A Review of Gastro-retentive Drug Delivery Systems for Antidiabetics and its present status

 

Aseem Kumar*, Anil Kumar Sharma, Rohit Dutt

School of Medical and Allied Sciences (SoMAS), G. D. Goenka University,

Sohna Road, Gurugram, Haryana, India.

 

ABSTRACT:

The present review provides concise information on status of gastro-retentive drug delivery systems for antidiabetic molecules. Present review emphasis on pharmacotherapy of diabetes via gastric retention of drug molecules. The gastro-retentive system is a proven useful tool for sustaining the drug release for the drugs having good absorption through the GIT, drugs with narrow therapeutic index and low dose drugs. The gastro-retentive dosage forms have also been developed for antidiabetic molecules and metformin hydrochloride, the first line drug in the treatment of diabetes is commercially available in the market in the form of sustained release formulations. As oral antidiabetic therapy is required for prolonged duration, the oral hypoglycemic may lead to side effects such as diabetic neuropathy, diabetic myopathy and many more. The primary reason for side effects is under-utilization of the drug molecule which can be improved using gastro-retentive drug delivery systems thereby minimizing the side effects. Despite being one of the most successfully systems, the commercial value gastro-retentive drug delivery systems is still below par. Gastro-retentive drug delivery systems for antidiabetic drug molecules are still awaited. The research is still in progress for gastro-retentive formulations which can attract industry utilizing these systems for humanely causes.

 

 

 

INTRODUCTION:

Oral route of administration has benefits such as low treatment costs and ease of administration, high level of patient conformity and so far remain the preferred route of administration¹. However drug absorption from oral route is not always uniform due to the physiological factors and gastrointestinal (GIT) system heterogeneity. Moreover, many involuntary variables influence drug uptake throughout the GIT such as variable pH, intestinal flora, gastrointestinal transit time, gastric secretions and absorption surface area². The traditional immediate release drug delivery systems are not able to combat the problems associated with low drug absorption in the gastrointestinal transit as these systems do not possess any additional characteristics to counter stomach motility and thus are not suitable for the drugs which are to be absorbed in the upper part of GIT.

 

 

Incomplete drug deliverance and subsequent reduction in bioavailability are the consequence that can be ascribed for the failure of traditional devices³. To overcome these issues, drug delivery systems that can control drug release and the residence time of the drug have been developed. Such systems are designed to reside in the upper GIT for a long period of time during which they regulated the release of the drug. The longer contact time with absorbing membrane of the gastro-retentive systems permits greater site absorption and greater bioavailability of drugs⁴. These systems are successfully developed and scaled up for commercial use. Additional benefits of gastro retentive drug delivery systems include: (i) Improved therapeutic effect for low-solubility drugs due increased drug solubility and absorption from stomach (ii) Reduction in drug dose and (iii) reduction in associated side effects⁵.

 

Gasrtoretentive drug delivery systems:

Gastroretentive dosage forms are designed to remain in the stomach for up to several hours thereby significantly enhancing the drug's residence time in the stomach. The prolonged gastric residence results in improves bioavailability of the drug due to higher solubility of drugs at stomach pH conditions thereby minimizing the drug loss. This system can also be utilized for local drug delivery to stomach and drug delivery to proximal small intestine⁶. The formulation technologies for gastroretention can be broadly classified based on different mechanism: high density (sinking) formulations, low density (floating) formulations, expandable systems, super porous hydrogel systems, mucoadhesive systems as well as magnetic systems.

 

Table 1: Techniques used for study gastroretention

 

These drug delivery systems localize the medication in the upper part of the GIT within a narrow absorption window. This enables the drug to act locally in the stomach and increases the formulation effectiveness through long intimate contact with the absorbing membrane. These are especially useful for drugs with poor absorption and stability in colon⁷. Various techniques such like Gamma, Gastroscopy, X-ray, Ultrasonography and Magnetic Resonance Imaging (MRI) have been adopted for testing gastro-retention time in the dosage form. These techniques are successful in tracing the movement of the dosage form throughout the GIT^8-11.  All these techniques along with the material required for their use is listed in the table 1.

