Flavonoid as Nutraceuticals: A Therapeutic approach to Rheumatoid Arthritis

 

Sangeeta Mohanty*, Abhisek Pal, Sudam Chandra Si

School of Pharmaceutical Sciences, Siksha O Anusandhan (Deemed to be University) Bhubaneswar, India.

*Corresponding Author E-mail: sangeetamohanty@soa.ac.in

 

ABSTRACT:

Rheumatoid arthritis (RA) is an autoimmune disease of inflammatory origin. It progressively affects the articular and extra-articular joints, mostly identified by hyperplasia, inflammation of synoviocytes, autoantibody production and bone/cartilage degradation. Etiology and underlying mechanism of RA is still unknown, causing an imbalance between inflammatory and anti-inflammatory pathways. The drawbacks in the safety, efficacy of existing treatment options, are driving the need for new, effective and safe medications. As, it is a priority for biological research in 21st century, current experimental outcomes focus on the potential of Nutraceutical in management of RA. Furthermore, we abridge the effect of various citrus flavonoids against Rheumatoid arthritis with main biochemical citations which can either improve or retard the RA by their, anti-inflammatory, anti-oxidant, anti-radical, immuno modulatory and enzyme inhibitory effects. The main aim of this review is to perform an up-to-date insight regarding pathophysiological basis of RA. A special focus is given on the effective dietary Nutraceutical, particularly effect of flavonoids (citrus) on prevention of the progression of Rheumatoid Arthritis. Finally, by using several plethora of evidence, this review suggests the promising future prospects of various dietary citrus flavonoids, their underlying mechanisms, which are having massive potential to be explored as safe and effective treatment strategies in RA.

 

KEYWORDS: Nutraceutical, Flavonoids, Rheumatoid Arthritis, Anti-inflammatory.

 

 


INTRODUCTION:

Currently, nutritional science has geared up significance in the field of research towards the health benefit of patients suffering from several autoimmune diseases such as Crohn’s disease, Alzheimer’s disease ,Parkinson’s disease, Obesity, Cardiovascular disease, Cancer, Diabetes mellitus (Type 1), Multiple sclerosis, and Rheumatoid arthritis. [1,2]

 

Nutraceutical is regarded as pharmaceutical nutrient which is regulated by FDA under the authority of Federal Food  D andC Act [3,4] .It is defined as any substance other than food which can be used in suppressing, protecting and treating the chronic diseases.

 

Nutraceutical support the structure and function of the body by bridging the gap between food and medicine, maintains healthy life by increasing the life expectancy of patients. Nutraceutical has gained importance due to its safety and efficacy [5]. In 1989, Stephen Di Felice, Managing Director cum chairman of the Foundation (Innovation in medicine) coined the term “Nutraceutical” from the word “Nutrition” and “Pharmaceutical”. These are sometimes referred as functional foods. Such products may range from isolated products, herbal products, genetically engineered foods or any other processed foods having health benefits beyond their basic nutrition. [6,7,8] Both pharmaceuticals and Nutraceutical are used to treat or prevent diseases but the later one have no patent protection in contrast to pharmaceuticals. Sharp tidal growth is seen mainly in European countries, United States and in India. [8,9,10] Compounds extracted from natural plants have drawn increasing attention for their clinical efficacy with little adverse effects. Furthermore, multiple research findings suggests that plant obtained from phenolic compounds i.e. citrus flavonoids possess anti-oxidant potential and is well capable of reducing the risk of developing RA [11]. Moreover, citrus flavonoids are responsible for down regulating and inhibiting the activities of several enzymes such as B (NF-κB) and MMPS, as they are very reactive towards ROS(reactive oxygen species) and also the expression of various genes associated in chronic inflammatory disease like RA [12].

 

Rheumatoid arthritis (RA) is considered as one of the gradually progressive debilitating disorder having vast etiologies involving biomechanical, biochemical and genetic factors. It is characterized by severe deforming symmetrical poly arthritis with no known cure as it is very difficult to restore the cartilage once destroyed . [13,14]. There are over 100 types of arthritis out of which the most common forms are Rheumatoid arthritis (RA), Osteoarthritis (OA), Psoriatic arthritis and Septic arthritis. RA is the most familiar arthritis associated with systemic complications leading to premature death [15]. RA occurs in 1% of population worldwide in which the prevalence of occurrence is more in men as compared to women. It is more common in European countries than in Asian and African populations [16].

