DESIGN, OPTIMIZATION AND EVALUATION OF EMPAGLIFLOZIN ORODISPERSIBLE TABLETS USING DIFFERENT SUPERDISINTEGRANTS

Objective: The objective of this study was to formulate orodispersible tablets containing empagliflozin by direct compression method with sufficient hardness and rapid disintegration time and to study the effect of functionality differences of super-disintegrants on the tablet properties. Methods: A two factor three level factorial design (3 2 Results: Formulation FD6 having 30 sec disintegration time, 98.84% drug release after 30 min, 2.8 kg/cm ) was used for the formulation optimization of orodispersible tablets of Empagliflozin and experimental trials were performed on all possible formulations, in which the amount of β -cyclodextrin, crospovidone and croscarmellose sodium were selected as independent variables (factor) varied at three different levels: low (-1), medium (0), and high (+1) levels. The drug release and disintegration time were used as dependent variables (response). All formulations were characterized for parameters such as diameter, hardness, weight, thickness, friability, disintegration time, drug release. Conclusion: Empagliflozin orodispersible tablets with different superdisintegrants were successfully prepared and formulation containing highest percentage of crospovidone was found best among all other formulations in terms of bioavailability and rapid onset of action. hardness and 0.292% friability was found best among all formulations and selected as an optimized formulation with rapid onset of action and enhanced bioavailability (more than 98% drug release within 30 min.) as compared to the oral empagliflozin tablet. the best formulation in terms of flow property, disintegration time (30.5 sec),, wetting time (30.1 sec), drug content and maximum percentage drug release 98.8% within 30 min. Thus, the present study demonstrated the potential of the formulated orodispersible tablets for rapid absorption, improved bioavailability, effective therapy, and improved patient compliance by defeating all the problems of swallowing as compared to the oral empagliflozin tablets. ) factorial design.


INTRODUCTION
Among all oral dosage forms; the tablet is most favored because of ease of administration, compactness, and flexibility in manufacturing. In addition, the solid dosage form has the advantage, due to high stability, easy transportation and high precision in administration. However, one of the problems with solid form is dysphagia, which is more common among children, the elderly, and other individuals with nausea and vomiting, aphthous stomatitis due to chemotherapy, Parkinson disease, motion sickness, lack of consciousness, and mental disability [1][2][3][4]. The pediatrics and geriatrics patients are of particular concern. To overcome this, orodispersible tablets have been developed. Orodispersible tablets dissolve completely and rapidly. Orodispersible tablets are considered as one of the novel solid dosage forms which turn immediately into liquid in less than a minute and release their drug into the mouth after taking into the mouth and touching saliva. These tablets have had a huge improvement in recent years due to high patient compliance and ease of administration. Orodispersible tablets have the benefits of solid dosage forms and after taking into mouth have the benefits of liquid dosage forms. Moreover, reduction of the first-pass metabolism, rapid onset of action, and higher bioavailability are expected [5][6][7]. Though, lack of strength and taste masking is of great concern.
The orodispersible tablets prepared by direct compression method, in general, are based on the action established by super disintegrants such as crospovidone and croscarmellose sodium.
Empagliflozin is a sodium glucose co-transporter (SGLT-2) inhibitor that is the new class of oral hypoglycemic agent and indicated as an adjunct to exercise and diet to improve glycemic control in adult patients of type-2 diabetes (non-insulin-dependent diabetes) [8]. The SGLT-2 co-transporters are responsible for reabsorption of glucose from the glomerular filtrate of the kidney, so inhibition of SGLT-2 promotes excretion of blood glucose. Empagliflozin also contributes to reduced hyperglycemia and assists in weight loss and reduction of blood pressure.
It works by stimulating the release of your body's natural insulin. Controlling high blood sugar helps prevent heart disease, strokes, kidney disease, blindness and circulation problems, as well as sexual function problems (impotence). Mechanism of action is produced by blocking potassium K+ channels in beta cells of islets of Langerhans. The increase in calcium will initiate more insulin release from each beta cell. It increases the concentration of insulin in the pancreatic vein. By this, it decreases glucose concentration.
In pharmaceutical field, the β-cyclodextrins are crystalline complexing agents, versatile that have the ability to increase the bioavailability, solubility, and stability of the drug, mask the color and taste of the drugs. In this work solubility of empagliflozin was enhanced by complexing it with β-cyclodextrin.
Since oral absorption of empagliflozin from oral tablet is comparatively poor (takes almost 3 h to get absorbed), hence an effort was made to enhance its absorption by formulating it as the orodispersible tablet. The objective of the present work is to develop orodispersible empagliflozin tablets and to study the effect of functionality differences of super disintegrants on the tablet properties [9]. Orodispersible tablets are gaining prominence as new drug-delivery systems. These dosage forms dissolve or disintegrate in the oral cavity within a minute without the need for water or chewing [10]. The objective of the study was to enhance safety and efficacy of drug molecule to achieve better compliance by solving the problem of difficulty in swallowing, to enhance the onset of action and to provide stable dosage form.

