US 2002O193322A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0193322 A1 Baiocchi et al. (43) Pub. Date: Dec. 19, 2002

(54) METHOD OF PREPARING Publication Classification PHYSIOLOGICALLY ACCEPTABLE AQUEOUS SOLUTIONS, AND SOLUTIONS (51) Int. Cl." ...... A61K 31/704; A61K 31/66; THUS OBTAINED A61K 31/60; A61K 31/551; A61K 31/525; A61K 31/522; (76) Inventors: Leandro Baiocchi, Roma (IT); Mauro A61K 31/57 De Gregorio, Roma (IT) (52) U.S. Cl...... 514/33; 514/171; 514/75; 514/263.31; 514/165; 514/217.05; Correspondence Address: 514/220; 514/282; 514/569; OBLON SPIVAK MCCLELLAND MAIER & 514/251 NEUSTADT PC FOURTH FLOOR (57) ABSTRACT 1755JEFFERSON DAVIS HIGHWAY A physiologically acceptable aqueous Solution, and water ARLINGTON, VA 2.2202 (US) Soluble compositions Suitable for obtaining it, comprising a first physiologically acceptable compound of an acidic (21) Appl. No.: 10/058,080 nature and a Second physiologically acceptable compound of a basic nature that are able to give rise to a precipitate in (22) Filed: Jan. 29, 2002 water, characterized in that it also contains a trisubstituted Salt of glycyrrhizic acid in a Sufficient quantity to form a (30) Foreign Application Priority Data clear Solution in water. Jan. 30, 2001 (IT) ...... RM2OO1A 000048 A method for preparing the Said Solution. US 2002/0193322 A1 Dec. 19, 2002

METHOD OF PREPARING PHYSIOLOGICALLY therapeutically useful concentration, and cases of partial ACCEPTABLE AOUEOUS SOLUTIONS, AND incompatibility in which it is possible to obtain solutions but SOLUTIONS THUS OBTANED only in a very restricted range of concentration. 0001. This application is based on application No. 0009. The problem of incompatibility is not solved by RM2001. A 000048 filed in Italy, the content of which is Separate administration of the Solutions of the different incorporated hereinto by reference. pharmacologically active compounds to the patient, unless there is a considerable interval of Space and/or time between 0002 The present invention relates to a method of pre the applications. Otherwise, in fact, incompatibility between paring physiologically acceptable aqueous Solutions and the two pharmacologically active compounds and inactiva water-Soluble compositions Suitable for obtaining them, as tion occur at the Site of actual application (See, for example, well as the Solutions and the compositions thus obtained. the case of cephalosporins and of aminoglycosides (REFI 0.003 More particularly, the present invention relates to page A-249)). In each case separate application, besides physiologically acceptable aqueous Solutions and water being inconvenient, proves completely impossible in Some Soluble compositions Suitable for obtaining them, compris cases, for example when one of the compounds performs the ing a first physiologically acceptable compound of an acidic functions of a preservative. nature, a Second physiologically acceptable compound of a basic nature and a trisubstituted Salt of glycyrrhizic acid. STATE OF THE ART 0010. In some cases the problem has been solved by BACKGROUND OF THE INVENTION using specific pharmaceutical formulations. Thus, the 0004. In therapeutic and cosmetic practice, both human incompatibility between certain carboxylic acids and certain and Veterinary, use is often made of aqueous Solutions basic decongestants is eliminated by means of a mixture of containing a carboxylic acid or an organic base, possessing polysorbates and a polyoxamer (U.S. Pat. No. 5,459,157). low intrinsic solubility (solubility of the undissociated com Moreover, it should be pointed out that in this case, as in pound). Their Salification (generally with alkali metals or other Similar cases, the concentration of these additives is hydrophilic amines of low molecular weight for the acids, very high (12%) relative to that of the pharmacologically and with hydrogen halides or hydrophilic organic acids of active compounds (0.05-0.1%). low molecular weight, for the bases) is employed to provide 0011 Glycyrrhizic acid, the principal component of the them with adequate Solubility. extract of Glycyrrhiza Glabra, was isolated by Karrer and 0005 Sometimes it is useful to have acqueous solutions Chao and its tricarboxylic acid structure was established by containing at least one carboxylic acid and at least one Ruzicka in 1943 (Merck Index, XII ed., 4515). Two epimers organic base at the same time. Since Solutions with basic pH of glycyrrhizic acid are known, designated 18O, and 18f3, but are needed for the Solubilization of weak organic acids, and the Second is the commonest and it is this that is being solutions with acid pH are needed for the solubilization of referred to whenever the nature of the epimer is nots weak organic bases, Such compounds often display a high expressly indicated (Runti, Fondamenti di chimica farma degree of incompatibility in ordinary aqueous Solutions ceutica Fundamentals of pharmaceutical chemistry, Trieste because mutual precipitation occurs on mixing them (see A. 1969, Vol. III, page 265). T. Florence & D. Attwood “Physiochemical Principles of 0012 Various salts of glycyrrhizic acid, called glycyr Pharmacy”, II edition, Portland Oreg., 1988, p. 154). rhizinates, have been described in the literature. 0006 Examples of this behaviour that are well known in 0013 A typical, commercially available monosubstituted the literature are the Solutions of acetylsalicylic acid (lysine salt is the monoammonium salt “Glycamil T.M.' of the com salt) with chlorpromazine (hydrochloride) or promethazine pany Indena of Milan. Typical disubstituted salts are the (hydrochloride) (Repertorio Farmaceutico Italiano 1989 dipotassium salt, “Ritamectant K2TM” of the R.I.T.A. Cor (REFI) page A-578); Solutions of furosemide (sodium salt) poration, and the mixed Salts of potassium, calcium and with organic bases (REFI, page A-808); Solutions of magnesium called “glycyrrhizines” (U.S. Pat. No. 4,176, dimenorfan (phosphate) with penicillin (Sodium salt) or of 228). A typical trisubstituted Salt is the tripotassium Salt sodium salicylate (REFI page A-646). (Voss et al., Ber. 70, 122, 1937). 0007. It should be noted, moreover, that the phenomenon 0014. The monosubstituted and disubstituted salts are is rather more complex than might appear at first sight widely used in the food and pharmaceutical industry, prin because, depending on circumstances, there may be precipi cipally as Sweeteners. tation of the acid compound, or of the basic compound, or of a mixture of the two, or of adducts, known as hydrophobic 0015 Apart from some mild therapeutic activities that ion pairs. In this last case, which is very common, there may have been under investigation for several years (antiulcer be formation of precipitates, even when one of the two activity, anti-AIDS activity, treatment of hepatitis B), certain components, for example quaternary ammonium com functions of glycyrrhizic acid and its Salts as “adjuvants' in pharmaceutical formulations have also been described from pounds, has good intrinsic Solubility. time to time. 0008. The incompatibility is more or less pronounced depending on the pK, on the nature and on the intrinsic 0016. The action of "enhancers' of absorption through Solubility of the components that determine it. In fact, cases the Skin and the mucous membranes is well documented of absolute incompatibility are encountered in practice, in (U.S. Pat. Nos. 5,183,802; 5,238,917; JP 3099023). which it is practically impossible to obtain Solutions con 0017 Japanese patent JP 10025255 proposes the use of taining the two pharmacologically active compounds at any glycyrrhizic acid, its Salts or its esters, for the preparation of US 2002/0193322 A1 Dec. 19, 2002

