than one acidic substance(s) can be used for the present invention. These acidic substances may be formulated with the active ingredient together with a surfactant, an organic solvent, a polyethylene glycol and/or the like, but they may also be used as a solution in water. Organic solvents to be used for the invention include methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate, and one or more than one of these may be used, optionally in the form of a solution in water. The polyethylene glycol used for the invention is not particularly restricted in terms of its molecular weight, but it preferably has a molecular weight in the range of 200 to 20,000, and more preferably in the range of 200 to 600. One or more than one type may be selected for use, optionally in the form of a solution in water. A soft capsule encapsuling a liquid, a hard capsule encapsuling a liquid and the like according to the present invention may be prepared by dissolving an appropriate amount of a benzamide derivative or its pharmaceutically acceptable salt, (i) in a liquid comprising one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; (ii) in a liquid comprising water and one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; (iii) in a liquid comprising one or more than one acidic substance(s), water and one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; or (iv) in a liquid comprising one or more than one acidic substance(s) and water, and making the soft capsule encapsuling a liquid, the hard capsule encapsuling a liquid and the like by a conventional method to those skilled in the art. The organic solvent which is used for preparing the soft capsules, the hard capsules and the like includes methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate; the polyethylene glycol which is used for preparing the soft capsules, the hard capsules and the like includes polyethylene glycols of molecular weight 200 to 600; the surfactant which is used for preparing the soft capsules, the hard capsules and the like includes polysorbate 80; and the acidic substance which is used for preparing the soft capsules, the hard capsules and the like includes mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic' acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of an amino acid and a mineral acid, such as glycine hydrochloride, aspartic acid hydrochloride and glutamic acid hydrochloride According to the invention, a solid formulation such as a powder, granules, tablets, pills and capsules may be prepared by adding to the active ingredient and one or more than one substance selected from the group consisting of surfactants such as sodium lauryl sulfate and sucrose ester of fatty acid; a polyethylene glycol such as polyethylene glycol 4000 and polyethylene glycol 6000; acidic substances including mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of an amino acid and a mineral acid, such as glycine hydrochloride, aspartic acid hydrochloride and glutamic acid hydrochloride, and further using an excipient, binder, disintegrator, lubricant, coating agent or the like for preparation, according to a conventional method to those skilled in the art. Excipients to be used for the present invention include D-mannitol, lactose, sucrose, corn starch, crystalline cellulose and the like. Binders to be used for the present invention include hydroxypropyl cellulose, polyvinylpyrrolldone, gelatin, glycerin, water and the like. Disintegrators to be used for the present invention include carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, partly pregelatinized starch, and the like. Lubricants to be used for the present invention include magnesium stearate, calcium stearate, and the like. Coating agents to be used for the present invention include hydroxypropylmethyl cellulose, methacrylic acid copolymers, hydroxypropylmethyl cellulose phthalate, and the like. The tablets may be tablets that are surrounded with a general coating if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets or film-coated tablets. Further the tablets can be double-layered or multilayered tablets which have separate layers of the active ingredient, the acidic substance, the surfactant and the like. An injection according to the present invention may be prepared by dissolving an appropriate amount of a benzamide derivative or its phamaceutically acceptable salt, (i) in a liquid comprising one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; (ii) in a liquid comprising water and one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; (iii) in a liquid comprising one or more than one acidic substance(s), water and one or more than one selected from the group consisting of organic solvents, polyethylene glycols and surfactants; or (iv) in a liquid comprising one or more than one acidic substance(s) and water, and making the injection by a conventional method to those skilled in the art. The organic solvent which is used for preparing the injection includes methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate; the polyethylene glycol which is used for preparing the injection includes polyethylene glycols of molecular weight 200 to 600; the surfactant which is used for preparing the injection includes polysorbate 80; and the acidic substance which is used for preparing the injection includes mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethylsulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of