 

Gastroretentive drug delivery system for antidiabetic drugs:

Diabetes is a physiological state associated with either non availability of insulin or its ineffectiveness within the human body. The complete absence of insulin characterizes type-1 diabetes while type-2 diabetes is characterized by resistance to the impacts of insulin within peripheral tissues of the body. Both types of diabetics have no insulin signaling impact on glucagon secretion which leads to hyperglycemia by enhancing hepatic glucose output from glucagon. Diabetes mellitus is caused by imbalanced carbohydrate metabolism and its impacts on other pathways¹⁷. According to the WHO, diabetes affects 285 million adult patients in 2010, 67% higher than in 2000 and an estimated 439 million in 2030 is 20% higher than the estimated 2030 study.¹⁸. Oral therapy is considered as the best path for administration of antidiabetic drugs owing to the highest patient compliance among other routes except insulin which is given as subcutaneous injection, owing to its degradation in GIT. Conventional drug delivery systems or modified drug release systems are the most commonly utilized drug delivery systems¹⁹. Modified release drug delivery systems are employed to obtain better therapeutic results, this concept is also applicable to the anti-diabetic drugs. The modified release drug delivery systems that has gained interest in the last decade is gastroretentive drug delivery. The techniques employed for development of such systems in modern days are as under:

 

At present the drugs available in market for the treatment of diabetes can be classified in to the following categories (Table 2):

 

Gastroretentive drug delivery systems for anti-diabetic drugs can be broadly divided in to the following:

 

1. Floating drug delivery systems (FDDS):

FDDS is one of the many approaches employed for achieving extended gastric retention, improving drug bioavailability and drug targeting in the stomach and upper intestines (Figure 1). These systems were originally depicted by Davis in 1968. FDDS perfectly suited for the drugs having selective absorption in the gastric region. Bulk density of these systems is a less than that of gastric fluids (almost 1.004g/cm³), so they show a good floating property. These devices float on gastric liquids for longer periods without influencing the gastric emptying rates and progressively discharge the drug at a required and regulated rate and the left over system is cleared from the stomach after releasing the drug, this results in minimal variation in plasma drug concentration and improved absorption of drugs via gastro-retention^20,21. Drugs like metformin hydrochloride which has potential absorption from stomach when given as Controlled Release/Sustained Release dosage form pass through the stomach (absorption region) at faster rate than its release and most of the drug is release in colon where the drug is poorly absorbed^22,23. Metformin hydrochloride should therefore be a given in gastro-retentive form while given as controlled release formulation for better efficacy²⁴, as gastro-retentive dosage form release the drug slowly for longer periods in the stomach for steady absorption in the intestines.

 

 

Table 2: Marketed anti diabetic product and their drug delivery systems

 

A slow but almost complete release of drug into the stomach is bound to increase drug bioavailability and its complete utilization, leading to minimizing doses and reducing gastrointestinal side effects. Multiunit floating dosage forms are supposed to release the drug at a predefined controlled rate and remain in the stomach for an extended period of time with very little dumping chances. In addition, they reduce associated GIT side effects and are unaffected by the concomitant intake of food, thereby reducing inter and intra-patient variation, improving patient compliance and increasing the uniformity of dosage form^25-27. 

 

Patel et al developed floating metformin hydrochloride microspheres by nonaqueous emulsifying technique utilizing ethylcellulose as polymer to control drug release. Developed formulations were assessed for pharmacopoeial as well as non-pharmacopoeial tests including drug-polymer compatibility by FTIR, percentage yield, drug entrapment efficiency, particle size determination, surface topography, in-vitro floatation and drug release studies. The results showed that the yields of the developed floating microsphere metformin hydrochloride were 58 - 87% and drug release from microsphere was 47 - 87% after 8 hours and the floating time of > 8 hrs for the prolonged drug release in the stomach, thereby enhancing bioavailability and patient compliance²⁸. Encapsulated floating repaglinide microspheres were designed and developed by Sharma et al to improve the residence time of the drug in GIT and thereby improve its systemic availability. The emulsion solvent diffusion techniques were used to formulate floating microspheres of repaglinide with ethylcellulose (EC) and methylcellulose hydroxypropyl (HPMC) (5 and 100 cps). The floating capacity and in-vivo antidiabetic activity of microspheres was carried out in alloxane-induced diabetic rats. The optimized formulation remained buoyant for six hours and showed marked reduction in blood glucose in comparison to the group of pure drugs²⁹. Kamila et al prepared floating rosiglitazone microspheres using non-aqueous emulsification/solvent evaporation techniques by encapsulation of medicine into Edragit RS-100. To attain predetermined target release, simplex lattice mixture layout was used. In-vivo formulation efficiency in streptozotocin-induced diabetic rats has been assessed, optimized formulations (microspheres) of rosiglitazone started to decrease blood glucose in the third hour until the ninth hour until blood glucose reached a standard level while in the case of pure medication the blood glucose declined from second hour to 5 hours³⁰.