Solid complexes with antiulcer, anti-inflammatory or anti nature and a Second physiologically acceptable compound of histaminic drugs for the purpose of improving their absorp a basic nature that are able to give rise to a precipitate in tion (rate of Solution). It is known, however, that the water, characterized in that it also includes a trisubstituted complexes that can be used for increasing the rate of Solution Salt of glycyrrhizic acid in Sufficient quantity to form a clear cannot be used for increasing equilibrium Solubility (A. J. Solution. Repta in “Technique of Solubilation of Drugs” (S. H. 0025 Moreover, in a further aspect, the present invention Yalkowsky ed. Marcel Dekker N.Y. 1981 page 135 ff.; pages relates to a composition comprising a first physiologically 149 and 151). acceptable compound of an acidic nature and a Second 0018. In two Japanese patent documents (Jpn. Kokai physiologically acceptable compound of a basic nature that 0283,318 and JP 3145432A) reference is made to clear are able to give rise to a precipitate in water, characterized Solutions containing Salts of glycyrrhizic acid, quaternary in that it also includes a trisubstituted Salt of glycyrrhizic ammonium compounds and respectively, Sodium condoitr acid in Sufficient quantity to form a clear Solution when the insulphate, borax and taurine in the first case, and lysozime Said composition is added to water. (hydrochloride) in the second. In the first case (C.A. 113, 0026. For the purposes of the present invention, the 65296x) the salt used is dipotassium glycyrrhizinate. glycyrrhizic acid can be either in the form of epimer 18C, or 0019 U.S. Pat. No. 4,481,187 discloses the use of gly of epimer 18B. The latter is preferred, however, because it is cyrrhizic acid or its Salts for Solubilizing oily Substances in more readily available commercially. water, Such as oil-Soluble hormones and perfumes. 0027. The cation of the trisubstituted salt of glycyrrhizic acid according to the present invention can be any physi 0020 JP 09 0872.01 discloses a liquid composition con ologically acceptable, organic or inorganic cation, for taining acetaminophenone, a Saccaride, a Salt of glycyrrhizic example Sodium, potassium, ammonium, calcium, magne acid and a glycol. Acetaminophenone, however, is neither sium, monoethanolamine, diethanolamine, triethanolamine, acid nor basic in nature. Indeed, it is neutral. lysine, arginine, tromethamine and the like. There is no 0021. In patents relating to the use of glycyrrhizic acid, limitation on the use of mixed trisubstituted Salts. generally reference is made to its Salts, without differenti 0028 Solutions of disodium monoammonium glycyr ating them. However, monoSubstituted and disubstituted rhizinate obtained by neutralizing the commercial ammo Salts are normally used in the examples given in these nium monoglycyrrhizinate with the required quantity of documents. Just occasionally, as in U.S. Pat. No. 4.278,657, aqueous Solution of Sodium hydroxide are easily accessible which proposes the use of glycyrrhizic acid and its Salts in and particularly advantageous. For example, with a 0.2 N Synergy with certain polysaccharides as emulsifiers of water solution of sodium hydroxide it is easy to obtain a solution and oil mixtures, examples with trisubstituted Salts are also of disodium monoammonium glycyrrhizinate at concentra given. However, neither this nor other patents describe or tions above 8%, the exact value depending on the Strength claim that the trisubstituted Salts have any property at all that of the commercial ammonium glycyrrhizinate used. Natu is different from the mono- and disubstituted Salts. rally, neutralization can also be carried out, as well as with Sodium hydroxide, with potassium hydroxide, with ethano BRIEF DESCRIPTION OF THE INVENTION lamine, with diethanolamine, with ammonia or with their 0022. It has now been found, unexpectedly, that the obvious equivalents. compositions comprising the Salt of a first physiologically 0029. Because the absolute concentration and the propor acceptable compound of an acidic nature and the Salt of a tions between the components in the composition of the Second physiologically acceptable compound of a basic invention are not determined by Stoichiometric requirements nature, which give rise to mutual precipitation in water, can but by therapeutic or pharmaceutical requirements and easily be Solubilized in water by adding a Suitable amount of because the phenomenon of mutual precipitation is governed a trisubstituted Salt of glycyrrhizic acid. Naturally, apart by the nature of the components, there is not an optimum from a first physiologically acceptable compound of an concentration of trisubstituted glycyrrhizinate that can be acidic nature and a Second physiologically acceptable com used in all cases. pound of a basic nature, other physiologically acceptable 0030. However, it is very easy to identify it in any compounds of an acidic and/or basic nature can also be individual instance by mixing together, with vigorous stir present. ring in water, a Salt of a first physiologically acceptable compound of an acidic nature and a neutral Salt of a Second DETAILED DESCRIPTION OF THE physiologically acceptable compound of a basic nature that INVENTION are able to give rise to a precipitate in water, at the concentration and in the proportions that are predetermined 0023. In a first aspect, the present invention therefore by therapeutic, pharmaceutical, cosmetic or Similar require relates to a method for forming an aqueous Solution com ments. Then an aqueous Solution of a trisubstituted glycyr prising a first physiologically acceptable compound of an rhizinate is added gradually, in portions, to the Suspension acidic nature and a Second physiologically acceptable com that forms, until a clear Solution is obtained. Preferably, the pound of a basic nature that are able to give rise to a total amount of water is preselected So that at the end of the precipitate in water, characterized in that a trisubstituted Salt operation the total volume is reasonably lower (5-10%) than of glycyrrhizic acid is added in Sufficient quantity to form a the required final Volume and then it is made up to Volume clear Solution. with water. Advantageously, the aqueous Solution of glycyr 0024. In a second aspect, the present invention relates to rhizinate is added very slowly and with vigorous stirring. In a physiologically acceptable aqueous Solution comprising a fact, attainment of equilibrium in a few hours is by no means first physiologically acceptable compound of an acidic C. US 2002/0193322 A1 Dec. 19, 2002

