CA2997992A1

CA2997992A1 - Herbal composition for the prevention and treatment of urinary infections

Info

Publication number: CA2997992A1
Application number: CA2997992A
Authority: CA
Inventors: Victor Gorev; Oleksandr Kostikov
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-03-12
Filing date: 2018-03-12
Publication date: 2019-09-12

Abstract

Present herbal composition is a dietary supplement that comprises Arctostaphylos uva-ursi extract, D-mannose and Vaccinium macrocarpon (cranberry) fruit extract in an oral dosage form. The composition is effective to prevent and treat urinary bacterial infections due to synergistic mechanisms of action of the ingredients and optimal dosages used.

Description

Herbal Composition for the Prevention and Treatment of Urinary Infections Field of the Invention Present invention relates to a novel herbal formulation for the treatment of urinary infections in human patients. Herbal ingredients with synergistic mechanisms of action were carefully chosen, and the dosages were calculated to ensure the maximum health effect.
Background Information Urinary tract infections (UTIs) are common bacterial infections that affect more than 150 million people worldwide each year (Harding and Ronald, 1994; Nicolle, 2005;
Stamm and Norrby, 2001). UTI is clinically divided into two major infections, according to the localization of the bacteria in the urinary tract - cystitis (lower UTI) and pyelonephritis (infection of kidneys). The incidence of pyelonephritis is fairly low (-0.3%-0.6%), however it is particularly dangerous as uncontrolled bacterial infection can spread to the bloodstream and cause sepsis. UTI may also be complicated by additional disorders such as pregnancy, renal failure, immunosuppression, etc..
Cystitis mostly affects women, for whom the lifetime risk is about 60%
(Foxman, 2014).
About third (20-30%) of those women will develop recurrent infection in 4-6 month despite antibiotic therapy (Foxman, 2002; Foxman, 2014). Recurrent UTI is treated with frequent antibiotic therapy, that can be six or more times a year (Ikaheimo et al., 1996).
Because of its high prevalence, UTI is associated with significant economic costs. An estimated financial burden of the UTI in the US is about $5 billion per year (Foxman, 2014).
The most common bacteria causing UTI is Escherichia coil (E. coil) that is responsible for 80-90% of uncomplicated UTI (Griebling, 2007; Foxman, 2014; Flores-Mireles et al.,

2 2015). Enterococcus species are the second cause of UTI, and are involved both in complicated and uncomplicated UTI (Flores-Mireles et al., 2015).
Upon entering the urinary tract, uropathogens bind to epithelial receptor to establish colonization. Both E. coli and enterococcal species accomplish this through the expression of distinctive adhesive pili on their surface.
The high prevalence of UTI, the considerable economical costs, and the rise of antibiotic-resistant uropathogens warrant the development of alternative methods of treatment.
Various herbs are historically used for the treatment of UTI, most common of which is cranberry. However, to our knowledge, there are no effective natural herbal product able to effectively prevent and treat the infection.
Present formulation (natural health product) has been developed based on the body of research and clinical data, and provides:
1) A unique combination of three most effective herbal ingredients (Arctostaphylos uva-ursi leaf or root extract, D-mannose and Vaccinium macrocarpon (cranberry) fruit extract), that were chosen based on their synergistic mechanisms of action and the effectiveness proven in clinical trials. In the present formulation the ingredients complement each other to exert an optimum effect, 2) An exact proportion of each ingredient in the present formulation allows an effective dose modification adjusted to the specific needs of each patient.
Summary of the invention: novelty and utility Ingredients of the formulation were carefully selected based on their mechanisms of action; they are able to induce a synergistic effect: Uva-ursi exerts an antibacterial action in the urinary tract, while cranberry and d-mannose prevent adhesion of bacteria to urogenital cells. The effective daily dosage was calculated based on the results of clinical studies: for the prevention of the recurrent infection (cranberry- 600 mg, d-mannose- 1 g,

