Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-01-29
2004-03-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S035000
Reexamination Certificate
active
06699841
ABSTRACT:
This application is based on application No. RM2001 A 000048 filed in Italy, the content of which is incorporated hereinto by reference.
The present invention relates to a method of preparing physiologically acceptable aqueous solutions and water-soluble compositions suitable for obtaining them, as well as the solutions and the compositions thus obtained.
More particularly, the present invention relates to physiologically acceptable aqueous solutions and water-soluble compositions suitable for obtaining them, comprising a first physiologically acceptable compound of an acidic nature, a second physiologically acceptable compound of a basic nature and a trisubstituted salt of glycyrrhizic acid.
BACKGROUND OF THE INVENTION
In therapeutic and cosmetic practice, both human and veterinary, use is often made of aqueous solutions containing a carboxylic acid or an organic base, possessing low intrinsic solubility (solubility of the undissociated compound). Their salification (generally with alkali metals or hydrophilic amines of low molecular weight for the acids, and with hydrogen halides or hydrophilic organic acids of low molecular weight, for the bases) is employed to provide them with adequate solubility.
Sometimes it is useful to have aqueous solutions containing at least one carboxylic acid and at least one organic base at the same time. Since solutions with basic pH are needed for the solubilization of weak organic acids, and solutions with acid pH are needed for the solubilization of weak organic bases, such compounds often display a high degree of incompatibility in ordinary aqueous solutions because mutual precipitation occurs on mixing them (see A. T. Florence & D. Attwood “Physiochemical Principles of Pharmacy”, II edition, Portland Oreg., 1988, p. 154).
Examples of this behaviour that are well known in the literature are the solutions of acetylsalicylic acid (lysine salt) with chlorpromazine (hydrochloride) or promethazine (hydrochloride) (Repertorio Farmaceutico Italiano 1989 (REFI) page A-578); solutions of furosemide (sodium salt) with organic bases (REFI, page A-808); solutions of dimemorfan (phosphate) with penicillin (sodium salt) or of sodium salicylate (REFI page A-646).
It should be noted, moreover, that the phenomenon is rather more complex than might appear at first sight because, depending on circumstances, there may be precipitation of the acid compound, or of the basic compound, or of a mixture of the two, or of adducts, known as hydrophobic ion pairs. In this last case, which is very common, there may be formation of precipitates, even when one of the two components, for example quaternary ammonium compounds, has good intrinsic solubility.
The incompatibility is more or less pronounced depending on the pK, on the nature and on the intrinsic solubility of the components that determine it. In fact, cases of absolute incompatibility are encountered in practice, in which it is practically impossible to obtain solutions containing the two pharmacologically active compounds at any therapeutically useful concentration, and cases of partial incompatibility in which it is possible to obtain solutions but only in a very restricted range of concentration.
The problem of incompatibility is not solved by separate administration of the solutions of the different pharmacologically active compounds to the patient, unless there is a considerable interval of space and/or time between the applications. Otherwise, in fact, incompatibility between the two pharmacologically active compounds and inactivation occur at the site of actual application (see, for example, the case of cephalosporins and of aminoglycosides (REFI page A-249)). In each case separate application, besides being inconvenient, proves completely impossible in some cases, for example when one of the compounds performs the functions of a preservative.
STATE OF THE ART
In some cases the problem has been solved by using specific pharmaceutical formulations. Thus, the incompatibility between certain carboxylic acids and certain basic decongestants is eliminated by means of a mixture of polysorbates and a polyoxamer (U.S. Pat. No. 5,459,157). Moreover, it should be pointed out that in this case, as in other similar cases, the concentration of these additives is very high (12%) relative to that of the pharmacologically active compounds (0.05-0.1%).
Glycyrrhizic acid, the principal component of the extract of
Glycyrrhiza Glabra,
was isolated by Karrer and Chao and its tricarboxylic acid structure was established by Ruzicka in 1943 (Merck Index, XII ed., 4515). Two epimers of glycyrrhizic acid are known, designated 18&agr; and 18&bgr;, but the second is the commonest and it is this that is being referred to whenever the nature of the epimer is not expressly indicated (Runti, Fondamenti di chimica farmaceutica [Fundamentals of pharmaceutical chemistry], Trieste 1969, Vol. III, page 265).
Various salts of glycyrrhizic acid, called glycyrrhizinates, have been described in the literature.
A typical, commercially available monosubstituted salt is the monoammonium salt “Glycamil™” of the company Indena of Milan. Typical disubstituted salts are the dipotassium salt, “Ritamectant K2™” of the R.I.T.A. Corporation, and the mixed salts of potassium, calcium and magnesium called “glycyrrhizines” (U.S. Pat. No. 4,176,228). A typical trisubstituted salt is the tripotassium salt (Voss et al., Ber. 70, 122, 1937).
The monosubstituted and disubstituted salts are widely used in the food and pharmaceutical industry, principally as sweeteners.
Apart from some mild therapeutic activities that have been under investigation for several years (antiulcer activity, anti-AIDS activity, treatment of hepatitis B), certain functions of glycyrrhizic acid and its salts as “adjuvants” in pharmaceutical formulations have also been described from time to time.
The action of “enhancers” of absorption through the skin and the mucous membranes is well documented (U.S. Pat. Nos. 5,183,802; 5,238,917; JP 3099023).
Japanese patent JP 10025255 proposes the use of glycyrrhizic acid, its salts or its esters, for the preparation of solid complexes with antiulcer, anti-inflammatory or antihistaminic drugs for the purpose of improving their absorption (rate of solution). It is known, however, that the complexes that can be used for increasing the rate of solution cannot be used for increasing equilibrium solubility (A. J. Repta in “Technique of Solubilation of Drugs” (S. H. Yalkowsky ed. Marcel Dekker N.Y. 1981 page 135 ff.; pages 149 and 151).
In two Japanese patent documents (Jpn Kokai 0283,318 and JP 3145432A) reference is made to clear solutions containing salts of glycyrrhizic acid, quaternary ammonium compounds and respectively, sodium condoitrinsulphate, borax and taurine in the first case, and lysozime (hydrochloride) in the second. In the first case (C.A. 113, 65296x) the salt used is dipotassium glycyrrhizinate.
U.S. Pat. No. 4,481,187 discloses the use of glycyrrhizic acid or its salts for solubilizing oily substances in water, such as oil-soluble hormones and perfumes.
JP 09 087201 discloses a liquid composition containing acetaminophenone, a saccaride, a salt of glycyrrhizic acid and a glycol. Acetaminophenone, however, is neither acid nor basic in nature. Indeed, it is neutral.
In patents relating to the use of glycyrrhizic acid, generally reference is made to its salts, without differentiating them. However, monosubstituted and disubstituted salts are normally used in the examples given in these documents. Just occasionally, as in U.S. Pat. No. 4,278,657, which proposes the use of glycyrrhizic acid and its salts in synergy with certain polysaccharides as emulsifiers of water and oil mixtures, examples with trisubstituted salts are also given. However, neither this nor other patents describe or claim that the trisubstituted salts have any property at all that is different from the mono- and disubstituted salts.
BRIEF DESCRIPTION OF THE INVENTION
It has now been found, unexpectedly, that the compositions comprising the salt of a first phys
Baiocchi Leandro
De Gregorio Mauro
Raymond Richard L.
Tucker Zachary C.
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