0031. The amount of trisubstituted glycyrrhizinate 0043. The physiologically acceptable compounds that are required to achieve Solubilization of the precipitates varies, preferred according to the present invention are those that in the examples given further on, between 0.27 and 2.7% display a therapeutically useful pharmacological or pharma (concentrations expressed as disodium ammonium glycyr ceutical activity. rhizinate). However, for the reasons previously presented 0044) The physiologically acceptable compounds of an concerning the nature of the phenomena involved and the acidic nature, characterized in that the aqueous Solutions of factors affecting them, a person skilled in the art will easily their salts (with alkali metals and alkaline earth metals, understand that the amount of trisubstituted glycyrrhizinate ammonium, hydroxyamines, basic amino acids, required could, in a particular case, also undergo reasonable tromethamine etc.) are incompatible with aqueous Solutions deviations, higher or lower relative to the aforesaid range, of Salts of organic bases, and belong to various chemical while remaining within the Scope of the present invention. therapeutic categories. 0.032 Having thus easily determined in the laboratory the 0045. A typical example of a first important class of these appropriate quantity of trisubstituted glycyrrhizinate compounds comprises the non-Steroidal anti-inflammatory required for the particular composition under consideration, drugs (NSAIDs). Typical examples of NSAIDs are arylal large-scale preparation of the Solutions of the invention will kanoic acids (ketoprofen, napoxen, ibuprofen, flurbiprofen, preferably be effected by mixing together, in the desired diclofenac, Sulindac and the like), anthranilic acids (mefe order, the predetermined quantities of the various compo namic acid, flufenamic acid and the like), Salicylic acids nents as Solids or as Solutions. (aspirin, diflunisal and the like), and Some heterocyclic acids 0.033 For example, the following are added, in this order, (indometacin, flunoxaprofen, ketorolac). to a preselected quantity of water: 0046. A typical example of a second class comprises 0034) a quantity of a base (for example sodium diuretics Such as ethacrynic acid, furosemide and the like. hydroxide, potassium hydroxide, ethanolamine, 0047 A typical example of a third class comprises anti diethanolamine, triethanolamine, tromethamine, allergic drugs Such as lodoxamide, tranilast and their ana lysine, arginine, or Sodium bicarbonate) Sufficient to logues. Salify either the two free carboxyls of the predeter mined quantity of ammonium glycyrrhizinate, or the 0048. A typical example of a fourth class comprises the preSelected quantity of a physiologically acceptable 21-phosphoric and 21 -hemisuccinic esters of corticoster compound of an acidic nature if the latter is used as oids. free acid as well as Salt, 0049 Further examples of therapeutically useful com 0035 the said physiologically acceptable compound pounds of an acidic nature characterized by the fact that of an acidic nature aqueous Solutions of their Salts are incompatible with aque ous Solutions of Salts of organic bases are carboxylic acids 0036) the monoammonium glycyrrhizinate, and belonging to other therapeutic classes Such as: aryloxy 0037 the ppreselected Cquantitv y of a neutral Salt of a alkanoic acids, Sorbic acid, pirfenoXone, folic acid, fusidic physiologically acceptable base. acid, theophylline-acetic acid, bendaZac, prostaglandins, 0.038 If the salt of the physiologically acceptable base is ACE inhibitors, penicillins, cephalosporins, quinolonics and an acid Salt, for example the Sulphate or those of dicarboxy the like. lic acids, due account of it is taken by Suitably increasing the 0050. The physiologically acceptable compounds of a initial quantity of base. Similarly, the quantity of base used basic nature, characterized in that the aqueous Solutions of will be reduced whenever the physiologically acceptable their Salts (with hydrogen halides, Sulphuric acid, phospho base is used in the free form as well as in the form of salt. ric acid, nitric acid, low molecular weight organic acids, 0.039 So far, no appreciable drawback has been observed hydroxylates and/or polycarboxylic acids and the like) are when using an excess of trisubstituted glycyrrhizinate, rela incompatible with aqueous Solutions of Salts of organic tive to the minimum quantity required for obtaining a clear acids, and these too belong to various chemical and thera Solution. Indeed, an improvement in Stability of the Solution peutic classes. has been observed in Some cases. 0051 A typical example of a first class of such com 0040. The compositions of the invention could also be in pounds comprises antihistamines Such as: chlorpheniramine, the form of powders for dissolving or as concentrated promethazine, azelastine, antazoline, cyproheptadine, Solutions for diluting in water, or in aqueous liquids, at the tonzylamine, diphenhydramine, emedastine, ketotifen and time of use. Forms that could be used for this purpose are the like. granules, freeze-dried products, tablets and the like, pro 0052 A typical example of a second class comprises duced by traditional galenical techniques, well known to a mucolytics Such as: ambroXol, bromexine and the like. person skilled in the art, comprising simple operations Such 0053 A typical example of a third class comprises vaso as granulation, tableting, dissolving, Sterilizing, freeze-dry constrictorS Such as: naphazoline, tetry Zoline, tramaZoline ing etc. and the like. 0041) Preferably, the physiologically acceptable com 0054) A typical example of a fourth class comprises pound of an acidic nature according to the present invention B-blockerS Such as: timolol, carteolol and the like. is a carboxylic acid. 0055 A typical example of a fifth class comprises anti 0042. In its turn, the physiologically acceptable com SpasmodicS Such as: ipratropium bromide, octylonium bro pound of a basic nature according to the present invention is, mide and the like, papaverine, rociverine, toripramide and preferably, an organic base. the like. US 2002/0193322 A1 Dec. 19, 2002