 

In combination with the gums (sodium alginate, sodium CMC, xanthan gum and guar Gum) Thulluru et al. developed effervescent floating pioglitazone tablets with synthetic polymer HPMC K100 M that can extend the release of drug up to 12 hours. Studies of in-vitro buoyancy have shown that the optimized formulation remains buoyant for 12 hours and in-vitro drug release was found to be almost complete in the same time. In-vivo studies of rabbit x-ray imaging showed that the formulation is capable to withstand repeated gastric contractions and remain intact in the gastric region for 12 hours³¹. Ahmed et al developed gastro-retentive tablets of sitagliptin tablets based on floating, the tablets were prepared using the polymers HPMC K100, Poly vinyl pyrrolidine and polyacrylic acid in different concentrations by direct compression method. The bulk mixture was characterized for flow properties and finished formulations were evaluated for pharmacopoeial tests. In-vitro dissolution in the stimulated gastric pH 1.2 and intestinal fluid pH 6.8 were carried and drug releases for optimized formulation were found to be between 92.9-99.28%. The study concluded that good release was observed when a combination of polymers was used instead of single polymer and necessity of combining different class of polymers to get the desirable pharmacokinetic profile³². Jeganath et al developed a non-effervescent gastro-retentive tablets of linagliptin (dipeptidyl peptidase-4 enzyme inhibitor) based on floating. The tablets were prepared using a combination of Hydroxy Propyl Methyl Cellulose-K15, Hydroxy Propyl Methyl Cellulose-E15 and chitosan as polymers and Accurel, Gelucire as low-density drug carriers. The tablets were successfully prepared by direct compression method. The developed formulations remain floating for more than 20 hours in 900ml of simulated gastric fluid pH 1.2 and in-vitro drug release was found to be 98% in 20 hours for the optimized formulation³³. Duggi et al developed poiglitazone hydrochloride floating matrix tablets for gastro-retention using a combination of polymers viz. hydroxy propyl methyl cellulose, xanthan gum and guar gum. The authors studied the effect of polymer concentration and viscosity on gastro-retention and drug release. Based on various combinations they developed the optimized formulation which started floating in 28 seconds and remain floated for more than 12 hours. The optimized formulation has swelling index of 91.8% and drug release up to 95.86% after 12 hours was attained. The authors concluded that floating, swelling and subsequent drug release is highly dependent on polymer concentration and its viscosity³⁴.

 

Figure 1: Depiction of floating drug delivery system in stomach

 

Figure 2: Depiction of expandable/swelling drug delivery systems

 

2. Expandable Systems:

Expanding drug delivery systems (figure 2) absorb water to increase their size and retain within the stomach due to their size which is usually larger than the diameter of the pyloric sphincter, thereby restricting its passage into the intestine. While formulating an expandable drug delivery system, following points should be taken care of:

a)   The dosage form should be small enough and convenient to swallow

b)   It should expand quickly to an effective size in order to prevent its premature passage from the stomach to intestine.

c)   The dosage form should erode so as to prevent a luminal blockage.

 

Expansion of delivery systems is usually accomplished by two mechanisms namely swelling and unfolding. Both these mechanisms result in an increase in size of the dosage form which restricts the passage of the delivery system through the pyloric sphincter into the intestine. Swelling occurs due to the absorption of water, usually by osmosis, whereas unfolding occurs due to the mechanical shape of the pharmaceutical carrier. Swelling systems offer an additional advantage over other gastro-retentive delivery systems in that they maintain a fed state in the stomach which suppresses housekeep waves offering a prolonged gastro-retention as the bulk of the system is located within the stomach^35,36. Boldhane et al manufactured effervescent based floating and swelling gastro-retentive tablets of metformin hydrochloride using sodium alginate as a gelling agent, sodium CMC as release modifier and polymer Eudragit NE 30D as release retardant respectively. The authors used 3² full factorial design to study the effect of concentration of sodium alginate and sodium CMC on release of drug, they selected time required for 50%, time required for 90% of cumulative drug release, Flag and f₂ as 4 dependent variable. The statistical model was employed to make the optimization process very effective and quick. The authors also concluded that Low floating time and higher % swelling of the formulation are essential to increase its residence time in the stomach, thereby improving the bioavailability of the drug³⁷.

