Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-26
2003-12-09
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06660743
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a therapeutic aqueous composition containing an hexahydro-5-pyrimidinamine compound and a polyalkoxylated fatty alcohol, together with a salification compound. The therapeutic composition has antimicrobial and/or antiseptic efficacy and may take the form of either an oral topical or non-oral topical composition.
2. Description of the Related Art
Hexahydro-5-pyrimidinamine compounds (5-amino-hexahydro-pyrimidine), such as hexetidine (1,3-bis(2-ethylhexyl) hexahydro-5-methyl-5-pyrimidinamine), are well known in the art for their broad spectrum antimicrobial activity and their antiseptic activity. These hexahydro-5-pyrimidinamine compounds are used in aqueous-based compositions for topical application to treat skin and body cavity infections. For example, these antimicrobial and/or antiseptic compositions are used in the treatment of oral infections such as gingivitis, sore throat, oral ulcers, periodontal disease, and for the control of mouth odor, and in the treatment of other topical infections such as cervical vaginal infections, ear infections, nasal pharyngitis, and epidermal phytoses.
Hexetidine, however, has long been known to lack stability. The hexahydro-5-pyrimidinamine ring system in hexetidine can be cleaved thermally and hydrolytically to produce the open-chain compound triamine and the condensed bicyclic heterocycle hexedine, see G. Satzinger et al.,
Analytical Profiles of Drug Substances
, 7, pp. 277-295, Academic Press, 1978. Therefore, the stability of hexetidine is uncertain.
WO-A-9209283 discloses that the stability of hexetidine compositions has been improved through the use of aqueous buffer solutions in conjunction with an anionic surfactant. Examples of these surfactants include POE sorbitan fatty acid esters (e.g. of the Tween® series) and POE castor oil derivatives. These compositions however suffer from some drawbacks. The solubilization of hexetidine is achieved thanks to the surfactant, but high amounts of surfactant may inhibit the antimicrobial activity of hexetidine. Also, the stability is still not sufficient for all intended applications.
U.S. Pat. No. 4,206,198 discloses a dentifrice composition which contains a foam producing amount of a nonionic surfactant and hexetidine. The nonionic surfactant is an ethoxylated adduct of a C-15 or C-16 fatty alcohol. These compositions however do not contain a major proportion of water and do not contain the hexetidine compound under a solubilized form (i.e. as salt form). The ethoxylated adduct of a C-15 or C-16 fatty alcohol would thus not appear as a useful candidate for solubilizing hexetidine in aqueous compositions, notably in compositions to be administrated per os.
It would be advantageous to further enhance both the solubility and the stability of hexetidine in aqueous compositions.
SUMMARY OF THE INVENTION
This invention is directed to a therapeutic aqueous composition comprising:
(i) a therapeutically effective amount of a hexahydro-5-pyrimidinamine compound, preferably hexetidine;
(ii) a salification acidic compound; and
(iii) a polyalkoxylated fatty alcohol.
The compositions of this invention are advantageously stable compositions that provide antimicrobial and/or antiseptic efficacy.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to the discovery that hexahydro-5-pyrimidinamine compounds can be solubilized thanks to the combined effect of:
(i) salification using an acidic compound;
(ii) micelles formation using polyalkoxylated fatty alcohol as a surfactant;
(iii) solvatation using an ol, if needed.
In the following, unless otherwise stated, all percentages are expressed in weight by volume (w/v) of the composition.
Hexahydro-5-pyrimidinamine Compounds
The hexahydro-5-pyrimidinamine compounds employed in this invention have antimicrobial and/or antiseptic efficacy. Any non-toxic hexahydro-5-pyrimidinamine compound may be employed. Suitable non-toxic therapeutically effective hexahydro-5-pyrimidinamine compounds are disclosed in U.S. Pat. No. 837,463 and U.S. Pat. No. 4,141,968, the disclosures of which are incorporated by reference herein. The hexahydro-5-pyrimidinamine compounds are either commercially available or may be readily prepared by one of ordinary skill in the art. The preferred antimicrobial and/or antiseptic hexahydro-5-pyrimidinamine compound is hexetidine (1,3-bis(2-ethylhexyl) hexahydro-5-methyl-5-pyrimidinamine).
Hexetidine has an unusual affinity for tissue. When applied topically, hexetidine adheres to tissue and is not eliminated prematurely from the site of action either physiologically or by pathological secretions. Hexetidine has a broad antibacterial spectrum which makes it very useful in preparations for topical application to skin and body cavity infections.
A therapeutically effective amount of an antimicrobial and/or antiseptic hexahydro-5-pyrimidinamine compound is present in the therapeutic composition of this invention. In a preferred embodiment, the hexahydro-5-pyrimidinamine compound is present in the therapeutic composition in an amount from about 0.025% to about 2.0%, preferably from about 0.05% to about 0.3%.
In the following, the description will be given with hexetidine as an exemplary compound of hexahydro-5-pyrimidinamine compounds, but it shall be understood that the following description applies mutatis mutandis to any of these hexahydro-5-pyrimidinamine compounds.
Polyalkoxylated Fatty Alcohol
The surfactant used in the present invention is a polyalkoxylated fatty alcohol. This type of surfactant is well-known in the art and is the adduct of alkyleneoxide (AO) with a fatty alcohol.
One polyalkoxylated fatty alcohol useful in the present invention can be represented by the formula:
R—(OA)
n
—OH (I)
where:
R is an alkyl radical corresponding to the fatty alcohol and may comprise from 10 to 24 carbon atoms, preferably from 12 to 18 carbon atoms;
A is an alkylene radical comprising from 2 to 4 carbon atoms, preferably 2 carbon atoms, such that the individual OA units may be the same or different, preferably the same, and where the OA units may be present as a block proximate to the radical R or randomly distributed through the length of the chain;
n is comprised between 2 and 100, preferably between 10 and 40.
Preferred polyalkoxylated fatty alcohols, notably those of formula (I) above, are those which are saturated.
Examples of fatty alcohols include lauryl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, myristyl alcohol; the preferred alcohol is lauryl alcohol.
Preferred surfactants, notably those of formula (I) above, are those having a high HLB value, such as an HLB value greater than 15.
The amount of surfactant used in the composition can vary within broad limits; it should be noted that the amount of surfactant that is used in not limited by the influence on the therapeutic properties of hexetidine, as would be in the case of Tween®. The surfactant is used in an amount sufficient to solubilize therapeutically effective amounts of hexetidine. In general, the surfactant will be present in the composition of the invention in an amount from about 0.005% to about 5%, preferably from about 0.08% to about 2%.
Salification Acidic Compound
The salification acidic compound used in the compositions of the invention serves for forming a (partial) salt of hexetidine and thus serves for solubilizing the hexetidine compound, inasmuch as the acidic component will salify the hexetidine and will form a salt, which is more readily solubilized thanks to the surfactant of the invention. The salification compound originates from an acid, which can be either organic or mineral.
Any acidic compound can be used, such as citric acid, phosphoric acid, hydrochloric acid, tartaric acid, acetic acid, propionic acid, pyruvic acid, aspartic acid, glycolic acid, and the like can be used. Preferred acids are the citric acid, phosphoric acid and hydrochloric acid, while citric acid is the most preferred acid.
The amount of salification acidic component is such that
Cances Joël
Munerot Jacques
Delacroix-Muirheid C.
Federman Evan J.
Jones Dwayne C.
Little Darryl C.
Warner-Lambert & Company
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