Formulation Optimization and Evaluation of Push Pull Osmotic Pump Tablet of Vildagliptin

Bari M. M.¹*, Ashwini V. Patil¹, Ubhale R. J.¹, Barhate S. D.¹, Mohd. Nasir²

¹Department of Pharmaceutics, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner, Dist - Jalgaon, Maharashtra, 424206.

²Medley Pharmaceuticals Ltd., Andheri (East), Mumbai - 400 093.

*Corresponding Author E-mail: manojbari40@gmail.com

ABSTRACT:

Purpose- The present study was to develop an oral push-pull osmotic pump tablet of vildagliptin, DPP-IV inhibitor drug; which is BCS class I drug. Method- The tablets were prepared by the wet granulation method using polyox and osmotic agent NaCl. The granules were compressed into bilayered tablet by conventional compression machine. The bilayered core osmotic tablets were coated with cellulose acetate in a conventional pan coating. In-vitro dissolution was evaluated using USP dissolution apparatus II in 0.1 N HCl pH 1.2 buffers for 2 hrs and phosphate buffer pH 7.5 for 22 hrs respectively. The formulated optimized batch VP1 were kept to stability studies for 3 months. Result- The formulated optimized batch VP1 of PPOP tablet shows 2hrs lag time with zero order release kinetic. In –vitro drug release was obtained 91.45 % up to 22hrs respectively. Polyox in push-pull layer along with osmotic agent and cellulose acetate controlled the drug release pattern from formulated PPOP tablet. No significant changes were observed upto the period of 3 months of storage during stability study. Conclusion- The PPOP tablet of vildagliptin was able to deliver the drug in controlled pattern over a long period of time by the process of osmosis. Conventional compression and pan coating method can be used to prepare PPOP tablet successfully.

KEYWORDS: PPOP, Bilayered tablet, Polyox, Sodium chloride, Vildagliptin, Cellulose acetate, Factorial design.

INTRODUCTION:

Push–pull osmotic systems (PPOS), also known as push–pull osmotic pumps, have been successfully developed and marketed to extend the release of poorly soluble compounds for various indications, such as hypertension, diabetes, and asthma. In these chronic disease treatments, PPOS were reported as a drug delivery technology reducing the food interaction often observed  with poorly soluble drug substances as well as enabling a once-a-day administration and thereby patient compliance.

Vildagliptin is the DPP-IV inhibitor class of drug with antidibetic activity. This in turn inhibits the inactivation of GLP-1 by DPP4, allowing GLP-1 to potentiate the secretion of insulin in the beta cells. Systemic bioavailability is 90% and elimination half life is 1.5hr.

MATERIAL AND METHOD:

MATERIAL:

Vildagliptin and cellulose acetate, Polyox WSR coagulants, polyox WSR N 80 were obtained as gift sample from Medley Pharma Ltd., Andheri.HPMC5cps, ethanol, were purchased from Jinendra Scientific Jalgaon.

METHOD:

Osmotic core tablets were prepared by wet granulation method using conventional tablet compression machine as a bilayered tablet. The core tablets were coated with cellulose acetate as a semi permeable membrane material in conventional pan coating.

Table 1: Formulation of Optimized batches of Push-Pull Osmotic Pump Tablet of Vildagliptin:^14,15 

Sr. No.	Ingredients	Batches (Pull Layer)
		VP1	VP2	VP3	VP4	VP5	VP6	VP7	VP8	VP9
1	Vildagliptin	100	100	100	100	100	100	100	100	100
2	Polyox WSR N80	85	80	85	92.06	80	77.92	85	90	90
3	MCC	10	15	10	2.94	15	17.08	10	5	5
4	HPMC 5CPS	4	4	4	4	4	4	4	4	4
5	Ethanol	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
6	Magnesium Stearate	1	1	1	1	1	1	1	1	1
	Total	200	200	200	200	200	200	200	200	200
Sr. No	Ingredients	Batches (Push Layer)
1	Polyox WSR coagulant	70.25	65.25	63.18	70.25	75.25	70.25	77.33	75.25	65.25
2	Sodium Chloride	25	30	32.07	25	20	25	17.92	25	30
3	HPMC 5CPS	4	4	4	4	4	4	4	4	4
4	Brilliant Blue Lake	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
5	Ethanol	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s	q.s
6	Magnesium Stearate	0.25	0.25	0.25	0.25	0.25	0.25	0.25	0.25	0.25
	Total	100	100	100	100	100	100	100	100	100