0056. A typical example of a sixth class comprises anti 0072 50 mg of tetryzoline hydrochloride Septics Such as: chlorhexidine, benzalkonium chloride, ben Zetonium chloride, benzoxonium chloride, dequalinium 0073 2 ml of aqueous solution of benzalkonium chloride and the like. chloride at 0.5% 0057. A typical example of a seventh class comprises 0074 The “Gly solution” was added in portions of antituSSives Such as: codeine and codeine-like drugs, OXola approx. 1 ml to the milky Suspension, with a few minutes mine, dimenorfan, cloperastine. between each addition, obtaining complete Solubilization after addition of 14.5 ml. The Solution thus obtained was 0.058 A typical example of an eighth class comprises made up to 100 ml with distilled water. Final composition: basic anti-inflammatory drugs. Such as: benzydamine and the like.

0059 A typical example of a ninth class comprises bron diclofenac sodium salt 100 mg chodilatorS Such as: Salbutamol, fenspiride and the like. tetryzoline hydrochloride 50 mg benzalkonium chloride 10 mg 0060 A typical example of a tenth class comprises sym GlyNH,Na, (14.5 ml of “Gly solution”) 1.2 g pathicolytics Such as: dapiprazole, praZosin, chlorpromazine Water, sufficient for: 100 ml and the like. 0061 Further examples of therapeutically useful com pounds of a basic nature belong to other classes Such as EXAMPLE 2 central analgesics, antibiotics, fluoroquinolones and the like. 0075 Solution of ibuprofen and chlorpromazine 0062) The compounds of the invention can also contain 0076 An aqueous solution containing 0.63 g of ibuprofen other traditional types of ingredients Such as pH adjusters, and 15.3 ml of 0.2 N. NaOH in a volume of 40 ml was antioxidants, Stabilizers, preservatives, Viscosity enhancers, prepared. Then a similar procedure was followed to that chelating agents, humectants, colouring matter, Substances described in Example 1 above, obtaining a Solution having for achieving isotonia, etc. With regard to isotonia, no the following composition: macroscopic effects due to the concentration of Sodium chloride in the Solutions are known. 0.063 A person skilled in the art will be able to introduce Ibuprofen 0.63 g many variants (Such as various Salts), without departing NaOH (0.2 N: 15.3 ml) 123 mg from the Spirit of the present invention, according to the chlorpromazine hydrochloride 0.70 g nature and quantity of the physiologically acceptable com GlyNH,Na, (22.8 ml of “Gly solution”) 1.90 g pounds used and the type of final composition to be water, sufficient for: 100 ml obtained. 0064. For example, the compound having acidic nature EXAMPLE 3 and the compound having basic nature may be a polymer Such as Xanthan gum, carboxymethyl cellulose, chitosan and 0077 Solution of ibuprofen and benzoxonium chloride the like. 0078. Following a similar procedure to that described in 0065. The following examples will serve to illustrate the Example 2 above, a Solution was prepared having the present invention, though without limiting it. following composition:

EXAMPLE 1. ibuprofen 0.70 g 0.066 Solution of diclofenac, tetryzoline and benzalko NaOH (0.2 N: 17 ml) 136 mg nium chloride benzoxonium chloride 70 mg GlyNH,Na, (13.8 ml of “Gly solution”) 1.15 g 0067 A) PREPARATION OF THE “GLY SOLUTION” water, sufficient for: 100 ml 0068 94.4 ml of a 0.2N solution of NaOH was added to 8.44 g of monoammonium glycyrrhizinate trihydrate. The resulting solution was brought up to the volume (100 ml) EXAMPLE 4 with distilled water. A Solution with 8.34% of disodium 0079 Solution of ketoprofen, chlorhexidine and benza monoammonium glycyrrhizinate (GlyNH-Na) was thus Ikonium chloride obtained, and will be designated as “Gly solution” herein after. 0080. Following a procedure similar to that described in Example 2 above, a Solution was prepared having the 0069 B) PREPARATION OF A SOLUTION OF following composition: DICLOFENAC, TETRYZOLINE AND BENZALKO NIUM CHLORIDE 0070 The following were added, in this order, with ketoprofen 0.50 g stirring, to 40 ml of water: NaOH (0.2 N: 9.85 ml) 79 mg chlorhexidine digluconate 0.10 g 0071 10 ml of aqueous solution of diclofenac benzalkonium chloride 0.10 g Sodium salt at 1% US 2002/0193322 A1 Dec. 19, 2002

EXAMPLE 8 -continued 0088 Solution of betamethasone 21-phosphate and ambroXol GlyNH,Na, (18 ml of “Gly solution”) 1.50 g 0089. The various ingredients were added, with stirring water, sufficient for: 100 ml and at room temperature, to 90 ml of water, obtaining a Solution having the following composition:

EXAMPLE 5 betamethasone 21-phosphate disodium salt 0.15 g ambroxol hydrochloride 0.27 g 0.081 Solution of naproxen and chlorpheniramine monoammonium glycyrrhizinate trihydrate 0.35 g sodium bicarbonate 0.07 g 0082 Bearing in mind, in the calculations of the quantity water, sufficient for: 100 ml of alkali required for also neutralizing the free carboxyl of the maleic acid in the chlorpheniramine maleate, 0.5 g of naproxen and 0.4 g of chlorpheniramine maleate were EXAMPLE 9 added, in that order, to 40 ml of an aqueous Solution 0090 Solution of naphazoline and diclofenac containing 16 ml of NaOH 0.2 N. The milky suspension 0091. The various ingredients were added in the order became clear on adding, with Stirring, 3.2 ml of “Gly Stated, with Stirring and at room temperature, to 90 ml of solution”. Solution composition: water, obtaining a Solution having the following composi tion:

naproxen 0.50 g diclofenac sodium salt 0.10 g NaOH (0.2 N: 16 ml) 128 mg tripotassium glycyrrhizinate 1.70 g chlorpheniramine maleate 0.40 g naphazoline hydrochloride 0.10 g GlyNH,Na, (3.2 ml of “Gly solution”) 0.27 g water, sufficient for: 100 ml water, sufficient for: 100 ml EXAMPLE 10

