Compositions comprising nitrofurantoin and uva ursi

Details Compositions comprising nitrofurantoin and uva ursi Compositions comprising nitrofurantoin and uva ursi

2002-05-07

2003-02-18

Lankford, Jr., Leon B. (Department: 1651)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

C514S579000

Reexamination Certificate

active

06521270

ABSTRACT:

TECHNICAL FIELD
The present invention relates to compositions and kits useful in treating infectious disorders.
BACKGROUND
Urinary tract infections (UTI) are a serious health problem affecting millions of people each year. UTI infections account for about 10 million doctor visits in the United States alone, with only respiratory infections occurring more often. Many remedies are taught for the treatment of UTI.
In particular, nitrofurantoin is a well-known antibacterial compound and has been used extensively as an active ingredient in antibacterial pharmaceutical compositions. Nitrofurantoin has been used successfully for many years for the treatment of UTI. Its presumed mode of action is based upon its interference with several bacterial enzyme systems. However, the development of antibiotic resistant strains of microbes continues to be problematic, thereby diminishing the effectiveness of many antibiotics.
Herbal remedies have also been used for the treatment of UTI. In particular,
Arctostaplzylos uva
-
ursi
, also known as bearberry, has been used as a urinary antiseptic. Indeed, teas and extracts of the leaves have been used as urinary tract antiseptic for centuries. The leaves of
uva ursi
contain hydroquinone derivates, mainly arbutin and methyl-arbutin. Upon consumption, arbutin is hydrolyzed in gastric fluid to hydroquinone. In alkaline urine, hydroquinone is mildly astringent and is an effective antimicrobial agent. It has been suggested that arbutin itself may contribute to the antiseptic activity of
uva ursi
. Despite this activity, in practice, large amounts of
uva ursi
must be consumed for any significant effect to occur and the urine must be alkalinized.
For the foregoing reasons, there is a continuing need to find more effective ways to treat UTI. Furthermore, there is a continuing need to find more effective ways to enhance the efficacy of existing antimicrobial compounds such as nitrofurantoin against UTI-causing microbes, particularly those resistant strains.
SUMMARY OF THE INVENTION
The present invention provides a composition comprising a safe and effective amount of nitrofurantoin and
uva ursi
. The invention further provides for a kit comprising (a) nitrofurantoin in a unit dose form; (b)
uva ursi
in a unit dose form; and (c) a package containing components (a) and (b). The administration of a composition or a unit dose form of a kit of the present invention to a subject in need thereof, is effective for the prevention and treatment of infectious disorders such as UTI, acute cystitis, and pyelonephritis. The invention is also effective for treating upper-gastrointestinal disorders.
All documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
I. Compositions and Kits
In accordance with the present invention, an antimicrobial composition and kit containing nitrofurantoin can achieve a higher efficacy of antimicrobial activity if complemented by
uva ursi.
Furthermore, the composition and kit comprising nitrofurantoin and
uva ursi
according to the present invention may exhibit synergism by lowering the MIC (minimum inhibitory concentration) and even FIC (fractional inhibitory concentration) of nitrofurantoin.
The compositions of the present invention comprise: (a) a safe and effective amount of nitrofurantoin; (b) a safe and effective amount of
uva ursi
; and (c) optionally, a pharmaceutically-acceptable carrier.
The kits of the present invention comprise: (a) nitrofurantoin in a unit dose form; (b)
uva ursi
in a unit dose form; and (c) a package containing components (a) and (b). In one mode, the kit of the present invention contains nitrofurantoin and
uva ursi
in a single unit dose form. In another mode, nitrofurantoin and
uva ursi
are in separate unit dose forms. In either instance, a plurality of doses can be present to provide prevention or treatment over a period of several days, or weeks. Still another mode, instructions to the kit are included.
As used herein, “nitrofurantoin” includes the compound N-(5-nitro-2-furfurylidene)-1-aminohydantoin, as well as its pharmaceutically acceptable salts, hydrates, and complexes. (See “6696. Nitrofurantoin”, The Merck Index, 12th ed. (1996, pp. 1134). Nitrofurantoin “complexes” refer to chemical complexes of nitrofurantoin with other chemical constituents that result in entities that retain at least a substantial portion of the antimicrobial activity of nitrofurantoin. Examples of such complexes include nitrofurantoin-phthaloyl glycine and nitrofurantoin-phthaloyl aminocaproic acid. A method for preparing nitrofurantoin is disclosed in U.S. Pat. No. 2,610,181, to Hayes, issued Sep. 9, 1952. A method for preparing macrocrystalline nitrofurantoin is disclosed in U.S. Pat. No. 3,401,221, to Brogmann et al., issued Sep. 10, 1968. See also, U.S. Pat. Nos. 2,898,335; 2,927,110; 3,007,846; and 3,446,802 to Michels; Gever & O'Keefe; Gever & Vincent; and Michels issued Aug. 4, 1959; Mar. 1, 1960; Nov. 7, 1961; and May 27, 1969 respectively.
“
Uva ursi
” is a plant, including plant parts such as leaves, stems, berries roots, flowers and the like, or an extract thereof of
Arctostaphylos uva
-
ursi
, and related members of its family Ericaceae including, but not limited to, Vaccinium, Arctostaphylos, Gaultheria, and Gaylussacia. Preferred species include,
Arctostaphylos adenotricha
, and
Arctostaphylos coactylis
, and
Arctostaphylos uva
-
ursi
most preferably
Arctostaphylos uva
-
ursi
. Mixtures of Ericaceae plants and/or extracts may also be used. Other names of
A. uva
-
ursi
include: beargrape, kinnikinnick, mealberry, mountain box, mountain cranberry, redberry leaves, sagackhomi, sandberry, hogberry, manzanita and bearberry.
A well-known homeopathic treatment for acute cystitis has been the use of
uva ursi
. It has now been found through in vitro microbiological testing that a combination of nitrofurantoin and
uva ursi
(hereinafter referred to as “the combination”) results in a significant reduction in the minimal inhibitory concentration (MIC) required to inhibit the growth of certain urinary tract pathogens (see “IV. Data”). Specifically, when the combination is tested against Pseudomonas, Porteus, Serratia, and Klebsiella there was a significant decrease in the MIC values for nitrofurantoin. Historically, all of these pathogens are known to be moderately or highly resistant to nitrofurantoin. Additionally, there is synergistic activity seen against Serratia as evidenced by the concurrent lowering of MIC for
uva ursi
. Together these results suggest that the combination may beneficial in the treatment of infectious disorders such as acute cystitis caused by pathogens not adequately eradicated by either nitrofurantoin or
uva ursi
alone.
As discussed above, the combination is effective for treating and preventing infectious disorders. Thus, the combination can be formulated into pharmaceutical compositions or packaged as a kit. Standard pharmaceutical formulation techniques are used, such as those disclosed in
Remington's Pharmaceutical Sciences
, Mack Publishing Company, Easton, Pa., latest edition.
A “safe and effective amount” of nitrofurantoin and
uva ursi
is an amount, taken concurrently, that is effective to treat an infectious disorder in an animal, preferably a mammal, more preferably a canine, feline, or human, still more preferably a human subject, without undue adverse effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of the present invention. The term “concurrently,” as used herein, means that
uva ursi
and nitrofurantoin are administered within 24 hours of each other, preferably conjointly. The specific “safe and effective amount” will, obviously, vary with such factors as the particular infectious disorder being treated, the physical condition of the patient, the duration of treatment, the nature of

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