 

3. Mucoahesive drug delivery systems:

When a pressure sensitive adhesive material comes in contact with a surface, a bond is a formed by the contact between then two and phenomenon is called adhesion. The same phenomenon is termed as mucoadhesion when a polymer carrying a drug forms a bond with the mucosa membrane of stomach and the system is called mucoadhesive drug delivery system (figure 3). At the absorption or application site, these systems extend the residence time of the dosage form as the dosage form remain in intimate contact with the underlying surface of absorption that improves the drug's therapeutic performance. Till date these systems are developed for local as well as systemic effects and can be administered via oral, buccal, nasal, rectal and vaginal routes depending on the site of action and absorption at the site³⁸. Polymers like carbopol, chitosan, polycarbophil, lectins etc. are usually incorporated in these systems for mucoadhesion. These naturally occurring bioadhesive polymers allow a device to stick to the mucous membrane and develop an interaction which is hydration mediated, receptors mediated or bonding mediated adhesion with the biological membrane³⁹.

 

Figure 3: Depiction of mucoadhesive drug delivery system

 

While designing mucoadhesive drug delivery systems, dosage form must be small and flexible enough to be acceptable for patients and should not cause irritation. Other valuable features of a mucoadhesive dosage form include a high drug loading capacity, controlled drug release (preferably unidirectional release), better mucoadhesive properties, smooth surface, tastelessness and convenient application. Erodible formulations offer more benefits as they do not require system retrieval at the end of desired dosing interval. Numerous valuable mucoadhesive dosage forms have been developed for a variety of drugs. Several typical molecules such as peptides, including thyrotropin-releasing hormone (TRH), insulin, octreotide, leuprolide, and oxytocin have been successfully given via the mucosal route, though with relatively low bioavailability (0.1–5%) due to their hydrophilic characteristics and large molecular weight as well as the inherent permeation and enzymatic barriers of the mucosa⁴⁰. Awasthi et al developed hollow floating gliclazide beads using a simple ionotropic gelation technique using a combination of low methoxyl pectin and hydroxypropylmethyl cellulose. Particle size analysis of beads revealed the size of dry beads in the range of 730-890µm based on the composition of polymer and concentration of calcium carbonate. The authors also concluded that the mean diameter of beads increases with increase in the concentration of gas forming agent which may be attributed to the increased viscosity of solution. The authors used fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction technique to confirm the drug's stable character. Formulations were assessed for mucoadhesion using goat stomach mucosal membrane. The optimized formulations showed excellent bioadhesive properties for a duration of 2h in the mucoadhesion experiment. The in-vitro drug release represents Fickian diffusion with swelling⁴¹. Glipizide microspheres were also developed by Patel et al through simple emulsification phase separation method using chitosan as polymer for mucoadhesion and glutaraldehyde as a cross-linking agent. A full factorial 3² design was used using two independent variables (polymer-to-drug ratio and stirring speed) and four dependent variables (percentage mucoadhesion, t₈₀, drug entrapment efficiency). The best exhibited formulation showed entrapment effectiveness of 75%, a swelling index of 1.42, a mucoadhesion of 78% after one hour and the drug release also maintained up to 12 hours. The in vivo research in Wistar mice also reveals an important hypoglycemic impact up to 12 hours⁴². Prasanthi et al developed mucoadhesive microspheres of linagliptin by ionotropic gelation and single emulsion methods using synthetic polymers like carbopol 934P, guar gum, HPMC K100M and sodium carboxy methyl cellulose. Spherical free flowing microspheres of linagliptin were successfully prepared by emulsification method. The developed mucoadhesive microspheres has swelling index of 1.03, entrapment efficiency of 85±0.57% and the mean particle size of 135±6µm. Mucoadhesion strength was found to be 87% in 7 hrs and drug release was shown to be 98.2±0.63% in 8 hrs and release kinetics followed anomalous transport mechanism. Radiographic studies were performed in rabbits and microspheres retained for 7 h in the rabbit stomach as confirmed by the images⁴³. Sarkar et al developed poly (acrylic acid)-grafted-gellan-based gastroretentive continuous release tablets of metformin hydrochloride based on swelling and mucoadhesion. Firstly authors synthesized poly (acrylic acid)-grafted-gellan by microwave-promoted cerric (IV) ion initiated graft copolymerization technique. The yield of polymer was found to be dependent on concentration of cerric (IV) ammonium nitrate and acrylic acid. Further they developed mucoadhesive sustained release tablet using metfomin hydrochloride as drug by wet granulation. The formulations developed showed sustained release potential in simulated gastric fluid (pH 1.2) over a period of 10 hours⁴⁴.