EXAMPLE 6 0092 Solution of ketoprofen, chlorpheniramine, chlo rhexidine and benzalkonium chloride 0083) Solution of furosemide and timolol 0093 4.0 g of ammonium glycyrrhizinate trihydrate and 2.0 g of ketoprofen are dissolved in 90 ml of NaOH 0.2 N. 0084. Following a procedure similar to that described in Add 0.2 g of hydroxyethyl cellulose dissolved in 20 ml of Example 5 above, a Solution was prepared having the lukewarm water, then, in this order: 1.0 g of chlorphe following composition: niramine maleate, 10 ml of 2% solution of chlorhexidine digluconate, 40 ml of 0.5% benzalkonium chloride and make up to 200 ml with distilled water. The solution thus obtained contains: furosemide sodium salt 0.89 g NaOH (0.2 N: 10.3 ml) 82 mg timolol maleate 0.89 g ketoprofen 1.00 g GlyNH,Na, (12 ml of “Gly solution”) 1.00 g monoammonium glycyrrhizinate trihydrate 2.00 g water, sufficient for: 100 ml chlorpheniramine maleate 0.50 g chlorhexidine digluconate 0.10 g benzalkonium chloride 0.10 g NaOH 0.39 g EXAMPLE 7 hydroxyethylcellulose 0.10 g water, sufficient for: 100 ml 0085 Solution of ketoprofen and chlorpheniramine 0.086 The following were added, in the order stated, with Stirring and at room temperature, to 90 ml of water: EXAMPLE 11 0094 Solution of ketoprofen and chlorpheniramine male ate diethanolamine 0.72 g 0.095 The following were mixed in a 10 ml flask: ketoprofen 1.00 g monoammonium glycyrrhizinate trihydrate 1.00 g chlorpheniramine maleate 0.30 g ketoprofen 1.00 g chlorpheniramine maleate 0.30 g monoammonium glycyrrhizinate trihydrate 1.00 g 0.087 Each component was added when all the preceding sodium bicarbonate 0.65 g components had dissolved. It was made up to 100 ml with distilled water, US 2002/0193322 A1 Dec. 19, 2002

0.096 all in the form of Solids. After homogenization for added. After 45 min of vigorous Stirring, a Solution was 15 minutes in a mortar, the mixture proved to be perfectly obtained, which was made up to 100 ml with distilled water. soluble in 100 ml of drinking water. Its composition was:

EXAMPLE 12 ketoprofen 0.5 g. 0097 Solution of ketoprofen and promethazine NaOH (0.2 N: 5.8 ml) 46 mg ambroxol base 0.33 g 0.098 (neutralization of the acids in situ) GlyNH-Na (24 ml of “Gly solution') 2.0 g water, sufficient for: 100 ml 0099] 1 g of promethazine hydrochloride and then 2.7 g of monoammonium glycyrrhizinate trihydrate (3.02 10 mol, 6.04 10 acid equivalents) were added to an aqueous EXAMPLE 16 solution obtained by dissolving 1.00 g of ketoprofen (3.93 10 mol) in 39.3 ml of NaOH 0.1N (3.93 10 mol) and then 0106 Solution of diclofenac, chlorpheniramine and ben diluting with distilled water to 60 ml. After 2 h with stirring Zalkonium chloride at room temperature, there were Still undissolved transparent 0107 To 40 ml of water, add 6.3 ml of a solution obtained crystals. 15.1 ml of NaOH 0.2N (3.02 10 mol) was added, by dissolving 4 g of ammonium glycyrrhizinate pentahy and the Suspension was left, with Stirring. After 2 h the drate in 43 ml of NaOH 0.2N and make up to 50 ml with Solution was Still cloudy and contained undissolved crystals. distilled water (solution with 8% of ammonium glycyrrhiz A further 15.1 ml of NaOH 0.2N (3.02 10 mol) was added, inate pentahydrate and 7.6% of GlyNH-Na). The following and a completely clear Solution was obtained. are then added, in this order: 0108) 3.8 ml of NaOH 0.2 N, 10 ml of an aqueous EXAMPLE 13 solution of diclofenac sodium salt at 1%, 0.3 g of chlorphe niramine maleate, 2 ml of aqueous Solution of benzalkonium 0100 Solution of ketoprofen and ambroxol chloride at 0.5% and 0.76 g of sodium chloride. It was diluted to 100 ml with distilled water. The composition of 0101 Following a procedure similar to that described in the Solution was: Example 2 above, a Solution having the following compo Sition was prepared: diclofenac sodium salt 0.10 g chlorpheniramine maleate 0.30 g ketoprofen 500 mg benzalkonium chloride 0.01 g NaOH (0.2 N: 9.85 ml) 79 mg GlyNH,Na, 0.48 g ambroxol hydrochloride 360 mg NaOH (3.8 mil: 0.2N) 0.03 g GlyNH-Na (24 ml of “Gly solution') 2.0 g NaCl 0.76 g water, sufficient for: 100 ml Water, sufficient for: 100 ml

