CROSS REFERENCE TO RELATED APPLICATIONS

This is a PCT application claiming priority from US provisional application no. 63213450, filed on 22 June 2021, the contents of which are incorporated herein in its entirety.

FIELD OF THE INVENTION

Tire invention in general relates to therapeutic potential of Calebin-A. Specifically, the invention relates to compositions comprising Calebin-A for the management of dysbiosis, increasing energy expenditure and regulating thermogenesis.

DESCRIPTION OF PRIOR ART

[Para001] Thermogenesis is garnering attention recently for maintaining a healthy living. Increasing energy expenditure serves the best way for the management of many conditions including obesity. Conversion of white adipose tissue (WAT) to brown or beige/brite (BAT) is reported as an effective mechanism to utilize the undue energy abundance and increasing the energy expenditure. Evidence suggests that non-shivering thermogenesis is a therapeutic target to improve many clinical conditions including obesity (Palmer BF, Clegg DJ. Non-shivering thermogenesis as a mechanism to facilitate sustainable weight loss. Obesity Rev. 2017;18(8):819- 831). While, WAT serves as a store house of energy, BAT lipids serve primarily as fuel for oxidative phosphorylation, primarily depending on UCP1 activity and increases energy expenditure by the production of ATP. BAT is also involved in heat production and helps in maintaining an adequate core body temperature. BAT also has deeper roles in the mammalian body system like Norepinephrine-induced thermogenesis, Metaboloregulatory Thermogenesis, as a secretory organ, in effective glucose and lipid clearance. Hibernation and Arousal etc. (Cannon et al., Physiol Rev 84: 277-359, 2004). Thus BAT, plays an important role in maintaining energy homeostasis. In various instances, wherein energy expenditure is essential like in obesity, metabolic disorders, diabetes, cold thermogenesis, sports endurance etc, change from WAT to BAT is crucial for the maintenance of an effective energy homeostasis. [Para002] In addition to the above, gut microbial diversity plays an important role in managing different clinical conditions. Intestinal microbes are sometimes considered to be a separate organ and also termed as “Organ within an organ” since it performs many functions that are normally not possible, including assimilation of indigestible components. Generally, these bacteria are divided into: a) commensal or physiological, which belong to the organism; b) pathogenic, which cause a disease; c) probiotic, which influence the host by improving the intestinal microbial balance (Perrotta G (2021) Intestinal dysbiosis: definition, clinical implications, and proposed treatment protocol (Perrotta Protocol for Clinical Management of Intestinal Dysbiosis, PID) for the management and resolution of persistent or chronic dysbiosis. Arch Clin Gastroenterol 7(2): 056-063. DOI: 10.17352/2455-2283.000100). Gut dysbiosis occurs when there is a disturbance in the normal homeostasis of microbial diversity due to diet, clinical conditions like obesity, sleep disturbances, exposure to pathogens, age, psychological stress, drugs/medication, alcohol consumption and physical activity. Dysbiosis is lurked to many disease conditions like inflammatory bowel disease, liver disease, celiac disease, colitis, Crohn’s disease, GI cancers etc. (Factors that influence the gut microbiota, thegutmicrobiome.com/factors-that- influence-gut-microbiota, accessed 14 June 2021). Studies have shown a direct correlation between dysbiosis and many clinical conditions such as diabetes, atherosclerosis, metabolic syndrome, autoimmune and neurodegenerative diseases, cardiac and circulatory disorders, atopic dermatitis, psoriasis, asthma and food allergies and intolerances. Additionally, since gut microbes also influence the mood, brain health and wellbeing, dysbiosis is also implicated in autism, epilepsy, neurodegenerative disorders, sleep disorders, eating disorders psychotic disorders, bipolar disorder, and personality disorders (Perrotta G (2021) Intestinal dysbiosis: definition, clinical implications, and proposed treatment protocol (Perrotta Protocol for Clinical Management of Intestinal Dysbiosis, PID) for the management and resolution of persistent or chronic dysbiosis. Arch Clin Gastroenterol 7(2): 056-063. DOI: 10.17352/2455-2283.000100). Gut microbes are also reported to modulate the intestinal hormones Ghrelin, GLP-1, leptin etc (Leeuwendaa et al., Gut peptides and the microbiome: focus on ghrelin, Curr Opin Endocrinol Diabetes Obes 2021, 28:243- -252, DOI: 10.1097/MED.0000000000000616) and thereby involved in the management of different clinical conditions like obesity, insulin resistance, increasing energy expenditure, preventing muscle atrophy etc (Wang et al., Gut microbiota mediates the antiobesity effect of calorie restriction in mice, Scientific reports, (2018):8: 13037, DOI: 10.1038/s41598-018-31353- 1 ; Pradhan et al., Ghrelin: much more than a hunger hormone, Curr Opin Clin Nutr Metah Care. 2013 November; 16(6): 619-624. doi: 10.1097/MCO.0h013e328365h9be). Thus, treating dysbiosis will be effective in management of many diseases and disorders.