 

Standard treatment strategies include a combination of both pharmacological approach and non-pharmacological approaches. Though palliative, but non pharmacological approach which includes nutritional and physical therapy with changing life style, do not stop the progression of the disease [17]. However, the patients were exclusively reluctant for the pharmacological treatments (use of NSAIDS, DMARDS, and Corticosteroids) due to deleterious side effects associated.

 

An interesting option which researchers explore performing thorough investigation, is the use of Nutraceutical as an alternative treatment against several chronic inflammatory disease particularly RA. It is however, suggested that the therapeutic efficacy achieved through diet is based on the physiologic activity of secondary metabolites such as flavonoids, tannins, poly phenols, glycosides etc [18,19].

 

Current status of Nutraceutical in Market Scenario:

Current Market research proposed that the Nutraceutical market was expanding worldwide and it would reach US $250 billion in coming years. Initially, it was placed at 66 billion dollars in 2002. Indian market grows at a rate of 21% per year [20]. In developed countries multiple factors i.e. unhealthy fooding with changing lifestyles ,high disposable income and increase in larger ageing populations are mostly responsible for encouraging the growth of the Nutraceutical industries [21].

 

Classification of Nutraceutical:

Classification of Nutraceutical is based on chemical structure, mechanism of action, and food source [22, 23].


 

Table No 1. Classification of Nutraceutical Based on chemical nature

Chemical nature/class

Types

Sources

Therapeutic benefits/uses

Carotenoids

Alpha and beta carotenoids

Carrot,various fruits,oats

Neutralizes free radicals which may damage the cells

Fibres (dietery)

Insoluble,soluble, wholegrains, Sulphides /Thiols

Wheat bran, psyllium,

Helps in maintenance of immune function.

Lycopene

 

Tomatoes,guava,papaya,pink colo grape fruit

Maintainance of prostate, reduction of cholesterol level,antioxidants

Flavonoids

Apples, Onion, Broccoli, Tea

 

Reduces risk of Coronary disease

Monosaturated Fatty acids

 

Nuts from trees

Reduces risk of Coronary disease

Tocotreinol

 

Different grains,palm oil

Effective in breast cancer, and improves cardiovascular health.

Saponins

 

soyabeans

Reduction of cholesterol level, effective against colon cancer.

Omega 3 fatty acids

 

Flax seed, salmon

Reduces cholesterol deposition, helps in maintaining brain function

Prebiotics /Probiotics

 

Lactobacilli, Bifido bacteria present in yogurt

Improves gastric disturbances

Glucosinolates

 

Cruciferous vegetables, cauliflower

Anticancer activity(bladder cancer)

Isoflavones

 

Soyabean, legumes

Antioxidant, anticancer activity(prostate, breast, bowel cancers mainly)

 

Table No 2. Classification of Nutraceutical Based on Based on food source

Plants

Animals

Microbes

Ascorbic acid, Allicin

CoenzymeQ10,shark liver oil,cod liver oil

B.infantis, Bifidobacterium

Capsaicin,Cellulose,Tomato,Podextracts

Selenium ,Zinc,

Lactobacillus acidophilus

Geraniol,Glutathione, Garlic,

Choline,Lecithin,

B.longum

Hemicellulose ,Lycophene,Quercetin,

Calcium,Zinc,Minerals,

Streptococcus salvarius

Lutein,alpha–Tocopherol,beta Carotene,Gallic acid,

Conjugated linoleic acid(CLA)

SaccharomycesBoulardii

Selenium,Minerals

EPA,DHA,Creatinine

 

 

Table No 3. Classification of Nutraceutical Based on mechanism of action

Antioxidant activity

Ascorbic acid, Tocopherols, Lycophene, Ellagic acid, Catehins, Gingerol, Tocotrienols, CLA

Anticancer activity

Capsaicin ,Curcumin ,Lutein , Limonene ,Genestein

Anti-inflammatory activity

EPA, GLA, Quercetin, Curcumin, Capsaicin, Linolenic acid

Bone protective activity

Soya protein, Calcium, CLA ,Inulin

Positive influence on blood lipid profile

Saponins, Guar, Resveratrol, MUFA, Quercetin ,Tannins

 


Rheumatoid arthritis:

Rheumatoid arthritis is an autoimmune disease of inflammatory origin progressively affecting articular and extra-articular joints, characterized by synovial inflammation and synovial hyperplasia .Destruction of hyaline articular cartilage and increased thickness of sub chondrial bone has been found to be the primary cause of stiffness, pain, disability and mortality. RA patients faces difficulty in absorption of specific nutrients [24]. Although several new drugs have been developed and are used now-a -days for treatment of RA, still many patients are interested in seeking a remedy to ease its symptom with dietary supplements and food. Recently, nutritional science has gained popularity and is an upcoming field of research towards the use of food for their diversified health benefits in people suffering from RA.