EXAMPLE 1.4 EXAMPLE 1.7 0109 Solution of diclofenac, chlorpheniramine, tetryzo 0102 Solution of ketoprofen and ambroxol line and benzalkonium chloride 0103) Following a procedure similar to that described in 0110. Following a procedure similar to that described in Example 2 above, and adding Sodium chloride at the end, a Example 16 above, a formulation was prepared with the Solution having the following composition was prepared: following composition:

ketoprofen 0.50 g diclofenac sodium salt 0.10 g NaOH (0.2 N: 9.85 ml) 79 mg chlorpheniramine maleate 0.30 g ambroxol hydrochloride 0.36 g tetryzoline hydrochloride 0.05 g GlyNH-Na (24 ml of “Gly solution') 2.0 g benzalkonium chloride 0.01 g NaCl 0.9 g GlyNH,Na, 0.41 g water, sufficient for: 100 ml NaOH (3.8 mil: 0.2N) 0.03 g NaCl 0.76 g Water, sufficient for: 100 ml

EXAMPLE 1.5 0104 Solution of ketoprofen and ambroxol (use of EXAMPLE 1.8 ambroxol base) 0111 Solution of diclofenac, chlorpheniramine and 0105 Referring to Example 13, the following are sus tetry Zoline pended in 40 ml of an aqueous Solution containing 46 mg of 0112 Following a procedure similar to that described in NaOH (5.8 ml of NaOH 0.2N):... 0.5g of ketoprofen, 0.33 Example 16 above, a formulation was prepared with the g of ambroxol base. Then 26.4 ml of “Gly solution” was following composition: US 2002/0193322 A1 Dec. 19, 2002