[Para003] Dysbiosis is generally treated with antibiotics and administration of many probiotics. Many plant extracts and ingredients have also been validated for their ability to modulate gut microbial composition (Perez-Burilloa et al., Plant extracts as natural modulators of gut microbiota community structure and functionality, Heliyon, Volume 6, Issue 11, November 2020, e05474). Calebin-A, also known as Feruloylmethyl ferulate, is a novel curcuminoid obtained from rhizomes of Curcuma longa, Zingiberaceae . It has been reported to elicit various biological functions, some of which are mentioned in the following prior art documents, which is incorporated herein by reference:

• Calebin-A , a novel component of turmeric, suppresses NF-KB regulated cell survival and inflammatory gene products leading to inhibition of cell growth and chemosensitization, Tyagi et. al., Phytomedicine. 2017 Oct 15;34: 171-181.

• Calebin-A induces cell cycle arrest in human colon cancer cells and xenografts in nude mice, Lion et. al., Journal of Functional Foods, Volume 26, October 2016, Pages 781-791

• Majeed et al., Anti-obesity potential of Calebin-A , US Patent no. 9328330.

• Majeed et. al., Method for the treatment of hypercholesterolemia, US patent no. 9668999.

• Majeed et. al., Calebin-A for hepatic steatosis, US patent no. 9737502.

• Majeed et. al., Composition and method for the protection of articular cartilage, US patent no. 9220703.

• Majeed et. al., Calebin-A for osteoporosis, US patent no. 9539232

[Para004] However, the ability of Calebin-A to promote thermogenesis and modulate gut microbiota remains unclear.

[Para005] The main object of the invention is to disclose the potential of Calebin-A in modulating gut microbial diversity and in the management of dysbiosis.

[Para006] It is another object of the invention if disclose the potential of Calebin-A in promoting increased energy expenditure and regulating thermogenesis.

[Para007] Tire present invention satisfies the above mentioned objects and provides further related advantages. SUMMARY OF THE INVENTION

[Para008] In a most preferred embodiment, the present invention discloses a method of managing gut dysbiosis in a subject, said method comprising step of : a) identifying a subject with gut dysbiosis and b) administering a composition comprising Calebin-A to said subject, to normalize the gut bacterial diversity.

[Para009] In another preferred embodiment, the present invention discloses a composition comprising Calebin-A for use in the management of gut dysbiosis in a subject, by normalizing the gut bacterial diversity.

[Para0010] In another preferred embodiment, the invention discloses a method of increasing energy expenditure in a subject, said method comprising step of: a) identifying a subject in need of increased energy expenditure; b) administering effective concentration of a composition comprising Calebin-A to said subject, to bring about increase in energy expenditure and thermogenesis.

[Para00ll] In another preferred embodiment, the invention discloses a composition comprising Calebin-A for use in increasing energy expenditure and thermogenesis in a subject.