an amino acid and a mineral acid, such as glycine hydrochloride, aspartic acid hydrochloride and glutamic acid hydrochloride. Alternatively, after dissolving in water the one or more than one selected from the group consisting of these acidic substances, an appropriate amount of a benzamide derivative or its pharmaceutically acceptable salt may be dissolved therein to obtain an injection prepared by a conventional method to those skilled in the art. In this case, a surfactant such as sodium lauryl sulfate and/or a sucrose ester of fatty acid, and/or a polyethylene glycol such as polyethylene glycol 4000 and/or polyethylene glycol 6000 may be used together therewith to improve the solubility of the benzamide derivative. There are no particular restrictions on the method of administration for the pharmaceutical formulation of the invention, and it may be administered by a method suitable for the preparation form, the age, gender and condition severity of the patient, and other factors. For example, tablets, pills, liquid drugs, syrups, suspensions, emulsions, granules and capsules are administered orally, while injections are administered intravenously either alone or in admixture with a conventional fluid solution comprising glucose, amino acids or the like; if necessary, they are administered intramuscularly, subcutaneously or intraabdominally. The dose for these pharmaceutical formulations according to the invention may be appropriately selected based on the method of administration, the age, gender and condition severity of the patient and other factors; however, the dose for most active ingredients may be about. 0.0001 to 100 mg per day per kilogram of body weight. Amount of the active ingredient per unit dosage form is preferably included in the range of about 0.001 to 1000 mg. Examples The present invention will now be explained in further detail by way of examples and a comparative example. It is to be noted, however, that the present invention is not limited by these examples in any way. Example 1 After thoroughly blending 100 mg of compound 1 with 10 ml each of 0.05 N hydrochloric acid solution, inethanol, ethanol, propylene carbonate, polysorbate 80, polyethylene glycol 400, polyethylene glycol 300, glycerin, dimethylacetamide or propylene glycol at room temperature, the supernatant obtained by centrifugal separation of each mixture was separated off and used as a pharmaceutical solution. Comparative control samples were also prepared by thoroughly dissolving 100 mg of compound 1 with 10 ml each of purified water, sodium acetate buffer solution at pH 4.0 or sodium phosphate buffer solution at pH 6.8 at room temperature, and separating off the supernatant obtained by centrifugal separation. Table 2 shows a result of measuring the concentration of compound 1 in each sample by HPLC analysis. All of the samples of the present invention contained dissolved compound 1 at a concentration of 5 mg/ml or greater, which is a sufficient concentration for an injection. On the other hand, all of the comparative control samples contained dissolved compound 1 only at a concentration of 0.2 mg/ml or less, and therefore the concentration necessary for an injection could not be guaranteed. Example 2 10.13 g of polyethylene glycol 400 and 1.08 g of polysorbate 80 and 200 mg of compound 1 were mixed together and, the mixture was completely dissolved by ultrasonic treatment for 30 minutes with occasional mixing. The solution was filled into hard gelatin capsules so that the dosage can be 1.5 mg/kg based on body weight for dogs before administration, to prepare a pharmaceutical formulation. Example 3 200 mg of compound 1, 700 mg of polyethylene glycol 4000, 800 mg of polyethylene glycol 6000, 600 mg of sodium lauryl sulfate and 1200 mg of sucrose ester of fatty acid were weighed out and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into hard gelatin capsules so that the dosage can be 1.5 mg/kg based on body weight for dogs before administration, to prepare a pharmaceutical formulation. Examplja4 200 mg of compound 1, 1350 mg of glutamic acid hydrochloride and 1950 mg of D-mannitol were weighed out and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into hard gelatin capsules so that the dosage can be 1.5 mg/kg based on body weight for dogs before administration, to prepare a pharmaceutical formulation. Comparative Example I 200 mg of compound 1 and 1000 mg of D-mannitol were weighed out and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into hard gelatin capsules so that the dosage can be 1.5 mg/kg based on body weight for dogs before administration, to prepare a pharmaceutical formulation. Example 5 Solubility evaluation test in water The content of each of the pharmaceutical formulations obtained in Examples 2 to 4 and Comparative Example 1 was mixed with water, and the solubility was evaluated by measurement of concentration of compound 1 by HPLC or observation of clarity and color in the supernatant. Table 3 shows the solubility evaluation result based on measurement of concentration of compound 1 by HPLC or observation of clarity and color in each supernatant, after the content of each of the formulations obtained in Examples 2 to 4 and Comparative Example 1 (amount of compound 1 is 20 mg) was mixed with 1 to 1000 ml of purified water. According to the result for Example 2, no precipitation of compound 1 was found with mixture of