 

4. Dual (floating and bioadhesive) systems:

These systems are usually available in the form of mucoadhesive beads, ion resin complexes, microspheres, films, and tablets which based on the combination of floatation and mucoadhesion properties together in a single dosage form. Sonar et al developed a bilayer, floating-bioadhesive dosage form based on a unique combination of floating and bioadhesive properties to extend the residence of rosiglitazone maleate in the stomach. The formulation comprises of two layers one is floating layer and other one is sustained release layer. Floating layer was prepared using 5% w/v PVP ethanolic solution and hydroxyl propyl methyl cellulose (HPMC) and sodium bicarbonate were added in the preparation to sustain the drug release. The optimized formulation showed a satisfactory profile of dissolution, detachment force, floating properties and followed first order drug release. The tablets stayed floating in the stomach for up to 8 hours, as determined in healthy human volunteers by gamma scintigraphy⁴⁵. Sah et al developed floating sitagliptin microsphere applying 3² factorial design to improve the gastric residence time and subsequent absorption of the drug in the stomach. The authors prepared microspheres using HPMC K4M and psyllium husk as swelling agents by ionotropic gelation method. In X-ray imaging in rabbits initially and after 24 hours of administration of dosage form, microspheres were found retained in the stomach. During in-vivo study sitagliptin was detected in plasma from swellable gastroretentive microsphere till the end of 24 hours post-administration, while the plasma concentration of conventional microsphere of sitagliptin was detectable till 12 hours post administration. The swelling of the developed formulation was found to be 191% to 240% and for the optimized formulation, in-vitro release of drugs was found to be 99.2% after 24 hours⁴⁶.

 

5. In-Situ Gelling systems (Raft Forming system):

Another method of gastroretention with excellent patient compliance is the in-situ gelling systems (also known as the raft forming system figure 4). These structures comprise of sodium alginate as polymer-forming gel in-situ with carbonate or bicarbonates as effervescent substances. These systems are in the solution form initially but when they come in contact the gastric fluid, they get swell to form viscous cohesive gel and generate carbon dioxide bubbles these bubbles are caught in the gel which cause drug delivery systems to float. Raft forming systems are used mostly for gastroesophageal treatment because they are likely to produce a layer on top of the gastric fluid^47,48. Metformin hydrochloride floating gastro-retentive tablets of based on in-situ gel technique were developed by Senjoti et al. Box-Behnken experimental design was used to develop tablets with effervescent and swelling properties using a combination of sodium bicarbonate and HPMC-PEO (Poly Ethylene Oxide) polymer. The developed tablets were able to float within 4 minutes, remain in floating condition for 24 h and sustained the release of drug for 12 hours. The authors also concluded that amount of polymer matrix (amount of HPMC and PEO), effervescent agent (sodium bicarbontate), and swelling enhancer (SSG) affected and floating and drug release from the formulation⁴⁹.

 

In-situ miglitide formulations, using gellan gum and sodium alginate as gelling agent, propylene glycol as co-solvent and calcium carbonate were developed by Mahmoud et al. Calcium carbonate dissociates in the acidic environment to release carbon dioxide which gets entrapped in the gel and helps in the floating. Developed formulations showed reasonable viscosity and formed a firm gel that floated over the surface in seconds and remained floating for 24 hours when it came into contact with simulated gastric fluid. In-vitro dissolution was achieved at 900 mL 0.1N HCl (pH 1.2), and the release of all formulations exceeds 70% in 24 hours. The in-vivo pharmacokinetic experiments were performed in 10 New Zealand rabbits and the results reveal 1.79 fold increase in C_max and 18.4 fold increase in AUC with the newly developed in-situ formulation compared to the one on the market. The authors concluded that use of propylene glycol in the formulation helped in solubilization the water insoluble drug⁵⁰.