MATERIALS AND METHODS
Empagliflozin was obtained as a gift sample from Novartis Pharmaceuticals (Hyderabad). β-cyclodextrin was purchased from chem. Center, Crospovidone and croscarmellose sodium were purchased from Yarrow Chem Products Ltd. Microcrystalline Cellulose, mannitol, magnesium stearate, talc, methanol, potassium chloride, silica gel G were obtained from Lobachem Pvt. Ltd.
Aspartame, potassium dihydrogen phosphate, sodium hydroxide, hydrochloric acid were obtained from Merck. All other chemicals and solvents used were of analytical grade.
Prior to formulation preparation, a calibration curve of empagliflozin was prepared in methanol, phosphate buffer pH 6.8 HCl, distilled water and then solubility of empagliflozin was determined in various mediums spectrophotometrically at 221.3 nm using UV-visible spectrophotometer (Shimadzu-1800). The compatibility of the drug was assessed by drug-excipient interaction study. The drug was mixed with various excipients in a 1:1 ratio in glass vials which were properly sealed and labeled and kept undisturbed at 50 °C temperature and 75% RH for 15 d. Physical and chemical observations of all the mixtures were done on the initial day and 15th day by thin layer chromatography (TLC) using silica gel G as stationary phase and toluene: methanol (7:3v/v) as mobile phase [11].

Formulation development
A two factor three level factorial design (3 2 10 mg of Empagliflozin with β-CD in the different ratio was taken. βcyclodextrin was taken in mortar-pestle. Subsequently, drug was incorporated slowly into it and trituration was further continued for one hour and passed through sieve no. # 60 [14][15][16]. ) was used for the formulation optimization of the orodispersible tablet of Empagliflozin and experimental trials are performed at all 12 possible formulations, in which the amount of β-cyclodextrin (β-CD), crosspovidone and croscarmellose sodium were selected as independent variables (factor) varied at three different levels: low (-1), medium (0), and high (+1) levels. The drug release and disintegration time were used as dependent variables (response) [12,13].

Bulk density
This was calculated by using the formula:

Tapped density
Tapped density was calculated by using the following formula:

Carr's index
Carr's index of the powder blend was determined by using the formula: Where, Vo = Tapped density of powder,

Angle of repose
The angle of repose was calculated by measuring the diameter and height of powder cone and putting the values to the following equation.
Where h= height of the cone. r = radius of the cone.

Solubility determination
An excess amount of prepared Empagliflozin: β-cyclodextrin inclusion complex at different concentration (1:1, 1:2) were separately dissolved in 5 ml phosphate buffer pH 6.8 in vials and sealed properly and stirred continuously at 37 °±2 °C. The process was repeated until saturation-solubility of inclusion complex. The solution was kept for 24 h at room temperature. The solution was filtered and adequately diluted with phosphate buffer pH of 6.8. The solution was analyzed using UV-visible spectrophotometer at 221.3 nm [22].

Physical characterization
All the batches were evaluated for weight variation, hardness, friability, thickness as per IP. The weight variation was determined by taking 20 tablets using electronic balance. Tablet hardness was determined for 10 tablets using a Monsanto tablet hardness tester. Friability was determined by testing 20 tablets in a Roche friability tester for 4 min at 25 rpm.

In vitro disintegration time
In vitro disintegration time was performed according to the monograph of IP. The six tablets for determining the disintegration time were placed in each tube of the disintegration test apparatus and the time required for the disintegration of each tablet was measured at 37±0.5 °C using 900 ml distilled water.

Drug content
Ten tablets were taken and the amount of drug present in each formulation of the tablet was determined. The tablet was crushed in a mortar-pestle and equivalent to 10 mg of drug was dissolved in phosphate buffer pH 6.8 in a 100 ml volumetric flask. Volume was made up to 100 ml. The sample was filtered through filter paper.
From this solution 1 ml was taken in a 10 ml volumetric flask and diluted with phosphate buffer pH 6.8. Further, 1 ml was taken and diluted up to 10 ml and analyzed for drug content by UV spectrophotometer at 221.3 nm using phosphate buffer (pH 6.8).

Wetting time and water absorption ratio
A piece of tissue paper folded twice was placed in a small petridish containing 10 ml of water. A tablet was put on the tissue paper and the time required for the water to diffuse from the wetted absorbent paper throughout the tablet was then recorded using a stopwatch.