BREIF DESCRIPTION OF DRAWINGS

[Para0012] Fig. 1 is the graphical representation of the body weight of mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05.

[Para0013] Fig. 2 is the graphical representation showing the organ weights of mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05.

[Para0014] Fig. 3 shows the photographs of organs from mice fed with high fat diet along with 0.1% and 0.5% Calebin-A.

[Para0015] Fig. 4 is the graphical representation showing the perigonadal, retroperitoneal and mesenteric white fat weights of mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05. [Para0016] Fig. 5 is the graphical representation showing the adipose tissue and muscle related weight (%) in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05.

[Para0017] Fig. 6 is the graphical representation showing the blood glucose levels in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05.

[Para0018] Fig. 7 is the graphical representation for acute cold tolerance test, body temperature change during cold exposure (4 °C for 7 h) in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests, p < 0.05.

[Para0019] Fig. 8 shows the calculated area under the curve of temperature change within 7 h in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A. Data are expressed as means ± SE (n=6). Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests (p < 0.05).

[Para0020] Fig. 9 is a graphical representation showing abundance of gut microbiota at the phylum levels in mice fed with high fat diet along with 0.1% or 0.5% Calebin-A.

[Para0021] Fig. 10 shows the UPGMA (unweighted pair group method with arithmetic mean) tree of gut microbiota in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A.

[Para0022] Fig. 11 shows the Firmicutes/Bacteroidetes ratio in mice fed with high fat diet along with 0.1% and 0.5% Calebin-A.

[Para0023] Fig. 12 shows the Effects of Calebin A on gut microbiota manipulation. (A) represent the ACE richness estimator, (B) represent the Shannon’s diversity index - Nonparametric Wilcoxon signed-rank test for paired data was used. *P<0.05, 430 **P<0.01. NS: not significant and (C) represent the beta diversity of principal coordinate analysis

[Para0024] Fig. 13 is the heatmap showing abundance of 35 genera altered by calebin A in in mice fed with high fat diet along with 0.1% or 0.5% Calebin-A.

[Para0025] Fig. 14 shows the change is abundance of genera - Rumimclostridium_9, Akkermcmsia. Butyricicocciis and Ruminococcaceae after treatment with Calebin-A. Significance of difference among the four groups was analyzed by one-way ANOVA and Duncan’s multiple range tests (p < 0.05).

[Para0026] The following embodiments discuss the further aspects of the invention

DESCRIPTION OF PREFERRED EMBODIMENTS

[Para0027] In a most preferred embodiment, the present invention discloses a method of managing gut dysbiosis in a subject, said method comprising step of a) identifying a subject with gut dysbiosis and b) administering a composition comprising Calebin-A to said subject, to normalize the gut bacterial diversity. In a related embodiment, the gut bacteria is selected from the group consisting of the Phylum Deferribacteres, Proteobacteria, Bacteroidetes, Verrucomicrobia Actinobacteria, Fusobacteria, Acidobacteria, Cyanobacteria, Tenericutes, Abs condi tabacteria and Firmicutes. In a related embodiment of the invention, management of dysbiosis is brought about by decreasing the Firmicutes-to-Bacteroidetes ratio and increasing the abundance of Ruminiclostridium_9, Akkermansia, Butyricicoccus and Ritminococcaceae . In a related embodiment of the invention, management of dysbiosis is effective in therapeutic management of diseases selected from the group consisting of obesity, cardiovascular complications, inflammatory bowel disease, Crohn’s disease, Celiac disease, metabolic syndrome, liver diseases and neurological disorders, diabetes, atherosclerosis, metabolic syndrome, autoimmune and neurodegenerative diseases, cardiac and circulatory disorders, atopic dermatitis, psoriasis, asthma and food allergies and intolerances. In another related aspect, the subject is a mammal. In a related embodiment, the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies and eatables.