 


Pathogenesis of Rheumatoid Arthritis with involvement of various factors:


Nutritional deficiencies of RA patients:

Poor nutritional status in RA patients leads to severe weight loss, anemic conditions, gastritis, peptic ulcers, and loss of appetite. Due to long term exposure of RA medicaments, conditions such as nutritional deficiencies can be seen in RA patients. Certain micro nutrient deficiencies observed in RA patients are those of Vitamin B6, B12, vitamin C, vitamin D, folic acid, calcium, selenium, magnesium. Folic acid deficiency is seen in patients using Methotrexate for RA treatment. Deficiency of vitamin B results in significant increase in the incidence of megaloblastic anemia. Furthermore, there is an apparent vitamin C deficiency as seen by low concentration. [25]

 

Drugs used in RA and its limitation:

Among the currently available treatments though effective, produces either symptomatic relief (NSAIDS) or modify the disease process through DMARDS. However, there use is limited due to unwanted side effects like cardiovascular complications, gastrointestinal ulcers, opportunistic infections which is due to immuno suppressants [25]. Patients with RA rely on other options like use of naturally available Nutraceutical. Flavonoids (vitamin P) considered as one of the group of over regular constituent of diet along with ascorbic acid (vitamin C) are important in the maintenance of capillary resistance and capillary wall integrity.

 

Arthritis drug market as per Market Share:

Arthritis drug market was well occupied by different players which include Johnson and Johnson, Abbott Laboratories, Pfizer, Roche etc. According to FDA, during 2007-2008, Abbott laboratories Humaria was considered to be the highest selling drug in arthritis market with sales growing 50% to $4.5 billion whereas Bristol-Myers Squibb’s Orencia is the fastest growing arthritis drug with sales increase of 91% to $441 million in the year 2007-2008 [26].


 

Table No 4. Arthritis drug market and its statistics

Rank

Market Share

Name of the Company

Name of the Drug

Revenue (USD)

Market Growth

1

2%

Merck

Arcoxia

0.38

14.60%

2

3%

BMS

Orencia

0.44

91%

3

5%

Roche

Rituxan

0.75

NA

4

16%

Pfizer

Celebrex

2.49

9%

5

20%

Johnson and Johnson

Remicade

3.7

18%

6

23%

Amgen

Enbrel

3.6

12.50%

7

28%

Abbott

Humaria

4.5

50%

 


Inflammation markers and Nutraceutical anti-inflammatory investigation:

For various autoimmune diseases like Rheumatoid arthritis, Cancer, Atherosclerosis, and other Cardio vascular diseases “Inflammation” plays a key role in the progression of diseased conditions. Mechanism of inflammation is very much complex involving various paths and signaling processes. However, a number of inflammation markers were explored in last decades as targets for different anti-inflammatory studies. Each marker is having its own potential in regulating or inducing inflammation, hence the concept of inflammation can be best understood through multiple marker evaluation.

 

1.     Cytokines inhibition in cells (TNF-alpha, interleukins):

Both TNF-Alpha and Interleukins are pro-inflammatory cytokine which triggers inflammation and acts as a precursor. These are basically protein-based drugs for treatment against various inflammatory diseases. Although  etanercept and infliximab are protein based drugs used for inflammation disease treatment but are associated with devastating side effects like neurological problems which leads to heart failure. Nutraceutical have therefore become of investigative interest to explore their role as lesser toxic TNF-alpha inhibitors for treatment of inflammation. Flavonoids such as catechin and quercetin acts as TNF-alpha inhibitors without known side effects [27].