3 Uva ursi- 800 mg), and for the treatment of an acute infection (cranberry ¨
1200 mg, d-mannose ¨ 2000 mg, Uva-ursi ¨ 1600 mg).
The invention will be an indispensable aid for persons with acute and chronic re-current infection, and an effective alternative to conventional antibiotic treatment.
Detailed description of the invention D-Mannose D-mannose inhibits adhesion of bacteria to urogenital mucosa and prevents entering and damaging cells. Specific mechanism has been revealed: d-mannose binds and blocks FimH adhesion located on bacterial fimbria, which prevents bacteria from binding to epithelial cells. Moreover, d-mannose is similar in structure to the binding site of urothelial glycoprotein receptors and acts a competitive inhibitor of bacterial adherence (Altarac and Papez, 2013).
Clinical studies have shown that the preventive effect of d-marmose is similar to the effect of antibiotics (nitrofurantoin ¨ a common antibiotics used for the treatment of UTI) when used for prophylaxis urinary infection (2 g daily, Kranjcec et al., 2014). Moreover, d-mannose induces considerably less side effects than nitrofurantoin (Kranjcec at al., 2014; Altarac and Papes, 2013).
Acute urinary infection: symptoms were significantly reduced with d-mannose taken 3 g daily for 3 days followed by 1.5 g daily for another 7 days; the infection has been cleared (Domenici et al., 2016).
Vaccinium macrocarpon (Cranberry) fruit extract Cranberry ( Vaccinium macrocarpon) has been traditionally used to treat urinary tract infections in women (Henig and Leahy, 2000). Several clinical trials confirmed that cranberry protects against urinary infections (Head, 2008; Wang et al., 2012).

4 A-type proanthocyanidins (Howell et al., 1998) contained in cranberry, and probably other constituents are able to inhibit the adherence bacteria to the urogenital mucosa via mannose-like receptors, and thereby prevent infection; the exact mechanism of action remains to be elucidated (Guay, 2009). An effective dosage of 400 mg/day cranberry extract was determined in clinical trials (Walker et al., 1997; Bailey et al., 2007).
Uva-ursi leaf or root extract Uva ursi is one of the most commonly used botanicals for urinary tract infections. It has antibacterial properties and, in addition, appears to have diuretic and anti-inflammatory effect (Head, 2008, review; EMA, 2012). Preliminary clinical study revealed that in women with chronic urinary infection (acute periods occurring at least 3 time per year), use of uva ursi extract for one month has prevented further relapses (Larsson et al., 1993).
Acute infection: uva ursi is most effective when taken at the first signs of infection, 700-800 mg 2-3 times daily up to 4.0 g per day (EMA, 2012).
The present formulation contains ingredients in the optimized dosage; their synergistic mechanisms of action and ensure the effectiveness of the treatment.
How the invention will be used Proposed formulation is designed to treat patients with chronic and acute urinary tract infection. The formulation contains herbal ingredients with synergistic mechanisms of action, and in optimal dosages. This invention will present an effective alternative, with less side effects, to the conventional treatment of urinary infections with antibiotics.
References Altarac S. and Papes D. Use of d-mannose in prophylaxis of recurrent urinary tract infections (UTIs) in women. BJU International, 2013;113: 9-10.
Bailey D.T., Dalton C., Daugherty F.J., et al.. Can a concentrated cranberry extract prevent recurrent urinary tract infections in women? A pilot study.
Phytomedicine, 2007;14: 237-41.