[Para0028] In another preferred embodiment, the present invention discloses a composition comprising Calebin-A for use in the management of gut dysbiosis in a subject, by normalizing the gut bacterial diversity. In a related embodiment, the gut bacteria is selected from the group consisting of the Phylum Deferribacteres, Proteobacteria, Bacteroidetes, Verrucomicrobia Actinobacteria, Fusobacteria, Acidobacteria, Cyanobacteria, Tenericutes, Absconditabacteria and Firmicutes. In another related aspect, management of dysbiosis is brought about by decreasing the Firmicutes-to-Bacteroidetes ratio and increasing the abundance of Ruminiclostridium_9, Akkermansia, Butyricicoccus and Ruminococcaceae. In a related embodiment, management of dysbiosis is effective in therapeutic management of diseases selected from the group consisting of obesity, cardiovascular complications, inflammatory bowel disease, Crohn’s disease, Celiac disease, metabolic syndrome, liver diseases and neurological disorders, diabetes, atherosclerosis, metabolic syndrome, autoimmune and neurodegenerative diseases, cardiac and circulatory disorders, atopic dermatitis, psoriasis, asthma and food allergies and intolerances. In another related aspect, the subject is a mammal. In a related embodiment, the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies and eatables.

[Para0029] In another preferred embodiment, the invention discloses a method of increasing energy expenditure in a subject, said method comprising step of: a) identifying a subject in need of increased energy expenditure; b) administering effective concentration of a composition comprising Calebin-A to said subject, to bring about increase in energy expenditure and thermogenesis. In a related aspect, increase in energy expenditure is brought about by decreasing the weight of perigonadal, retroperitoneal, and mesenteric white adipose tissues, increasing the weight of inguinal white adipose tissue (iWAT) and brown adipose tissue, and regulating body temperature. In a related embodiment of the invention, increase in energy expenditure results in decrease in body weight and organ weights and reduction in circulating glucose levels. In another related embodiment of the invention, increase in energy expenditure is effective in the management of conditions selected from the group consisting of obesity, metabolic disorders, diabetes, cold thermogenesis and sports endurance. In a related embodiment, the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies and eatables.

[Para0030] In another preferred embodiment, the invention discloses a composition comprising Calebin-A for use in increasing energy expenditure and thermogenesis in a subject. In a related aspect, increase in energy expenditure is brought about by decreasing the weight of perigonadal, retroperitoneal, and mesenteric white adipose tissues, increasing the weight of inguinal white adipose tissue (iWAT) and brown adipose tissue, and regulating body temperature. In another related aspect, increase in energy expenditure results in decrease in body weight and organ weights and reduction in circulating glucose levels. In yet another related aspect, increase in energy expenditure is effective in the management of conditions selected from the group consisting of obesity, metabolic disorders, diabetes, cold thermogenesis and sports endurance. In a related embodiment, the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies and eatables.

[Para0031] The following illustrative examples further specifically disclose the preferred embodiments of the invention, with obesity as an illustrative example:

[Para0032] Example 1: Methodology:

[Para0033] Calebin-A, commercially available as CurCousin ™, is obtained from Sabinsa Corporation, NJ, USA. C57BL/6J mice were fed either a normal or high-fat diet (HFD) supplement with Calebin-A (0.1 and 0.5%) diet for 12 weeks. Blood was collected via cardiac puncture immediately and centrifuged to collect plasma. Organs including liver, kidneys, spleen, gastrocnemius muscle, and adipose tissues (perigonadal, retroperitoneal, mesenteric, brown, and beige) were photographed and weighed. Plasma and organs were frozen at-80 °C before being analyzed. The biochemical parameters such as fasting blood glucose were analysed using approved methods. For themiogenesis experiments, mice were individually housed in precooled cages and exposed to a cold temperature (4 °C) for 7 hours with free access to food and water. Their rectal temperatures were measured hourly using a rectal probe thermometer. The composition of the gut microbiota was assessed by analyzing 16S rRNA gene.