Table 2: Coating Solution Composition for Optimized Batches of PPOP Tablet of Vildagliptin

Ingredient	Batches
	VP1	VP2	VP3	VP4	VP5	VP6	VP7	VP8	VP9
Cellulose acetate	10	10	10	10	10	10	10	10	10
PEG 3350	0.62	0.64	0.66	0.68	0.70	0.72	0.74	0.76	0.78
Acetone	132	132	132	132	132	132	132	132	132
Purified water	6.0	6.0	6.0	6.0	6.0	6.0	6.0	6.0	6.0
Weight gain (%w/w)	10	9	8	9	9	8	9	8	10

Evaluation of Push-Pull Osmotic Pump Tablet:¹³

1) Weight Variation:¹⁷

● Weigh individually 20 whole tablets, and calculate the average weight.

●  The requirements are met if the weights of not more than 2 of the tablets differ from the average weight by more than the percentage listed in the accompanying table and no tablet differ in weight by more than double that percentage.

2) Thickness:¹⁸

Tablet thickness is an important parameter to be controlled to facilitate packaging. Tablet thickness must be controlled within a ± 5% variation of a standard value. Thickness of all the formulations was measured using a Vernier caliper. It is expressed in mm.

3) Hardness:¹⁹

Tablets require a certain amount of strength or hardness to withstand mechanical shocks of handling in manufacture, packaging, and shipping. Tablet hardness of all the formulations were measured using a Monsanto hardness tester. It is expressed in kg/cm².

4) Friability:¹⁹

Friability is a measure of the resistance of the tablet to abrasion. Friabilator subjects the tablets to the combined effects of abrasion and shock by utilizing a acrylic chamber that rotates at 25 rpm, dropping the tablets form a height of 6 inches with each revolution. Twenty tablets were weighed accurately and placed in the friabilator and was operated for 100 revolutions or 4 minutes.

The tablets were then dedusted and weighed. The weight loss of 0.5 to 1% is considered as acceptable limits for conventional uncoated tablets.

5) Drug Content:^13,20

Five tablets of each batch of formulation were weighed and crushed in mortar. Powder equivalent to 10 mg of vildagliptin was weighed and dissolved in 10 ml of Phosphate buffer pH 7.5. This was the stock solution from which 0.1 ml sample was withdrawn and diluted to 10 ml with Phosphate buffer pH 7.5. The absorbance of this solution was measured at wavelength 209.20 nm using double beam UV-Visible spectrophotometer.

In-Vitro Drug Release Study of Optimized Batches of Ppop Tablet of Vildagliptin:^13,21

In-vitro drug release study of optimized batches were performed by employing the USP type II method (Electrolab TDL-08L) at 37^ᵒ±0.5^ᵒC at 50rpm and 0.1N HCl pH 1.2 for 2hrs, phosphate buffer pH 7.5 for 22hrs as dissolution medium. During the study 5ml sample were withdrawn at every hour at same amount of fresh dissolution medium was replaced. The withdrawal sample ware diluted to the required concentration and analyzed spectrophotometrically (UV1800, Shimadzu) at 210.70 and 209.20nm.

Study of Kinetics and Mechanism of Drug Release:²²

The in- vitro release data for the optimized batch was fitted to various release kinetic models. The best model was found to be describing the kinetic of drug release. To understand the drug release kinetic and mechanism of drug release, all the in-vitro release data were fitted to various kinetic models such as zero order, first order, and Higuchi and Korsmayer-Peppas models. Different model expressing drug release Kinetic were shown in Table No.6

RESULT AND DISCUSSION:

Table 3: Precompression Parameters of Optimized Batches of PPOP Tablet of Vildagliptin