 

Figure 4: Depiction of raft forming drug delivery system

 

Figure 5: Depiction of superporous hydrogel swelling systems

 

6. Superporous Hydrogels:

Superporous hydrogel (figure 5) is characterized by a three-dimensional network of hydrophilic polymer, which absorbs a huge amount of water in a short period of time, due to the presence of interconnected microscopic pores. These highly swollen hydrogels remain in the stomach for a long period of time when used as drug carriers, releasing virtually all loaded drugs, large volumes and sheer bulk of these hydrogels does not allow them to be transported through the pylorus to the next organ. This distinct swelling characteristic enables them to be used as gastro-retentive carriers that provide a sustained release through extended gastric retention. Not only are hydrogels needed to swell rapidly, but they should also be biocompatible, biodegradable, better swelling properties, strong mechanical strength and remain static in acidic situation⁵¹. Park et al developed hydrogels of chitosan-glycol and chitosan by a gas blowing method and studied their swelling behaviours in acidic solution to explore their use as a stomach retention dosage form. Firstly the stock solution of chitosan and glycol-chitosan were prepared dissolving the former in 0.01M acetic acid and latter in water respectively. The pH of the solution was adjusted to 5 by adding acetic acid, then sodium bicarbonate (blowing agent) is added to the solution and mixed vigorously by stirring for 30seconds. Foaming started immediately and completed in 2 minutes. The formed hydrogels were stored at room temperature and freeze dried before use. Both the chitosan and glycol chitosan hydrogels revealed higher swelling ratio in acidic environment than in distilled water probably due to the cationization of amine groups in acidic environment. The results also indicated that swelling of hydrogels with increasing density of crosslinking agent⁵².

 

Gupta et al formulated chitosan/poly(vinyl alcohol) interpenetrating polymer-type superporous hydrogels of Rosiglitazone maleate utilizing glyoxal as crosslinker. To induce the porous structure, sodium bicarbonate was used as a foaming agent. The swelling of the formulation depended on the amount of chitosan and crosslinker. The drug release from the superporous hydrogels was maintained for 6 hours successfully⁵³.

 

7. Magnetic Systems:

These devices contain a tiny inner magnet in the design and an external magnet is positioned on the abdomen above the stomach location. Gastro retention of the dosage form can be improved by applying an extracorporeal magnet for localization to a specific part. The site of magnet should be designated with very high precision to acquire the desired results in such systems. Thus, the factual significance of such systems is frequently doubtful⁵⁴. Angelopoulou et al developed magnetically targetable nanocarriers of the sodium-glucose transporter protein (SGLT2) inhibitor dapagliflozin for the selective delivery of dapagliflozin in tumors. The dapagliflozin-loaded PMMA-g-PEGMA nanoparticles showed concentration-dependent toxicity against the A549 cancer cell line. The application of an external magnetic magnet increases the uptake of nanoparticles by cells, leading to increased cytotoxicity. The developed nanoparticles exhibited satisfactory drug loading efficiency and high colloidal stability. Dapagliflozin release from the nanoparticles responded to an AC magnetic field to induce dapaglifozin release in close proximity to the tumor area confirming accumulation of the dapaglifozin-loaded nanoparticles at the tumor cells due to magnetic targeting⁵⁵.

 

CONCLUSION:

Gastro-retentive drug delivery systems are successfully developed and reported for antidiabetic drugs by researchers and they can do wonders if the same are available commercially. These systems are very useful for the drugs which are absorbed from the stomach. Further investigation in human volunteers still needs to done before scaling up them in to commercials. However with the advent new molecules like DDP-4 and SGLT2 inhibitors there has been a significant progress in the field of drug discovery. The formulation work is still in progress to develop the gastro-retentive dosage form of these drugs which can be commercialized. With increasing population of diabetics there is further scope of development in this field for the economical products with better therapeutic results and reduced side effects especially for prolonged use.

 

CONFLICT OF INTEREST:

The authors confirm no conflict of interest.

 

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Received on 27.12.2019           Modified on 13.02.2020

Accepted on 08.04.2020         © RJPT All right reserved