water at any proportion. For Examples 3 and 4, it was found that the solubility was about 4 times and about 100 times that of Comparative Example 1, Table 3: Solubility of each pharmaceutical formulation in water In the table, the symbol x represents no dissolution of compound 1, and the symbol O represents complete dissolution of compound 1. Oral absorptivity evaluation test The pharmaceutical formulations obtained in Examples 2 to 4 and Comparative Example 1 were orally administered to fasted male beagles with 20 ml of water. Approximately 2.5 ml of blood was intravenously sampled into a heparinized container at 15, 30 and 45 minutes and 1, 2, 4, 6 and 9 hours after administration, and the blood was centrifuged and the plasma was collected. The active ingredient was separated by solid phase extraction from the plasma, and the concentration was measured by high performance liquid chromatography. The result is shown in Fig. 1. Examples 2 to 4 all had higher absorptivity than the comparative example 1. Table 4 shows the pharmacokinetic parameters for the oral administration of the pharmaceutical formulations obtained in Examples 2 to 4 and Comparative Example 1 to the fasted male beagles with 20 ml of water. Examples 2 to 4 all exhibited a higher AUC and Cmax than those of the comparative example 1, and improved absorptivity with oral administration. Table 4: Pharmacokinetic parameters for each pharmaceutical formulation The values in the table are average values with n=3. Industrial Applicability Pharmaceutical solutions are prepared by dissolving a benzamide derivative or a pharmaceutically acceptable salt thereof in organic solvents and/or acidic liquids, and pharmaceutical formulations are prepared by adding surfactants, acidic substances and/or polyethylene glycols to a benzamide derivatives or a pharmaceutically aceptable salt thereof, thus providing pharmaceutical formulations with high oral absorptivity and injections, that contain as active ingredients high concentrations of benzamide derivatives or their pharmaceutically acceptable salts, which are useful as histone deacetylase inhibitors. Claims 1. A composition comprising an effective; amount of an extract or compound obtained; from the plant Glycyrrluza glabra and usefui.as a bio-enhancer arid' bidavailability facilitator together with a therapeutically effective amount of one or more 'antibiotics, anti-infective agents or anti-cancer agents. 2. A composition as claimed in claim 1 containing'an extract of leaves, stem, roois of stolon of Glycyrrhiza glabra, glycyrrhizic acid or glycyrrhizin, or a combination thereof. 3. A composition as claimed in'claim 1, wherein glycyrrhrzin and glycyrrhiiic acid are obtained from the plant Glycyrrhiza glabra. 4. A composition as claimed in claim 1," wherein the-extract of roots of Glycyrrhiza glahra is licorice. • ' . ' " ' ' 5. A composition as claimed in claim 1, wherein the anti-infective agents are selected from anti-bacteria], anti-fungal and anti-tuberculosis agents. 6. A composition as claimed in claim 1, wherein the concentration of glycyrrhizin ranges from 0.05 to SOwcight % of the anti-bacterial compbunds. 7. A composition as claimed in claim I, wherein the concentration -of g]ycyrrlii?.in' ranges from 0.25 to 20weight % of the anti-fungal agents. 8. A composition as claimed in claim 5, wherein the-ami-bacterial, agents are selected from the group consisting of j3-lactams, macrolides, quitiolones, fluoro-quinblones, aminoglycosides, glycopeptides, rifamycins, folate inhibitors, tetracyclines. unti- tuberculosis agents or microbicidal compounds. ' •' . 9. • A composition as claimed in claim 9, whereJn'the quinolones 'and fluoro-quinolones are selected from the group consisting of nalidixic acid,.norfIoXacin. ciproflaxacin,. sparfloxacin or similar other compounds. 10. A composition as claimed in claim 9, wherein the p-Laeiam& are selected from the group comprising penicillin, flucloxacillin, cloxacukkub, methicillin, cepnalosporins or carbapenenms. 1J.A composition as claimed in. claim 9, wherein the maerolides are selected from erytHromycih, clarithr-dinycm;, azithromycin:or other similar compounds. 12. A composition as claimed in claim 9, wherein the aminoglycosides are selected from the group consisting of streptomycin, gentamicin, amikacin or similar compounds. • 13. A composition as claimed in claim 9, wherein the glycopeptides are selected from varicomycin, teicoplahin or other similar compounds. 14. A composition as claimed in claim '9, wherein the rifamycins-are. rifampicin or similar compounds. ' 15. A composition as claimed in claim 9, wherein the folate inhibitors are selected from trimethoprim, sulphonamides or similar compounds. 16. A composition as claimed in claim 9, wherein the micrbbiocidal compounds arc selected from slreptogramins and oxazolidinpnes. 17. A composition as claimed in- claim 5, wherein the anti-tuberculosis agents are selected from the group comprising isoniazid,- pyrazinamide, etharnbutol or similar compounds. : ' * ' . * * • 18. A composition as claimed in claim 5,'whereiri the 'anti-fungal agents are selected from' the group consisting of polyene, triazole, imidazole, clotrimazolc or fungicidal compounds. 19. A composition as claimed in claim 19, wherein'tHe polyene is selected from nystatin or similar compounds. 20. A composition as claimed. in claim 19, wherein the triazole is selected from fluconazoie, itraconazole andor similar compounds. 