	Bulk Density (g/ml)	Tapped Density (g/ml)	Carr’s Index (%)	Hausner’s Ratio	Angle of Repose (ᵒ)
Pull layer
VP1	0.34 ± 0.01	0.39 ± 0.02	12.82±3.42	1.14±0.02	30.66± 0.34
VP2	0.39 ± 0.005	0.45 ± 0.01	13.33±2.96	1.15±0.04	35.81± 0.43
VP3	0.32 ± 0.00	0.37 ± 0.00	13.51±0.00	1.15±0.00	33.84± 0.40
VP4	0.37 ± 0.01	0.46 ± 0.01	20.93±3.97	1.24±0.04	33.04± 0.30
VP5	0.41 ± 0.005	0.50 ± 0.01	18±0.88	1.21±0.01	34.65± 0.39
VP6	0.39 ± 0.01	0.46 ± 0.02	15.21±1.39	1.17±0.02	35.32± 0.72
VP7	0.40 ± 0.011	0.48 ± 0.01	16.33±1.25	1.19±0.04	31.44± 0.83
VP8	0.33 ± 0.01	0.38 ± 0.01	13.15±0.32	1.15±0.005	32.55± 1.47
VP9	0.35 ± 0.01	0.42 ± 0.00	16.66±2.38	1.2±0.03	34.17± 0.95
Push layer
VP1	0.33 ± 0.01	0.38 ± 0.00	13.15±2.63	1.15±0.03	28.73±0.72
VP2	0.32 ± 0.02	0.39 ± 0.01	17.94±3.23	1.21±0.04	31.10±0.74
VP3	0.31 ± 0.00	0.37 ± 0.00	18.91±0.00	1.19±0.00	33.17±0.46
VP4	0.34 ± 0.02	0.40 ± 0.02	15±4.88	1.17±0.06	32.10±1.52
VP5	0.35 ± 0.01	0.42 ± 0.01	16.66±0.38	1.2±0.01	35.07±0.48
VP6	0.34 ± 0.01	0.41 ± 0.01	17.07±4.69	1.20±0.06	34.32±0.10
VP7	0.26 ± 0.015	0.36 ± 0.02	27.77±0.76	1.38±0.015	33.99±0.23
VP8	0.29 ± 0.01	0.36 ± 0.00	19.44±2.78	1.24±0.04	33.66±0.39
VP9	0.30 ± 0.01	0.37 ± 0.01	18.91±4.64	1.23±0.08	32.61±0.79

*All the values were in mean ± SD, n= 3

Table 4: Post Compression Parameters of Optimized Batches of PPOP Tablet of Vildagliptin

Post Compression Parameter	Batches (Uncoated Tablet)
	VP1	VP2	VP3	VP4	VP5	VP6	VP7	VP8	VP9
Weight variation (mg)	300 ± 1.15	299 ± 0.57	298 ± 0.57	298 ± 0.57	299 ± 1.0	298 ± 0.57	299 ± 0.57	299 ± 1.73	297 ± 1.73
Thickness (mm)	5.24±0.02	5.23± 0.005	5.24± 0.005	5.30± 0.02	5.24± 0.03	5.23± 0.03	5.28± 0.02	5.26± 0.02	5.28± 0.05
Hardness (Kg/cm^2)	4.7 ± 0.05	4.5 ± 0.1	4.8 ± 0.11	4.9 ± 0.15	4.4 ± 0.26	4.7 ± 0.1	4.6 ± 0.15	4.6 ± 0.25	4.8 ± 0.15
Friability (%)	0.80 ± 0.01	0.65 ± 0.015	0.67 ± 0.01	0.73 ± 0.01	0.69 ± 0.01	0.72 ± 0.01	0.68 ± 0.02	0.79 ± 0.01	0.77 ± 0.01

*All the values were in mean ± SD, n= 3

Post Compression Parameter	Batches (Coated Tablet)
	VP1	VP2	VP3	VP4	VP5	VP6	VP7	VP8	VP9
Weight variation (mg)	330 ± 0.57	328 ± 2.51	329 ± 2.0	328 ± 1.52	328 ± 2.0	329 ± 1.15	327 ± 2.51	329 ± 2.0	330 ± 2.08
Thickness (mm)	5.53±0.01	5.52± 0.005	5.54± 0.01	5.75± 0.058	5.52± 0.01	5.53± 0.02	5.55± 0.01	5.55± 0.02	5.59± 0.01
Hardness (Kg/cm^2)	5.9 ± 0.05	5.0 ± 0.1	5.8 ± 0.11	5.3 ± 0.15	5.4 ± 0.26	5.7 ± 0.1	5.6 ± 0.15	5.6 ± 0.25	5.8 ± 0.15
Drug content (%)	92.97	93.88	94.33	92.16	92.65	91.47	92.78	95.98	93.33

*All the values were in mean ± SD, n= 3

Fig.1: In – Vitro Drug Release from Optimized Batches of PPOP Tablet of Vildagliptin (VP1-VP9)

Data Analysis and Optimization:

Two factor, three level central composite design (CCD) was used and response surface methodology applied to investigate the relative significance of the two variables, Polyox N80 (X1) and NaCl (X2) and their interaction on the responses i.e. percentage drug release (Y1), hardness (Y2) and thickness (Y3). Based on preliminary trials, levels of Polyox N80 were selected as 40, 42.5, and 45 % whereas levels of NaCl were 20, 25, 30%.