 

2.     NF-kB inhibition in cells:

NF-kB (Nuclear factor kappa B) is basically a complex of protein, mostly involved in cellular responses to stimuli such as bacterial/viral antigens, oxidized LDL, UV irradiation, free radicals and stress. It plays major role in modulating the immune response against infection. However, nuclear factor kappa B suppression limits the production of pro inflammatory gene expressions by reducing the level of inflammation. Thus, making it a biomarker for inflammation. Nutraceutical such as curcumin, green tea can be cited as an example of anti-inflammatory material via NF-kB inhibition [28].

 

3. Secretary phospholipases A2 (s-PLA2) inhibition :

s-PLA2 inhibitors catalyzes the hydrolysis of phospholipids which yields precursors of pro-inflammatory lipid  mediators (platelet activating factor and bioactive eicosanoids). These are regarded as a sub-family of phospholipases A2 enzymes. However, inhibition of s-PLA2 would prevent inflammatory eicosanoids formation prior to the COX reactions .Nutraceutical are discovered as a great source throughout thousands of years of civilization and used for screening for anti-inflammatory agents [29].

 

4. Lypooxygenase (LOX) inhibition:

Lypooxygenase are basically dioxygenase enzymes (iron containing non heme portion) distributed in plants, animals and fungi, helps in catalyzing distinct cellular reactions. The fatty acid hydro peroxides products which were formed during reaction process have been identified as mediator of series of inflammatory diseases. Hence, LOX inhibitors have significant role in inflammation treatment including diseases like RA, Atherosclerosis, Inflammatory bowel disease and Cancer. Furthermore, LOX 5 inhibitors have been identified as a potential inhibitor because it will counteract the side effects like gastric damage (i.e.aspirin) associated with COX-1inhibitors [30].

 

5. Cyclooxygenase (COX) inhibition:

COX is officially known as prostaglandin endoperoxide synthase. The two well known iso forms of COX are COX-1 and COX-2. Both COX-1 andCOX-2 are similar in their identity and in their amino acid sequence. Inhibition of COX can provide relief from the symptoms of pain and inflammation. COX-1 inhibitors  possess anti-inflammatory activity but is associated with gastric and hemorrhagic side effects. However, Cyclooxygenase -2 can ameliorate the pain and inflammation with decreased risk of acute injury and chronic ulcer [31]. A classic example of anti - inflammatory COX inhibition is Aspirin which shows severe side effects, hence it can be well replaced by natural COX inhibitors. A variety of flavonoids, Fish oils, Hyperforin, Calcitorin, Culinary mushrooms and willow bark extract can be used as an ancient remedy for reducing pain and inflammation.

 

Flavonoids as Nutraceutical: New approach in Chronic Inflammatory Disease (RA):

Nutraceutical has witnessed the explosive growth in last five years .For any pharmaceutical development process, it is a must to have clinical tests and studies to elucidate the therapeutic efficacy. Flavonoids are naturally occurring plant secondary metabolites that are predominantly found in plants, vegetables, seeds, legumes, grain,  tea, bear, wine, nuts and fruits [32]. Around 4000 flavonoids discovered so far with diverse range of bioactivities. Basic structures of flavonoids consist of 15 carbon atoms, three rings of which two are benzene rings connected with a 3-carbon chain. Due to relatively low toxicity and its wide distribution, as compared to other active plant metabolites, human can ingest significant amount of flavonoids in their diet. The most beneficial effects of flavonoids are due to its anti-oxidant, immuno modulatory, antiradical and anti-inflammatory properties. However, flavonoids exhibit a wide range of biological activities arising mainly from their anti-oxidant potential hence is capable for modulating several enzymes along with cell receptors [33,34,35]. Flavonoids are synthesized by phenyl propanoid metabolic pathway as a result of which six subgroups of flavonoids are formed with distinct structural patterns  [36,37,38]. Furthermore, these flavonoids can be recognized for their antiviral and antibacterial activity, anti inflammatory, anti allergic and anti angiogenic effects, apoptotic, cytostatic, analgesic, hepatoprotective, estrogenic properties. Common immuno modulatory effects of flavonoid in arthritic condition is mainly due to stimulation of apoptosis cells (Macrophages,Neutrophils) and inhibition of pro-inflammatory cytokines (Tumour Necrosis Factor-α,Interleukin-6,IL-1β), chemokines (MCP1, CXCL1, CXCL5, CXCL9), synoviocytes proliferation and matrix metalloproteinases (MMP1, MMP3, MMP9, MMP13).

