Chlorhexidine is the international common accepted name for N,N-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide (also known as 1,6-di(4″-chlorophenyldiguanido)hexane), and has an empirical formula of C22H30Cl2N10, a molecular weight of 505.45 g/mol, and a chemical structure of formula (I):

Chlorhexidine is a well-known topical antiseptic and disinfectant that has been used for more than 30 years. Products comprising chlorhexidine are used for a number of applications such as, for example, daily hygiene application, oral antiseptic applications, hand and skin disinfection, and general disinfection (e.g., equipment, surfaces and textiles). Chlorhexidine is a highly active bactericidal agent having a broad activity with low levels of toxicity and strong skin binding properties. Chlorhexidine is primarily bactericidal against gram-positive and gram-negative bacteria, and its activity extends to yeasts, including Candida albicans. The bactericidal activity of chlorhexidine differs from that observed with povidone-iodine or 70% isopropyl alcohol. For example, chlorhexidine has demonstrated an immediate bactericidal effect as well as a cumulative effect that persists for hours and even days after it is applied, and unlike iodophors, the germicidal activity of chlorhexidine has shown statistically significant efficacy in reducing bacterial counts in the presence of blood and other protein-rich biomaterials.
Chlorhexidine is often applied preoperatively to disinfect materials and surfaces or skin of a patient prior to surgery. An important consideration for the user is the appearance of a chlorhexidine solution. For example, upon visual inspection, the user needs to be able to determine that a) the antiseptic solution has been applied, and b) where the antiseptic solution has been applied. However, chlorhexidine by itself forms clear, colorless solutions which makes it difficult for the user to make such a determination. Thus, it is desirable to use colored chlorhexidine solutions.
Numerous problems are encountered when color additives (e.g., tints or dyes) are added to an antiseptic solution of chlorhexidine in amount sufficient to stain a patient's skin or surgical field before surgery. The tint or dye can react with chlorhexidine to form a precipitate, which can lead to non-uniform distribution of the colored antiseptic solution upon its application. In addition, the coloring additive can react with chlorhexidine to form impurities thereby partially inactivating the chlorhexidine solution and increasing the impurity profile of the antiseptic solution. In addition, the chemical stability of the product is lessened resulting in a shortened shelf life.
The development of colored solutions of chlorhexidine, with a sufficient shelf life has proven to be difficult. Moreover, the development of colored solutions of chlorhexidine, advantageously prepared by efficient formulation processes has proved problematic.
U.S. 2004/0179889 (“the '889 publication”) acknowledges the problems associated with colored chlorhexidine solutions. The '889 publication purportedly describes that the problems can be alleviated by using a specific, specialized applicator for applying chlorhexidine solution. The disclosed applicator comprises at least one ampoule formed of a frangible material and adapted to contain liquid to be applied; at least one hollow body defining an internal chamber adapted to receive at least one ampoule; and at least one porous element that contains colorant, wherein the porous element is positioned such that liquid flows through the porous element when at least one ampoule is fractured and colorant is transferred to the liquid to be applied.
The use of specific applicators to administer antiseptic solution or to reconstitute the solution prior to its use, is inconvenient and is not feasible for some applications.
WO 2007/130981 (“the '981 publication”) supposedly discloses a solution of chlorhexidine together with cationic dye in an amount sufficient to stain patient's skin. It is believed that since chlorhexidine pharmaceutically acceptable salts are cationic compounds, they are compatible with other cationic and non ionic substances, but are chemically incompatible with anionic compounds.
The use of cationic dyes, as well as products comprising cationic dyes, can pose a health hazard. Numerous disadvantages are related to using cationic dyes in antiseptic formulations, including adverse toxicological and carcinogenic effects. Reports of hypersensitivity and hyperkinetic activity, especially among children, add to concerns over the safety of using cationic dyes in products.
Moreover, the '981 publication describes that an anionic dye may be used provided that the antiseptic solution also comprises a cationic excipient. The '981 publication also describes that anionic dyes, including FD&C dyes, form a precipitate with chlorhexidine, even at very low concentrations. The precipitate forms as an insoluble salt of a chlorhexidine cation and at least one dye anion. As such, adding an anionic dye alone to an aqueous chlorhexidine solution removes a significant fraction of the chlorhexidine from solution, thereby decreasing the efficacy of the solution.
WO 2007/130982 (“the '982 publication”) attempts to solve the above described problems by providing solutions of chlorhexidine together with an anionic dye and a cationic excipient (e.g., cationic detergents, surfactants or excipients containing quaternary nitrogen. The '982 publication describes the use of a cationic excipient together with an anionic excipient is essential and that as the negative charge of an anionic dye is “hidden” from the chlorhexidine by a cationic excipient, the chlorhexidine-dye salt will not immediately form.
However, using additional excipients in antiseptic solution, especially cationic excipients may cause dangerous adverse affects related with allergies, intolerance and/or irritation.
In addition, according to the Summary of Product Characteristics for CHLORAPREP® 2% (w/v)/70% (v/v) cutaneous solution, chlorhexidine is incompatible with anionic agents (e.g., http://www.medicines.org.uk/emc/medicine/22302/SPC/chloraprep/).
The disclosure of each of the '889 publication, the '981 publication, the '982 publication, and the Summary of Product Characteristics for CHLORAPREP® are incorporated herein by reference.
In view of the foregoing, there is a need to provide colored antiseptic solutions comprising chlorhexidine which are safe, have improved properties and good chemical stability. There is also a need for colored antiseptic chlorhexidine solutions which can be prepared by efficient formulation processes.