9. A method according to claim 7, characterized in that the therapeutically useful compound of an acidic nature is Selected from the group comprising: ketoprofen, napoxen, diclofenac sodium salt 0.10 g chlorpheniramine maleate 0.30 g ibuprofen, flubiprofen, diclofenac, Sulindac, mefenamic tetryzoline hydrochloride 0.05 g acid, flufenamic acid, aspirin, diflunisal, indometacin, GlyNH,Na, 0.40 g flunoxaprofen, ketorolac, ethacrynic acid, furosemide, NaOH (3.8 mil: 0.2N) 0.03 g lodoxamide, tranilast, 21-phosphoric and 21-hemisuccinic NaCl 0.76 g esters of corticosteroids, Sorbic acid, pirfenoXone, folic acid, Water, sufficient for: 100 ml fusidic acid, theophylline-acetic acid and bendazac. 10. A method according to claim 7, characterized in that the therapeutically useful compound of a basic nature is EXAMPLE 1.9 Selected from the group comprising antihistamines, muco 0113 Solution of diclofenac and lomefloxacin lytics, vasoconstrictors, B-blockers, antispasmodics, anti Septics, antituSSives, basic anti-inflammatory drugs, bron 0114) Taking into account the remarks made regarding chodilators, Sympathicolytics, analgesics and antibiotics. Example 5 above and following a similar procedure, a 11. A method according to claim 7, characterized in that Solution was obtained with the following composition: the therapeutically useful compound of a basic nature is Selected from the group comprising: chlorpheniramine, promethazine, azelastine, antazoline, cyproheptadine, diclofenac sodium salt 0.10 g tonzylamine, diphenydramine, emedastine, ketotifen, lomefloxacin hydrochloride 0.30 g ambroXol, bromexine, naphazoline, tetry Zoline, tramazoline, NaOH (7.8 ml 0.1 N) 31 mg timolol, carteolol, ipratropium bromide, octylonium bro GlyNH,Na, 2.53 g mide, papaverine, rociverine, toripamide, chlorhexidine, water, sufficient for: 100 ml benzalkonium chloride, benzetonium chloride, benzoXo nium chloride, dequalinium chloride, codeine, codeine ana 1. A method of forming an aqueous Solution comprising logues, oxolamine, dimenorfan, cloperastine, benzydamine, a first physiologically acceptable compound of an acidic Salbutamol, fenspiride, dapiprazole, chlorpromazine, pra nature, and a Second physiologically acceptable compound ZoSin, lomefloxacin and the like. of a basic nature which are able to give rise to a precipitate 12. A pharmacologically acceptable Solution comprising a in water, characterized in that a trisubstituted Salt of glycyr first physiologically acceptable compound of an acidic rhizic acid is added in Sufficient quantity to form a clear nature and a Second physiologically acceptable compound of Solution. a basic nature that are able to give rise to a precipitate in 2. A method according to claim 1, characterized in that the water, characterized in that it also contains a trisubstituted cation of the trisubstituted Salt of glycyrrhizic acid is Salt of glycyrrhizic acid in Sufficient quantity to form a clear Selected from the group comprising Sodium, potassium, Solution. ammonium, calcium, magnesium, monoethanolamine, 13. A pharmacologically acceptable composition com diethanolamine, triethanolamine, lysine, arginine, prising a first physiologically acceptable compound of an tromethamine and their mixtures. acidic nature and a Second physiologically acceptable com 3. A method according to claim 2, characterized in that the pound of a basic nature that are able to give rise to a triSubstituted Salt of glycyrrhizic acid is monoammonium precipitate in water, characterized in that it also contains a disodium glycyrrhizinate obtained by neutralizing commer triSubstituted Salt of glycyrrhizic acid in Sufficient quantity cial monoammonium glycyrrhizinate with a Sodium hydrox to form a clear Solution when the Said composition is added ide Solution. to Water. 