 

In recent years, there is a greater interest in Nutraceutical, which includes several dietary supplements and herbal products for reducing inflammation and pain. However, many of these plant derivatives work by inhibiting the mediators of inflammation. Control of cytokine action is still a major factor to be considered in pharmaceutical drug research. As long term use of anti-inflammatory drugs produces secondary side effects, it is primordial to explore alternate therapies for inflammatory diseases [39]. Flavonoids, recognized as highly diverse class of secondary metabolites, considered as one such group of compounds which can be used as alternative research strategies for diseases related to inflammation mainly.


Table no 5. Classification of Flavonoids, their Chemical characteristics, and typical food sources

Subgroups of Flavonoids

C-ring functional and C-ring unsaturation

Prominent Food Flavonoids

Rich food sources

Flavanones

4-oxo,none

Hesperidine,Naringenin,Eriodictyol

Citrus foods

Flavones

4-oxo,2-3 double bond

Apigenin

Green leafy spices

Flavonol

3 hydroxy, 3-O-gallate

Catechin,Epicatechin3gallate,Gallocatechin

Redwine,redgrapes,chocolate

Flavonols

3 hydroxy,4-oxo

Quercetin,Myricetin,Kaempferol

Broccoli,Tomato,Cherry

Isoflavones

4-oxo

Genistein,Daidzein

Soya foods and legumes

 


Effect of Citrus Flavonoids in Rheumatoid Arthritis:

Citrus plants are very good source of flavonoids. So far, the most important flavonoids isolated from citrus fruits are Naringin, narirutin, nobelitin, naringenin and hesperidin. However, the anti-inflammatory mechanism of flavonoids are highly related to its chemical structure. Important features associated in anti-inflammatory activity of flavonoids includes (a) Presence of a planar ring structure in the flavonoids molecule; (b) At C2-C3 position, presence of unsaturated C-rings; (c) Presence of no. of hydroxyl groups in A ring (at C5&C7 position) and B rings (C31&C41position); (d) Lack of -OH groups on ring B eliminates the activity; (e) Non glycosylation of the molecule; (f) presence of keto group at C4 position in C ring [40,41,42]. To a better knowledge of anti-inflammatory or structure activity relationship of citrus flavonoids, the literature by Ribeiro et al. can be reviewed.

 

Hesperidin:

Hesperidin, commonly found in citrus fruits is a flavonone glycoside composed of hespertein (aglycon part)and rutinose. Different in vivo and in vitro studies contributed significant role in anti-inflammatory studies.[43] Guardia et al., 2001, reduces paw edema and arthritic score in rats treated with adjuvant carageenan induced arthritis. Bone destruction, pathological changes in vascular proliferation, synovial hyperplasia ,splenic histology were reduced in hesperitin treated AIA rats.[44] Kometani et al., 2008, studied CIA induced mice when treated with alpha glucosyl hesperidin attenuated joint damage, clinical score, plasma C-Reactive protein, inflammatory cell infilteration, pannus formation and synovial cell proliferation.[45] Rovensky et al., 2009, used a combination of both detralex (hesperidin + diosmin)and Methotrexate in AIA rats improved paw edema ,scores and bone mineral density. Several other studies showed reduction in clinical scores and production of NO (measured by serum nitrite) with AIA rats. [46] Li et al 2010 , 2013.,studied the proliferation of fibroblasts like synovial tissues obtained from AIA rats, However the paw edema and clinical scores can be reduced by administration of 7,31-dimethoxyhesperidin.Few other studies also revealed hesperidin induced apoptosis in synovial hyperplasia, stimulated with TNF-alpha. [47,48] In an another study performed by same researcher in 2010 on Adjuvant induced arthritis in rat synoviocytes, reduction in TNF-α and IL-1β mRNA and protein occurred. [49] In a study by Umar et al 2012., hesperidin treated the Collagen induced arthritic rats by ameliorating the cartilage elastase activity, which is a measure of in filtration and neutrophil activation. [50] Choi and Li et al 2007., performed studies on AIA rats and revealed that production and expression of IL-6 and TNF-α was reduced with 7,31dimethoxyhesperetin. Furthermore hesperetin significantly decreased the production of IL-6 and MMP-3 in human synovial cells stimulated with interleukin -1beta. [51] According to Lin et al 2003 and Murakami et al 2000., Nobelitin inhibited TRAP activity and osteoclastogenesis in vitro. Furthermore, expression of pro MMP-1mRNA, proMMP-1 and proMMP-3and production of COX-2 mRNA, PGE2 and protein was reduced in IL-1β stimulated human synovial fibroblasts treated with nobiletin. [52,53]

