Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Elemental chlorine or elemental chlorine releasing inorganic...
Reexamination Certificate
1999-12-13
2002-12-31
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Elemental chlorine or elemental chlorine releasing inorganic...
C424S400000, C514S557000
Reexamination Certificate
active
06500466
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
This application is based on German Application DE 198 57151.8, filed Dec. 11, 1998, which disclosure is incorporated herein by reference.
FIELD OF THE INVENTION
The invention provides formulations which contain chlorhexidine base which can be converted into aqueous solutions of chlorhexidine salts. The invention is also directed to these solutions and the new chlorhexidine salts on which they are based. The formulations, solutions and salts can be used as disinfectants and to prepare disinfectants.
BACKGROUND OF THE INVENTION
Chlorhexidine, the formal chemical name for which is 1,1′-hexamethylene-bis-[5,4-chlorophenyl]-biguanide, is a strongly basic substance with a very low solubility in water. Sparingly water-soluble salts are produced by reacting the chlorhexidine base with a number of acids. Chlorhexidine base and, in particular, its water-soluble salt with D(+)-gluconic acid [CAS-No. 526-95-4] are important antibacterial substances and are used in both the human and animal sectors. The low toxicity and general compatibility with cationic and anionic detergents must be stressed. Chlorhexidine digluconate is provided as a 20% aqueous solution and is currently the only commercially available water-soluble form of the base. Liquid formulations of chlorhexidine digluconate (CHD-gluconate) are modified in many different ways and are used as antibacterial additives in cosmetics, skin disinfectants and for the treatment of wounds in veterinary medicine, as an udder disinfectant and also for disinfecting surfaces.
The composition and appearance of gluconate solutions are subject to the requirements of the European Pharmacopoeia and the American Pharmacopoeia. One of the purity requirements is a concentration of p-chloroaniline limited to 500 ppm. In a reaction which is the reverse of forming the chlorhexidine base from hexamethylenebicyanoguanidine and p-chloroaniline, p-chloroaniline can be reversibly eliminated from these solutions on dissolving the base in D(+) glucono-6-lactone, the internal ester of D(+)-gluconic acid, wherein the solutions discolor and become increasingly yellow to brown. Decomposition of chlorhexidine solutions depends on the pH of the solution and in particular on the storage temperature. Tests show (FIG.
1
), that the permissible p-chloroaniline values are exceeded after about one month when stored at a constant temperature of 40° C. Solutions of CHD-gluconate which are stable over the long-term have not hitherto been disclosed. The use of these solutions in regions with a tropical climate is therefore a problem which has not hitherto been resolved satisfactorily. Therefore, there is a need for chlorhexidine salt solutions which tend to decompose to only a small extent when used under extreme climatic conditions, in particular at high temperatures. Unfortunately, almost all the salts of chlorhexidine are sparingly soluble in water or cannot be used as human or veterinary disinfectants due to the toxicological properties of the anion. For example, the salts of chlorhexidine with hydrogen chloride, fluorophosphoric acid, bishydroxymethylpropionic acid, acetylsalicylic acid, tartaric acid, 4-hydroxybenzoic acid, 5-sulfosalicylic acid, glyoxalic acid, thioctic acid, L-malic acid, sulfanilic acid, nicotinic acid, sarcosine, L(+)-glutaminic acid, citric acid, nitrilotriacetic acid, trimethylolacetic acid, sorbic acid and many more, are sparingly soluble in water.
Although 20% aqueous solutions can be obtained with amidosulfuric acid, captopril, laevulinic acid, N-acetylglycine and S-(−)-pyrolidinone-5-carboxylic acid, these can spontaneously crystallize during inoculation or after standing for a long time. Although chlorhexidine ascorbate is very soluble in water, it is more light sensitive and more unstable than the gluconate.
SUMMARY OF THE INVENTION
Accordingly, the object of the invention is to provide storage-stable formulations which contain chlorhexidine in a water-soluble form. The formulation should be easy to prepare and should be able to be converted into aqueous chlorhexidine salt solutions. In addition, the acids required for salt production should be toxicologically harmless.
It has now been found that salts of chlorhexidine which are very soluble in water can be prepared by reacting the chlorhexidine base with the following acids or the acid lactones thereof:
Lactobionic acid (I) [CAS-No. 96-82-2], D-galactone-&ggr;-lactone (II) [CAS-No. 2782-07-2], L-mannono-&ggr;-lactone (Ill) [CAS-No. 22430-23-5], D-(−)-gulono-&ggr;-lactone (IV) [CAS-No. 6322-07-2], D-(+)-galacturonic acid (V) [CAS-No. 91510-62-2] and &agr;-D-heptaglucono-&ggr;-lactone (VI) [CAS-No. 60046-25-5].
Furthermore, it was found that powdered mixtures of the chlorhexidine base with selected sugar acids or lactones thereof in accordance with the formulae (I) to (VI) and with gluconic acid or gluconolactone are substantially more stable than the readily accessible aqueous solutions of chlorhexidine salts obtained from the mixtures by dissolving in water.
The invention also provides an aqueous solution of a chlorhexidine salt with a concentration of at least 0.01 wt. %, which is characterized in that the chlorhexidine salt is selected from the set of salts of chlorhexidine with lactobionic acid (I), D-galactonic acid (II′), L-mannonic acid (III′), D-(−)-gulonic acid (IV′), D-(+)-galacturonic acid (V) and &agr;-D-heptagluconic acid (VI′). The concentration of chlorhexidine salt is generally in the range 0.01 to 30 wt. %, in particular 1 to 20 wt. %.
Furthermore, the invention also provides new water-soluble chlorhexidine salts, characterized by the acid anion of a sugar acid from the set lactobionic acid (I), D-(+)-galacturonic acid (V), D-galactonic acid (II′), L-mannonic acid (III′), gulonic acid (IV) and &agr;-D-heptagluconic acid (VI′).
Storage trials using salt solutions according to the invention have shown that their storage stabilities are comparable to that of chlorhexidine gluconate solutions. The problem of long-term p-chloroaniline production cannot be solved by the invention of new anions. Surprisingly, however, powdered formulations according to the invention are very storage-stable; see FIGS.
1
and
2
.
REFERENCES:
patent: 5565487 (1996-10-01), Yu et al.
patent: 6051609 (2000-04-01), Yu et al.
patent: 0 181 161 (1986-05-01), None
patent: 0 200 607 (1986-11-01), None
patent: 2 752 731 (1998-03-01), None
patent: WO 90/10434 (1990-09-01), None
patent: WO 98/46217 (1998-10-01), None
Jørgensen Judith N.
Merz Friedhelm
Trageser Martin
Werle Peter
Degussa - AG
Di Nola-Baron Liliana
Page Thurman K.
Pillsbury & Winthrop LLP
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