4. A method according to claim 1, characterized in that a 14. A composition according to claims 12 and 13, char base is added in Sufficient quantity to ensure Salification both acterized in that the cation of the trisubstituted Salt of of the physiologically acceptable compound of an acidic glycyrrhizic acid is Selected from the group comprising nature, and of the carboxyls of the glycyrrhizic acid. Sodium, potassium, ammonium, calcium, magnesium, 5. A method according to any one of the preceding claims, monoethanolamine, diethanolamine, triethanolamine, characterized in that the physiologically acceptable com lysine, arginine, tromethamine and their mixtures. pound of an acidic nature is a carboxylic acid. 15. A composition according to claims 12 and 13, char 6. A method according to any one of the preceding claims, acterized in that the Salt of glycyrrhizic acid is disodium characterized in that the physiologically acceptable com monoammonium glycyrrhizinate obtained by neutralizing pound of a basic nature is an organic base. commercial monoammonium glycyrrhizinate with a Sodium 7. A method according to any one of the preceding claims, hydroxide solution. characterized in that both the physiologically acceptable 16. A composition according to any one of the preceding compound of an acidic nature and that of a basic nature claims from 12 to 15, characterized in that the physiologi possess a therapeutically useful pharmacological activity. cally acceptable compound of an acidic nature is a carboxy 8. A method according to claim 7, characterized in that the lic acid. therapeutically useful compound of an acidic nature is 17. A composition according to any one of the preceding Selected from the group comprising non-Steroidal anti-in claims from 12 to 15 characterized in that the physiologi flammatory drugs, diuretics, antiallergic drugs, 21-phospho cally acceptable compound of a basic nature is an organic ric and 21-hemisuccinic esters of corticosteroids, prostag base. landins, ACE inhibitors, penicillins, cephalosporins and 18. A composition according to any one of the preceding fluoroquinolones. claims from 12 to 17, characterized in that both the physi US 2002/0193322 A1 Dec. 19, 2002 ologically acceptable compound of an acidic nature and that Selected from the group comprising antihistamines, muco of a basic nature possess a therapeutically useful pharma lytics, vasoconstrictors, B-blockers, antispasmodics, anti cological activity. Septics, antituSSives, basic anti-inflammatory drugs, bron 19. A composition according to claim 18, characterized in chodilators, Sympathicolytics, analgesics and antibiotics. that the therapeutically useful compound of an acidic nature is Selected from the group comprising non-Steroidal anti 22. A composition according to claim 18, characterized in inflammatory drugs, diuretics, anti-allergic drugs, 21-phos that the therapeutically useful compound of a basic nature is phoric and 21-hemisuccinic esters of corticosteroids, proS Selected from the group comprising: chlorpheniramine, taglandins, ACE inhibitors, penicillins, cephalosporins and promethazine, azelastine, antazoline, cyproheptadine, fluoroquinolones. tonzylamine, diphenydramine, emedastine, ketotifen, 20. A composition according to claim 18, characterized in ambroXol, bromexine, naphazoline, tetry Zoline, tramazoline, that the therapeutically useful compound of an acidic nature timolol, carteolol, ipratropium bromide, octylonium bro is Selected from the group comprising: ketoprofen, napoxen, mide, papaverine, rociverine, toripamide, chlorhexidine, ibuprofen, flurbiprofen, diclofenac, Sulindac, mefenamic acid, flufenamic acid, aspirin, diflunisal, indometacin, benzalkonium chloride, benzetonium chloride, benzoXo flunoxaprofen, ketorolac, ethacrynic acid, furosemide, nium chloride, dequalinium chloride, codeine, codeine ana lodoxamide, tranilast, 21-phosphoric and 21-hemisuccinic logues, oxolamine, dimenorfan, cloperastine, benzydamine, esters of corticosteroids, Sorbic acid, pirfenoXone, folic acid, Salbutamol, fenspiride, dapiprazole, chlorpromazine, pra fusidic acid, theophylline-acetic acid and bendazac. ZoSin, lomefloxacin and the like. 21. A composition according to claim 18, characterized in that the therapeutically useful compound of a basic nature is