 

Naringenin:

Naringenin is a colorless bitter flavonone in grapefruit, pomelo as well as lime and its variants, obtained mainly from the citrus fruits and is a metabolite of naringin. It is known to exhibit various biological activities i.e. anti-inflammatory, anti-cancer, anti-oxidative and hypoglycemic effects, bone growth promotion, sedative, anti-fungal, antiatherosclerotic, immunity system modulator, free radical scavenger and carbohydrate metabolism promoter. [54] Li et al 2015.,suggested that Naringin  treated collagen induced arthritic mice could ameliorate effectively the expression of TNF-α, m-RNA in knee joints and the expression of IL-17,IL-1β,MCP-1 mRNA in the ankle tissues respectively. [55] Ahmed et al 2014 and Kawaguchi et al 2011., reported that Naringin and its aglycone naringenin reduced the clinical scores and paw edema in CIA/AIA rats along with significant histopathological changes. Furthermore, the expressions of IL-β, TNF-α, IL-17 and MCP-1 m-RNA was ameliorated in the knee joints and ankle tissues of both CIA/AIA treated mice.[56,57]

 

Nobelitin:

Nobelitin  is polymethoxy flavones obtained from citrus fruits having several activities like anti-inflammatory, anti tumor invasion, anti-tumor  proliferation and metastasis .

 

Lin et al 2003., worked on the citrus flavonoid namely Nobelitin  which is having the capacity to inhibit catabolic factors production (MMP-3and MMP-9) and mediators of inflammation (PGE2) in both rabbit and human synovial fibroblasts. Nobelitin is having the potential to reduce the cartilage degradation and also exhibit the chondroprotective activity [58]. Imada et al 2008., worked in normal human synovial fibroblasts and suppression of IL-1β induced ADAMTS-4 and 5 mRNA expression was found with Nobelitin, further it supports the activation of MMP inhibitor (TIMP-1) [59]. Ishiwa et al 2000., worked on synovial fibroblasts and articular chondrocytes of rabbit and revealed , Nobelitin acts by suppressing IL-1 induced MMP-9 mRNA expression and production of PGE2 [60].

 

CONCLUSION:

Rheumatoid arthritis is a chronic disease with no known cure and a priority of biological research in current scenario. Scientific evidence suggests, despite of several upcoming treatment options, current treatment medications are limited due to their toxicity and side effects. However, with the growing interest in plant phytochemicals (i.e. nutraceuticals) among people with rheumatoid arthritis, patients always look for alternate therapeutic options. This review suggested the role of citrus flavonoids namely Hesperidin, Naringin, Nobelitin affecting the joint state in several animal models, inhibiting cartilage destruction, cellular proliferation, edema, pannus formation and cell infiltration whilst modulating MMP and cytokine function. Modulation of cellular activities of neutrophil; macrophages; recruitment and production of pro-inflammatory cytokines; altered pro-inflammatory gene expression are the main important mechanisms by which these citrus flavonoids are exhibiting the anti-arthritic effects/potential in RA. Furthermore, the inhibition of bone loss is mainly attributed due to inhibition of osteoblastic function and promotion of osteoblastic activity.

 

A vast number of studies were performed both in vitro and in vivo animal models suggested, citrus flavonoids induces immuno modulatory mechanisms against mediators of inflammation, hence, provides protection against joint destruction. However, not enough clinical data with bioavailability studies were available on citrus flavonoids and their anti-inflammatory effects in rheumatoid arthritis. Nutraceutical could be a promising preventative for RA. Citrus flavonoids could have a more effective and less toxic therapeutic potential for the treatment of Rheumatoid arthritis. Further research with the aim of determining the disease modifying properties of these citrus flavonoids should include human trials and interpretation of their anti-inflammatory and anti-arthritic mechanism of actions.

 

ACKNOWLEDGEMENT:

The authors are thankful to School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University) for constant help, support and encouragement in carrying out this work.

 

CONFLICT OF INTEREST:

There are no conflicts of interests.

 

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Received on 05.07.2019            Modified on 10.08.2019

Accepted on 04.09.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(2):991-998.

DOI: 10.5958/0974-360X.2020.00184.5