5 Domenici L., Monti M., Bracchi C., Giorgini V., Colagiovanni L., Muzii P., Panici B. D-mannose: a promising support for acute urinary tract infections in women. A
pilot study.
Eur Rev Med Pharmacol Sci, 2016;20: 2920-2925.
EMA European Medicines Agency. Assessment report on Arctostaphylos uva-ursi (1.) Spreng. Folium, 2012.
Flores-Mireles A.L., Walker J.N., Caparon M., Hultgren S.J. Urinary tract infections:
epidemiology, mechanims of infection and treatment options. Nat. Rev.
Microbiol. 2015;13:269-284.
Foxman B. Epidemiology of urinary tract infections: Incidence, morbidity, and economic costs. Am. J. Med. 2002;113:5S-13S.
Foxman B. Urinary tract infection syndromes: Occurrence, recurrence, bacteriology, risk factors, and disease burden. Infect. Dis. Clin. N. Am. 2014;28:1-13.
Griebling T.L. Urinary tract infection in women. In: Litwin M.S., Saigal C.S., editors. Urologic Diseases in Amerca. U.S. Government Printing Office;
Washington, DC, USA: 2007. pp. 587-620.
Guay D.R. Cranberry and urinary tract infections. Drugs, 2009; 69 :775-807.
Harding G.K., Ronald A.R. The management of urinary tract infections: what we have learned in the past decade. Int. J. Antimicrob. Agents. 1994;4:83-88.
Head K.A. Natural approaches to prevention and treatment of infections of the lower urinary tract. Alt Med Rev, 2008;13: 227- 244.
Henig Y.S., Leahy M.M. Cranberry juice and urinary tract health: science supports folklore. Nutrition. 2000;16(7-8):684-687.
Howell AB, Vorsa N, Der Marderosian A, Foo LY (1998). Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. N Engl J Med., 1998;339 :1085-1086.
Ikaheimo R., Siitonen A., Heiskanen T., Karkkainen U., Kuosmanen P., Lipponen P., Makela P.H. Recurrence of urinary tract infection in a primary care setting:
Analysis of a 1-year follow-up of 179 women. Clin. Infect. Dis. 1996;22:91-99.
Kranje'ec B., Pape g D., Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol, 2014,32:79-84.
Larsson B., Jonasson A., Fianu S. Prophylactic effect of UVA-E in women with recurrent cystitis: a preliminary report. Curr Ther Res, 1993;53: 441-443.

6 Nicolle L.E. Catheter-related urinary tract infection. Drugs Aging.
2005;22:627-639.
Stamm W.E., Norrby S.R. Urinary tract infections: disease panorama and challenges. J.
Infect. Dis. 2001;183:1-4.
Walker E.B., Barney D.P., Mickelson J.N., et al.. Cranberry concentrate: UTI
prophylaxis. J Fam Prac, 1997;45: 167-8.
Wang Ch.H., Fang C.C., Chen N.C. Cranberry-containing products for prevention of urinary tract infections in susceptible populations. Arch Intern Med, 2012;172: 988-996.

Claims

Claims THE EMBODIMENTS OF THE INVENTION FOR WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition, dietary supplement or natural health product comprising, as the active ingredients, Arctostaphylos uva-ursi (Uva ursi) leaf or root extract, 40 mg (10:1, equivalent to 400 mg of standard extract);
D-Mannose, 500 mg;
and Vaccinium macrocarpon (Cranberry) whole fruit extract, 10 mg (30:1, equivalent to 300 mg of standard extract), wherein the formulation exerts at least 3 actions selected from the group consisting of:
relieves burning sensation, relieves frequent urination, relieves discomfort, exerts bacteriostatic action, reduces count of Escherichia colt in the urinary tract, reduces count of Enterococcus bacterial species in the urinary tract, prevents bacteria from adhering to the epithelial cells in the urinary tract, prevents bacteria from colonization on the urothelial cells.

2. The composition according to claim 1, further comprising at least one excipient.

3. The composition according to claim 2, wherein at least one excipient is selected from the group consisting of: hypromellose, magnesium stearate, microcrystalline cellulose.

4. The composition according to claim 1, further comprising pharmaceutically acceptable excipients and / or binders and / or vehicles.

5. Use of an effective amount of the present formulation of claims 1 to 4 affects pathological processes in humans associated with a bacterial infection of the urinary tract, for example cystitis, and reduces damage caused by the infection to tissues.

6. The use according to claim 5, wherein the tissue damage caused by pathological processes occurs in the human with a disease or condition selected from the group consisting of: bacterial infection of the urinary tract caused by Escherichia Coli, infection of the urinary tract caused by Enterococcus species, other bacterial strains.

7. Use of an effective amount of the present formulation of claims 1 to 4 to reduce the count of Escherichia Coli and/or Enterococcus species in the urinary tract in the human.

8. The use according to claims 1 to 4, wherein the present formulation is designed as an oral dietary supplement or natural health product.

9. Use of an effective amount of the present formulation of any of claims 1 to 4 to act to relieve symptoms associated with urinary tract infections, and to prevent (recurrent) urinary tract infections.

10. The pharmaceutical composition, dietary supplement or natural health product according to claim 1, for use in oral administration, wherein said use comprises the administration from 500 to 2000 mg/day of D-mannose, from 40 to 160 mg/day of Arctostaphylos uva-ursi root or leaf (10:1) extract, and from 10 to 40 mg/day of Vaccinium macrocarpon (cranberry) fruit (30:1) extract.