21. A composition as claimed in claim 19, wherein the imidazole is selected from ketoconazole or similar compounds. 22. A composition as olaimfed in claim 19, wherein the furvgicidal'compound:is selected from griseofulvin or terbinafine. 23'. A composition as claimed in claim 1-, wherein; the anti-cancer, a'genf is selected from the group consisting of Paelitaxel (Taxol), Docetaxe.l (Takotere), . Vinblastine (Velban), Vincristine (Oncovin) or Vinorelbine (Navelbihe). . . 24. A composition as claimed in claim 1, wherein the concentration-of glycyrrhizm ranges from 10 to 10,000 folds of the- weight of the anti-cancer .compound. 25. A composition as.claimed in claim 1, wherein licorice preparation from' one gram of dried root is equivalent to 40 mg of glycyrrhizin. 26. A method for enhancing the bio-availability of anti-infective agents or anti-cancer using herbal extracts or compounds derived from the exrtract across biological membranes in living systems; said method-comprising the steps of administering to a subject in need thereof, a composition comprising an effective amount of the. bioenhancer obtained from the plant Glycyrrhiza glabra, and any one of anti-infective agents or, anti-cancer agents.. , . . ;. 27. A method as claimed in claim 28, wherein, the bio-enhancer is selected.from the extract of Glycyrrhiza glabm, glycyrrhizin, glycyrrhizic acid or-combinations thereof. 28. A method as claimed in claim 28, wherein the bioenhancer is obtained from the roots, stem, stolon or leaves of'the piant-Glycyrrfiiza glabra. 29. A method as claimed in claim 28, wherein the anti-infective agents are sjslecr'ed from . anti-bacterial, anti-fungal, or anti-tuberculosis agents. 30. A method as claimed in claim. 31, wherein the anti-bacterial agents ore selected .from the group comprising (3-lactams, macrolides, .quiriolones, fluoro-quinolones, aminbglycbsides, glycopeplides, rifamycins, folate inhibitors, tiitracyclmes:, anti-tuberculosis agents or' microbicidal compounds. 31. A method as claimed in claim 31, wherein-concentration of glycyrrhizin ranges from 0.05 to 50 weight % of the anti-bacterial agents. • 32. A method as claimed in claim 32, wherein the quinqlbnes anct fluoroquinplones are selected from the group consisting of 'nalidixic acid, rioifloxacin, ciprofloxacin, sparfloxacin or similar other compounds. . 33. A method as' claimed in claim 32, wherein th&p-Lactams .are selected fito.m the group consisting of penicillin, flucloxacillin; cloxacukkub, methicillin, cephalospbrins or carbapenenms. 34. A method as claimed in claim 32, wherein the macrolides are selected from erythromycin, clarithromycin, azithromycin or other similar compounds. 35. A method as claimed in claim 32, wherein:the aminoglycosides -are selected from the group consisting of streptomycin, gentamicin, bmikaein or:similar compounds. 36. A method as claimed in claim 32, wherein the glycopeptides are selected from vancomycin, teicoplanin or other similar compounds. 37. A method as claimed in claim .32, wherein the rifamycins .are rifampicin or similar compounds. 38- A method as claimed in claim 32, wherein the anti-tuheroulosik agents selected from the group consisting of isoniazid, pyrazinamide, ethambutoi .or other similar compounds. 39. A method as claimed in claim 31, wherein concentration of glycyrrhizin rapges: from 0.25 to 20 weight % of the ami-fungal agents.. . . , 40. A method as claimed in claim 31, wherein the anti-fungal agenfis seiected from the group consisting of polyene, triazole; irriidazole, clotritnazofe or other fungiciclal compounds. 41. A method 03 claimed in claim 28, wherein the anti-cancer agent is seje'cted from the group consisting of Paclitaxel (Taxol), DbcetaxeJ'(Taxotejie), .Vinblastine (Velban), Vincristine (Oncovin) or Vinorelbirie (Navelbine): 42. A method as claimed in cjjaim 31, wherein the concentration of glycyrrbi'zin ranges:- from 10 to iO.OOO folds of the weight .of the .anti-cancer agentl ; 43. A method as claimed'-in,'claim. 27, wherein- administration j of the composition circumvents the side effects of chemotherapy by substantially reducing the dosages .of therapeutic agents comprising'of anti-bacterial,-anti-fungal and anti-cancerous agents wherein, the side effects of those agents can be bone marrow suppression, liver and kidney toxicity, pulmonary scarring, high .• fevers, . skin reactions, Nausea and vomiting, hair loss, skin rash, mouth sores, diarrhoea, loss of appetite and confusion, lethargy and ambulation problems (ataxia), anaphylactic reactions (consisting of fast heart rate, wheezing, lowered blood pressure and facial edema, cerebellar dysfunction (consists of slurring of speech, 'Walking problems, as well as eye rrtotion problems), loss of periods .(menses), ovarian failure can occur, painful soft'tissue ulcers, cardiotoxicity, hypersensitivity reactions, abnormal Wood pressure, sweating,; bleeding, shortness of breath and many related problems 44. A method as claimed in claim 27, wherein, the bioenhancer improves the uptake of anti-infectives, or anticancer agent? when glycyrrhizin is provided prior .to the treatment with these molecules. 45. Use of the-extract or the compound.obtiained from the plant.Glycyrrhiza-glabra, as ii bioenhancer and bioavailability and facilitator drugs molecules selected from anti- infective and anti-cancer agents.

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