Bis-amido polybiguanides and the use thereof to disinfect...

Details Bis-amido polybiguanides and the use thereof to disinfect... Bis-amido polybiguanides and the use thereof to disinfect...

2000-09-19

2001-11-13

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S155000, C564S182000, C564S189000, C564S190000, C564S191000, C564S236000, C528S422000, C514S616000, C514S839000, C514S840000, C424S429000, C424S464000, C422S001000, C422S028000, C523S122000, C523S169000, C524S612000

Reexamination Certificate

active

06316669

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is directed to new polymeric biguanides having potent antimicrobial activity and little, if any, toxicity relative to human tissues. The amidopolybiguanides disclosed herein have many industrial applications, but are especially useful as antimicrobial preservatives in pharmaceutical compositions. The invention is particularly directed to the use of these compounds in compositions and methods for disinfecting contact lenses, and to the preservation of various types of ophthalmic products.
Contact lenses are exposed to a broad spectrum of microbes during normal wear and become soiled relatively quickly. Routine cleaning and disinfecting of the lenses are therefore required. Although the frequency of cleaning and disinfecting may vary somewhat among different types of lenses and lens care regiments, daily cleaning and disinfecting is normally required. Failure to clean and disinfect the lens properly can lead to a multitude of problems ranging from mere discomfort when the lenses are being worn to serious ocular infections. Ocular infections caused by particularly virulent microbes, such as Pseudomonas aeruginosa, can lead to loss of the infected eye(s) if left untreated, or if allowed to reach an advanced stage before treatment is initiated. It is therefore extremely important that patients disinfect their contact lenses in accordance with the regimen prescribed by their optometrist or ophthalmologist.
Unfortunately, patients frequently fail to follow the prescribed regimens. Many patients find regimens to be difficult to understand and/or complicated, and as a result do not comply with one or more aspects of the regimen. Other patients may have a negative experience with the regimen, such as ocular discomfort attributable to the disinfecting agent, and as a result do not routinely disinfect their lenses or otherwise stray from the prescribed regimen. In either case, the risk of ocular infections is exacerbated.
Despite the availability of various types of contact lens disinfecting systems, such as heat, hydrogen peroxide, and other chemical agents, there continues to be a need for improved systems which: 1) are simple to use, 2) have potent antimicrobial activity, and 3) are nontoxic (i.e., do not cause ocular irritation as the result of binding to the lens material). Conventional contact lens cleaners with potent antimicrobial activity also have rather high toxicity. There is, therefore, a particular need in the fields of contact lens disinfection and ophthalmic composition preservation for safe and effective chemical agents with high antimicrobial activity and low toxicity.
The use of polymeric biguanide compounds as disinfecting agents is well known. Commercially available polybiguanides are hexamethylene biguanide polymers that have end groups consisting of a cyanoguanidine group and an amino group, respectively. The widely-used polybiguanide Cosmocil CQ (polyhexamethylene biguanide or “PHMB”) has strong antimicrobial activity, but rather high toxicity. A principal objective of the present invention is to provide polymeric biguanides that preserve antimicrobial activity comparable to PHMB, but are less toxic to human tissue than PHMB. As explained below, this objective has been achieved by means of a unique modification of the terminal amino groups of PHMB.
The present invention is directed to satisfaction of the above-cited needs and objectives.
SUMMARY OF THE INVENTION