For water absorption ratio
The wetted tablets were reweighed. The water absorption ratio R was determined using the following equation Where, Wa = Weight of the tablet after water absorption Wb = Weight of the tablet before water absorption [23][24] In vitro drug release study In vitro drug release study was determined by dissolution test apparatus. The water level was maintained in the water bath up to the specific mark and 900 ml of phosphate buffer pH 6.8 was poured in dissolution vessel. The tablets were put in each vessel and paddle was allowed to rotate at 50 rpm for 30 min and the temperature was maintained at 37±0.5 °C. At the definite time intervals 5, 10, 15, 20, 25, 30 min the aliquots of the dissolution medium (5 ml) were withdrawn and the same volume of the medium (6.8 pH phosphate buffer) was replaced to maintain the sink condition. The samples were analyzed for drug release by UV-visible spectrophotometer at λ max 221.3 nm using phosphate buffer pH 6.8 as blank.
At the same time in vitro drug release data of formulated optimized orodispersible tablet was compared with the marketed oral empagliflozin tablet.         Distilled water 0.106±0.002 *All data are given in mean±SD, n=3 Drug: β-CD (1:2) 11.525±0.006 *data are given in mean±SD, n=3

Drug-excipient interaction study
The drug (Empagliflozin) was found to be compatible with various excipients which were selected for the formulation of the orodispersible tablet. The compatibility was assessed by TLC and the retention factors of all ratios found similar.

Evaluation of precompression parameters of powder
The bulk density, tapped density, Carr's index, Hausner's ratio and angle of repose of selected formulations were performed and shown in table no.7.8. The results show that all formulations that possess a good flow property.

Evaluation of post-compression parameters of orodispersible tablet
The orodispersible tablet of Empagliflozin was evaluated for weight variation, hardness, thickness, friability, disintegration time, drug content, wetting time and water absorption ratio. The results of the studies were shown in the below table:

In vitro drug release study of orodispersible tablet
The percentage cumulative drug release from formulations FD1 to FD12 was determined. The formulation FD6 showed the highest release (%) within 30 min.        The bulk density, tapped density, Carr's index, angle of repose and Hausner's ratio of optimized formulations ware performed and shown in table no. 14. All the results show that the optimized formulations possess a good flow property.

Evaluation of post-compression parameters of optimized tablet (FD6)
The orodispersible tablet of Empagliflozin was evaluated like weight variation, hardness, thickness, friability, and disintegration time, drug content, wetting time and water absorption ratio and in vitro drug release study. The results of the study were shown in below table:   In vitro drug release study of the orodispersible tablet (FD6) The percentage cumulative drug release from formulations (FD6) was found to be approximately 98% within 30 min.

DISCUSSION
In this work, we have attempted to enhance the solubility of empagliflozin in aqueous media by making the inclusion complex. The FDTs were prepared by direct compression method. Empagliflozin orodispersible tablets were prepared by direct compression method using different super-disintegrants (crospovidone and croscarmellose sodium) and other excipients. A total number of 12 formulations were prepared by direct compression method. The pre-formulation studies such as bulk density, tapped density, the angle of repose, compressibility index and Hausner ratio were evaluated. All the data obtained from physicochemical parameters such as hardness, friability, and weight variation, drug content, wetting time, disintegration time, dispersion time and in vitro drug dissolution are found within limits. Results showed that crospovidone has greater super-disintegration power as compared to croscarmellose sodium in the same percentage (12.5%) for orodispersible tablets [25]. Therefore out of all formulations, F6 was found satisfactory in terms of rapid onset of action, enhanced absorption as compared to the marketed oral empagliflozin tablet.

CONCLUSION
The present research work envisages the applicability of superdisintegrants such as crospovidone and croscarmellose sodium in the design and development of orodispersible tablets of Empagliflozin utilizing the (3 2 In the present work solubility of the drug was enhanced by using inclusion complex. The formulations prepared using direct compression, were evaluated for precompression parameters which were found to be within limits. The increased concentration of the super-disintegrants enhanced the porosity of the tablet, due to which it reduced the disintegration time and wetting and maximum drug release in 30 min. Compressed tablets were evaluated for post-compression parameters which were found to be good. From all the results it is concluded that formulation FD6 containing crospovidone was found to be the best formulation in terms of flow property, disintegration time (30.5 sec),, wetting time (30.1 sec), drug content and maximum percentage drug release 98.8% within 30 min. Thus, the present study demonstrated the potential of the formulated orodispersible tablets for rapid absorption, improved bioavailability, effective therapy, and improved patient compliance by defeating all the problems of swallowing as compared to the oral empagliflozin tablets.