[Para0034] Example 2: Effect of Calebin-A on energy' expenditure

Body Weight and Organ weights

[Para0035] Fig. 1 shows that after 12 weeks of induction, the weight difference between the HFD and ND groups was approximately 10g, and Calebin-A (0.1 and 0.5%) given at different doses was able to significantly reduce the weight of the mice and had a dose-dependent reaction.

[Para0036] The results of organ weight (Fig. 2) showed that the weight of liver and spleen increased significantly after being induced by an HFD. High-dose Calebin-A could significantly reduce liver weight to no difference from the ND (normal) group but could not significantly reduce spleen weight. For kidney, there was no significant difference between the groups. [Para0037] From the appearance of the organs (Fig. 3), it can be found that the liver color becomes lighter due to lipid accumulation after an HFD is given, and the sample was able to improve the liver color and make it closer to the dark red of the ND group.

[Para0038] The anti-obesity effect of Calebin-A also reflected in adipose tissues (Fig. 4). First, perigonadal, retroperitoneal, and mesenteric adipose tissues represent white adipose tissue (WAT) in mice. After an HFD, the weight and volume of WAT increased significantly. Low-dose Calebin- A (0.1%) reduced the weight of WAT, but there was no significant difference from the HFD group. High-dose Calebin-A (0.5%) significantly reduced the weight of perigonadal and mesenteric fats. [Para0039] Fig. 5 indicated that the weight of iWAT and BAT was induced by an HFD, and the weight of iWAT and BAT was slightly decreased by Calebin-A. This signifies that Calebin- A was effective in increasing energy expenditure by decreasing the white adipose tissue content and increased brown adipose tissue weight, which can be utilized for energy release.

Blood glucose levels

[Para0040] The fasting blood glucose of the HFD group was the highest and was significantly higher than the ND group (Fig. 6). Supplementation with Calebin-A lowered fasting blood glucose, and the high-dose group (0.5%) significantly reduced the fasting blood glucose that rises after the induction of an HFD.

[Para0041] Example 3: Effect on Calebin-A on thermogenesis

[Para0042] Cold Tolerance Test

The adaptive thermogenesis of mice was evaluated through an acute cold tolerance test. In this experiment, the mice were placed in a cold environment for a short period of time (4°C for 7 hours) to observe tire rectal temperature, which is the central temperature of the mice’s body. The mice with better adaptive thermogenesis capacity will have a smaller drop in body temperature and can better maintain their core temperature through heat production. Fig. 7 & 8 show that mice given high-dose Calebin-A (0.5%) had fewer body temperature changes and were better able to maintain their own temperature, whereas mice in the HFD group had the sharpest temperature reductions. This result shows that the HFD mice were not able to maintain their own temperature in a low- temperature environment. The temperature change graph is represented by the area under the curve (AUC). The high-dose Calebin-A (0.5%) group was significantly higher than the HFD group, which demonstrates that Calebin-A can reduce the obesity induced by an HFD in mice through the thermogenesis mechanism. [Para0043] Example 4: Effect of Calebin-A on Gut Microbial diversity

[Para0044] The overall composition of the bacterial community in the different groups was assessed by analyzing the degree of bacterial taxonomic similarity between metagenomic samples. The gut microbiota of obese humans and HFD-fed mice is characterized by an increased Firmicutes-to-Bacteroidetes ratio (F/B ratio). The results showed that after 12 weeks of HFD treatment, the microbiota composition changed, and the ratio of Firmicutes and Bacteroidetes also altered. (Fig. 9, Fig. 10 and Fig. 11). It can also be seen that Proteobacteria had an upward trend after Calebin-A treatment. In terms of the change trend of the bacterial phyla, the change of high- dose Calebin-A is most similar to the composition of the ND group, followed by the HFD group. Hence, providing an HFD can change the microbiota composition, and giving a high dose of Calebin-A can make the change in the composition close to that of the ND group.