Regression Equation for the Quadratic and Linear Models:¹⁶

% Drug Release

Final equation in terms of coded form

% DR = 91.45– 0.3058X₁ – 0.1473X₂ – 0.1350X₁X₂ – 1.16X₁² – 2.11X₂²

Concerning dissolution, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear negative sign. It revealed that % drug release increases with decrease in polyox WSR N80 and NaCl. Less amount of polyox WSR N80 and NaCl was expected to increase the % drug release due to controlled release of tablet. ANOVA was used to identify the significant effect.  The result was found to be significant at that level of probability (p<0.05).

Hardness (Kg/cm²)

Final equation in terms of coded form-

Hardness= 4.68+ 0.0979X₁ + 0.0729X₂

Concerning hardness, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear positive sign. It revealed that hardness increases with increase in polyox WSR N80 and NaCl. Polyox WSR N80 42.5% w/w and NaCl 25% w/w were selected as the optimum concentration that showed the maximum hardness of 4.68kg/cm². It was observed that further increase in concentration of polyox WSR N80 to the increase the hardness.  ANOVA was used to identify the significant effect. Obtained value of F is larger than critical F-value, the result was found to be significant at that level of probability (p<0.05).

Thickness (mm)

Final equation in terms of coded form

Thickness = 5.53 + 0.0514X₁ + 0.0032X₂ + 0.0100X₁X₂ + 0.0431X₁² – 0.0044X₂²

From the results of multiple linear regression analysis, the coefficients X1 and X2 bear a positive sign for thickness of tablet. Addition of more amounts ofpolyox WSR N80 and NaCl increases the thickness. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (p<0.05).

Table 5: Results of Analysis of Variance for Batches by CCD of Vildagliptin PPOP Tablet

Y1= % Drug Released Model Residual Total	SS*	DF*	MS*	F*	P value Prob.>F
	37.5 3.67 41.17	5 7 12	7.50 0.5242 ---	14.31 --- ---	0.0015 –significant --- ---
Y2= Hardness Model Residual Total	0.0874 0.0695 0.1569	2 10 12	0.0437 0.0069 ---	6.29 --- ---	0.0170 -significant --- ---
Y3= Thickness Model Residual Total	0.0353 0.0105 0.0457	5 7 12	0.0071 0.0015 ---	4.72 --- ---	0.0331-significant --- ---

*DF indicates degrees of freedom; SS sum of square; MS mean sum of square and F is Fischer’s ratio.

Fig.2: 3D Response Surface Graph Showing the Influence of Polyox N80 (X1) and NaCl (X2) On the % DrugReleased (Y1)

Fig.3:3D Response Surface Graph Showing the Influence of Polyox N80 (X1) and NaCl (X2) On the Hardness (Y2)

Fig.4: 3D Response Surface Graph Showing the Influence of Polyox N80 (X1) and NaCl (X2) On the Thickness (Y3)

Fig.5: Overlay Plot Showing Composition of Optimized Batch of PPOP Tablet of Vildagliptin

Table 6: Results of Drug Release Kinetics Model

Batch	R^2
	Zero Order	First Order	Higuchi	Korsmeyer- Peppas
VP-1	0.964	0.947	0.936	0.905

Fig.6: Graph of Zero Order Kinetic Model

CONCLUSION:

Osmotic drug delivery system uses the osmotic pressure as a driving force to deliver the drug in a controlled pattern over a long period of time by the process of osmosis. The formulated and optimized batch of PPOP tablet of vildagliptin VP1 released 91.45% for a period of 24 hrs for once a day administration of vildagliptin. Since once a day formulation for vildagliptin is much needed for the treatment of diabetes. Conventional compression and pan coating method can be used to prepare PPOP tablet successfully. The developed formulations have a great market potential.

CONFLICT OF INTEREST:

The authors declare that have no competing interests.

ACKNOWLEDGEMENT:

Authors specially wish to express their sincere thanks to Department of Pharmaceutics, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research Jamner, Dist. Jalgaon, Maharashtra for providing the laboratory facility to carry out this research work.

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Received on 04.01.2022         Modified on 08.04.2022

Accepted on 04.06.2022 ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech. 2022; 12(3):207-212.

DOI: 10.52711/2231-5713.2022.00034