The present invention is directed to polybiguanides having an amido moiety at the terminal groups. These compounds have antimicrobial activity comparable to PHMB, but are generally less toxic than PHMB. The invention is also directed to contact lens disinfecting compositions which contain the subject compounds, and to various ophthalmic compositions (e.g., pharmaceuticals, artificial tears, and comfort drops) and other types of pharmaceutical compositions that contain the compounds for purposes of preserving the compositions against microbial contamination.
The modification of the bis-amino moieties of known polybiguanides to bis-amido moieties containing the substituents described herein results in good antimicrobial activity and lowered toxicity over prior art compounds. Also, the addition of specified substituents to the PHMB polymer changes its physicochemical and biochemical properties to afford a compound whose toxicity profile is lower than that of PHMB, yet maintains the antimicrobial activity of PHMB.
As discussed above, Cosmocil CQ is a widely-used, commercially available polyhexamethylene biguanide (“PHMB”) disinfectant containing one terminal amino group. PHMB has strong antimicrobial activity, but rather high toxicity. A key difference between the compounds of the present invention and conventional PHMB is the modification of the two terminal amino groups of PHMB to form bis-amido groups. This modification has resulted in the production of a new class of compounds having properties that are superior to those of PHMB. This invention also involves a modification of the PHMB polymer to include other substituents that change its physical, chemical, and is biochemical properties to provide compounds whose toxicity profiles are lower than that of PHMB, while still maintaining the potent antimicrobial activity of PHMB.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The compounds of the present invention are polybiguanides in which the terminal groups are amido moieties. The compounds have the following formula:
RC(═O)NH—X—[NHC(═NH)NHC(═NH)NH—X—]
n
NHC(═O)R  (I)
wherein:
n is a whole number in the range of 1 to 100;
X is saturated or unsaturated alkyl, cycloalkyl, alkyl substituted with cycloalkyl, aryl, or aralkyl, with the proviso that the X groups contain 1 to 40 carbon atoms (C
1
to C
40
) and are unsubstituted or substituted with any number of N, O, S, P, B, F, Cl, Br, or I; and
R is a saturated or unsaturated alkyl (C1 to C50), cycloalkyl (C3 to C50), alkyl substituted with cycloalkyl, polyethylene oxide having a molecular weight of 50 to 10,000 (M.W. 50-10,000), polypropylene oxide having a molecular weight of 50 to 10,000 (M.W. 50-10,000), any combination of the above groups, unsubstituted aralkyl, aralkyl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, unsubstituted aryl, or aryl substituted with any number of N, O, S, P, B, F, Cl, Br, or I.
The R substituents in compounds of formual (I) optionally include amide, urea or other covalent linking functional groups.
As utilized herein, the term “alkyl” includes straight or branched chain hydrocarbon groups. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxyl.
The preferred compounds are those wherein n is 4 to 16, X is alkyl or aralkyl, and R is polyethylene oxide (M.W. 100 to 2,000) or polyethylene oxide (M.W. 100 to 2,000) alkyl ether are preferred. The following compounds are particularly preferred:
Compound
n
X
R
A
10
hexamethylene
C
13
H
27
alkyl chain
B
18
hexamethylene
polyethylene oxide (M.W. 550)
succinimidyl methyl ether
C
13
hexamethylene
C
12
H
25
(OCH
2
CH
2
)
10
NHC(═O)CH
2
CH2
3
(RLM-100)
Compound B above is the most preferred.
The synthesis of the bis-amido polybiguanide compounds of formula (I) is illustrated by Scheme 1 below:
wherein n, X and R are as defined above.
The synethesis is carried out by reacting a diamine (II) of the formula NH
2
—X—NH
2
with sodium dicyanamide to yield a cyanoguanidine (III) of the formula
NCNHC(═NH)NH—X—NHC(═NH)NHCN.
The resulting cyanoguanidine is reacted with the same diamine (II) to yield a bis-amino polybiguanide (IV) of the formula:
NH
2
—[X—NHC(═NH)NHC(═NH)NH]n—X—NH
2
.
The bis-amido polybiguanide (I) is obtained by reacting the bis-amino polybiguanide (IV) with an activated ester (V) of the formula:
RC(═O)ONHS,
wherein NHS may be N-hydroxysuccinimide or another activating group.
The general synthesis of the bis-amino polybiguanide (IV) is performed by reacting an &agr;,&ohgr;-diamino 2HCl compound (II) with so

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