[Para0045] Fig. 12 indicate the ACE estimator and Shannon index use to evaluate the richness and evenness of the microbiota after different treatments. The results show that the richness and evenness of the microbiota were reduced after HFD treatment. The richness and evenness of the group also tended to decrease after Calebin-A treatment, but there was no significant difference in evenness between the groups. However, the richness was significantly decreased by the high dose of Calebin-A. It is speculated that this result is related to the significant increase in the proportion of Proteobacteria and Verrucomicrobia after Calebin-A administration and the decrease in the proportion of other bacterial phyla. When analyzing the differences in the composition of the intestinal flora in each group, principal component analysis (PCA) is used to classify the flora, which isa widely used method to analyze microbiota. PCA can involve multi-dimensional data dimensionality reduction while maintaining a focus on data contributing the most characteristic differences so as to effectively find information on the most important element methods and structures. Using PCA analysis it is possible to find the coordinate axis that can reflect the difference between samples to the greatest extent so that the difference of multi-dimensional data can be reflected on the two-dimensional coordinate in a linear combination, enabling differences between individuals or groups to be observed. If the community composition of the sample is more similar, the distance in the PCA diagram is closer. Fig. 12C shows that the ND group is farther away from the group given HFD, the group treated with the different dose of Calebin-A is closer because of its similar composition, and the position of the HFD group falls between the two. Hence, feeding different samples will affect the microbiota composition. [Para0046] To further study the relationship between changes in intestinal flora and Calebin- A, a heatmap was used to show the abundance of the first 35 OTUs that significantly affected the HFD and Calebin-A (Fig. 13). The results showed that the Ruminococcaceae and Butyricicoccus genus of mice significantly decreased after HFD treatment, and the administration of different doses of Calebin-A increase the content of Rumimclostridlum_9, Akkermansia, Butyricicoccus and Ruminococcaceae (Fig. 14)

[Para0047] Calebin-A was very effective in the management of dysbiosis due to obesity. The examples related to the management of dysbiosis in obesity shown herein is merely an illustrative example and it will be understood that Calebin-A will be effective in managing dysbiosis related to other clinical conditions like cardiovascular complications, inflammatory bowel disease, Crohn’s disease, Celiac disease, metabolic syndrome, liver diseases and neurological disorders, diabetes, atherosclerosis, metabolic syndrome, autoimmune and neurodegenerative diseases, cardiac and circulatory disorders, atopic dermatitis, psoriasis, asthma and food allergies and intolerances. Calebin-A can be administered with other probiotics for the effective management of dysbiosis.

[Para0048] Example 5: Formulations containing Calebin-A

[Para0049] The composition comprising Calebin-A is formulated along with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents, stabilizing agents, dispersible gums, bioavailability enhancers or carriers and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies or eatables.

[Para0050] In a related aspect the bioavailability enhancer is selected from the group of piperine (BioPerine®), quercetin, garlic extract, ginger extract, and naringin. In another related aspect, the stabilizing agent is selected from the group consisting of rosmarinic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfite, propyl gallate, cysteine, ascorbic acid and tocopherols. In yet another related aspect, the dispersible gums are selected from the group consisting of Agar, Alginate, Carrageenan, Gum Arabic, Guar Gum, Locust Bean Gum, Konjac Gum, Xanthan Gum and Pectin.

[Para0051] Tables 1-5 provide illustrative examples of nutraceutical formulations containing bisdemethoxycurcumin [Para0052] Table I: Tablet

[Para0053] Table 2: Capsule

541 Table 3: Powder

[Para0055] Table 4: Gummy formulation [Para0056] Table 5: Candv formulation

[Para0057] The above formulations are merely illustrative examples, any formulation containing the above active ingredient intended for the said purpose will be considered equivalent. [Para0058] Other modifications and variations of the invention will be apparent to those skilled in the art from the foregoing disclosure and teachings. Thus, while only certain embodiments of the invention have been specifically described herein, it will be apparent that numerous modifications may be made thereto without departing from the spirit and scope of the invention and is to be interpreted only in conjunction with the appended claims.