11. The pharmaceutical composition, dietary supplement or natural health product according to claim 1, for use in oral administration, wherein said use comprises the administration from 500 to 2000 mg/day of D-mannose, from 400 to 1600 mg/day of Arctostaphylos uva-ursi root or leaf standard extract, and from 300 to 1200 mg/day of Vaccinium macrocarpon (cranberry) fruit standard extract.

12. The present formulation containing about 7.3 weight percent of Arctostaphylos uva-ursi (Uva ursi) leaf or root extract (10:1), about 90.9 weight percent of D-Mannose, about 1.8 weight percent of Vaccinium macrocarpon (Cranberry) fruit extract (30:1), wherein the formulation exerts at least 3 actions selected from the group consisting of:
relieves burning sensation, relieves frequent urination, relieves discomfort, exerts bacteriostatic action, reduces count of Escherichia coli in the urinary tract, reduces count of Enterococcus bacterial species in the urinary tract, prevents bacteria from adhering to the epithelial cells in the urinary tract, prevents bacteria from colonization on the urothelial cells.

13. The composition according to claim 12, further comprising pharmaceutically acceptable excipients and / or binders and / or vehicles.

14. The formulation of claim 12, wherein the formulation includes one or more excipients selected from the group consisting of: hypromellose, magnesium stearate, microcrystalline cellulose.

15. The formulation comprising, according to claim 12, wherein the formulation is a 550 mg formulation.

16. The formulation according to one of claims 12 or 14 wherein the formulation is an oral dosage form.

17. The formulation according to claim 12, wherein the oral dosage form is selected from the group consisting of: a tablet; a capsule; a caplet.

18. Use of an effective amount of the present formulation of any of claims 1 to 4 to act to relieve symptoms associated with urinary tract infections, and to prevent (recurrent) urinary tract infections.

19. The present formulation containing between about 2.3 weight percent and about 9.3 weight percent of Arctostaphylos uva-ursi (Uva ursi) leaf or root extract (10:1), between about 85 weight percent and 95 weight percent D-Mannose, between about 1 weight percent and 3 weight percent Vaccinium macrocarpon (Cranberry) fruit extract (30:1), wherein the formulation exerts at least 3 actions selected from the group consisting of:
relieves burning sensation, relieves frequent urination, relieves discomfort, exerts bacteriostatic action, reduces count of Escherichia coli in the urinary tract, reduces count of Enterococcus bacterial species in the urinary tract, prevents bacteria from adhering to the epithelial cells in the urinary tract, prevents bacteria from colonization on the urothelial cells.

20. The composition according to claim 12, further comprising pharmaceutically acceptable excipients and / or binders and / or vehicles.

21. The formulation of claim 12, wherein the formulation includes one or more excipients selected from the group consisting of: hypromellose, magnesium stearate, microcrystalline cellulose.

22. The formulation comprising, according to claim 19, wherein the formulation is a 550 mg formulation.

23. The formulation according to claims 19 to 21 wherein the formulation is an oral dosage form.

24. The formulation according to claim 19, wherein the oral dosage form is selected from the group consisting of: a tablet; a capsule; a caplet.

25. The pharmaceutical composition, dietary supplement or natural health product according to claim 19, for use in oral administration, wherein said use comprises the administration from 500 to 2000 mg/day of D-mannose, from 40 to 160 mg/day of Arctostaphylos uva-ursi root or leaf (10:1) extract, and from 10 to 40 mg/day of Vaccinium macrocarpon (cranberry) fruit (30:1) extract.

26. The pharmaceutical composition, dietary supplement or natural health product according to claim 19, for use in oral administration, wherein said use comprises the administration from 500 to 2000 mg/day of D-mannose, from 400 to 1600 mg/day of Arctostaphylos uva-ursi root or leaf standard extract, and from 300 to 1200 mg/day of Vaccinium macrocarpon (cranberry) fruit standard extract.

27. Use of an effective amount of the present formulation of any of claims 1 to 4 to act to relieve symptoms associated with urinary tract infections, and to prevent (recurrent) urinary tract infections.