Formulation and Evaluation of Sustained Release Floating Drug Delivery System of Candesartan Celexitil

 

Mukesh P. Ratnaparkhi*

Department of Pharmaceutics, Marathwada Mitrah Mandal College of Pharmacy,

Thergoan (Kalewadi), Pune-33.

 

ABSTRACT:

The objective of this study was to develop the Candesartan celexitil gastro retentive sustained release floating matrix tablet using gas generating approach to prolong the gastric residence time. This can be achieved by formulating modified gastro retentive sustained release dosage forms which resides in the stomach for the sufficient time to release the drug in vicinity of the absorption zone. The tablet were prepared by direct compression, by employing semi-synthetic polymer like HPMC K15M and HPMC K100M in various concentrations. Sodium bicarbonate was employed as gas generating agent. The powdered blend evaluated for angle of repose, bulk density, tapped density, compressibility index, Hausner ratio. The results obtained were satisfactory. Compressed formulation were further evaluated for thickness, friability, hardness, swelling index, and In-vitro dissolution studies. All the formulations showed good results which were in compliance with  Pharmacopoeia standards. A 3² Factorial design was used to select the optimized formulation wherein  HPMC K15(X1) and HPMC K100M were taken as a independent variables and floating lag time(FLT), Floating time(FT), Percentage Drug Release(%) after 12hrs,were taken as dependent variables. Optimization studies were carried out by using the Design Software Version 8.0.1. The in-vitro cumulative % drug release of all formulations ranged from F₅ at the end of 12hrs. The in-vitro drug release followed by Higuchi model and the drug release mechanism was found to be non-fickian type. This kinetic studies were carried out by using the PCP Disso Version 2.08 software, and the model with the higher correlation was considered to be the best model .

 

 

 

INTRODUCTION:

Candesartan celexitil is an orally active non-peptide angiotensin-II receptor antagonist, used in the treatment of hypertension due to mainly blocked of AT1 receptor. The main reason for low therapeutic effectiveness of Candesartan celexitil is its narrow absorption window, narrow therapeutic index, poor bioavailability as 25-35%, and short biological half-life 1.5-2 h. Historically, oral route has been the most predominant route of drug delivery due to its ease of administration, low cost of therapy, patient compliance and flexibility in its formulation. Variable and too rapid gastrointestinal transit has been the major limitation of oral sustained release delivery. Rapid gastrointestinal transit results in incomplete release of drug from the delivery device leading to diminished efficacy of the administered dose.

 

For improved availability of administered dose, novel dosage forms having the ability to retain in the stomach for longer duration are being formulated. Gastro-retentive dosage form is a type of novel drug delivery system which can remain in the stomach for prolonged period of time and thereby increases gastric residence time of drugs. Gastro-retention helps to improve bioavailability of drugs^[1,2].

 

Drugs which are easily absorbed from the gastro-intestinal tract and those with short half-life are quickly eliminated from the systematic circulation need frequent dosing. To overcome this problem, gastro-retentive drug delivery systems which provide effective plasma drug concentration for longer periods thereby reducing the dosing frequency are being formulated. It also has an advantage of minimizing the fluctuations in plasma drug concentration by delivering the drug in a controlled and reproducible manner. Pharmaceutical research is becoming progressively more oriented towards the development of special dosage form which releases drug slowly throughout GI tract^[1,3,4].

 

It has application also for the drug delivery to the stomach and proximal small intestines providing better availability of new product with new therapeutic possibility and substantial  benefits for patient. Therefore, the different approaches have been proposed to retain the dosage forms in the stomach including bio-adhesive system, swelling and expending system, floating system and delayed gastric emptying devices ^[5,6]. The principle of buoyant preparation offers the practical approach to achieve increased gastric residence time for the dosage form and sustained drug release using gel forming hydrocolloids such as hydrophilic gums, gelatin, alginates and cellulose derivatives^[5]. Optimization techniques have been applied to the present study to systematically study the influence of process variables on the formulation of dosage forms. These designs provides an effective means for studying the effect of various parameters on the dependent variables^[7].

 

MATERIALS AND METHODS:

Materials:

Candesartan celexitil was received as a gift sample from Cadila HealthCare Pvt.Ltd., HPMC K15M and HPMC K100M grade was procured as gift sample from Colorcon Pvt. Ltd., Magnesium stearate, Lactose, Sodium bicarbonate, Microcrystalline Cellulose were obtained from Research Chem Lab Pvt. Ltd.

 

Method:

Preparation of Sustained Release Tablets

Candesartan celexitil sustained release tablets were prepared by direct compression method. Powder mix was sifted using sieve no.80# and was lubricated by talc and magnesium stearate. Finally, tablet were punched using single 8mm punch tablet machine. All tablets were stored in airtight container at room temperature for further study. Formulation of Factorial design batches is shown in Table no.1.

 

Evaluation:

Fourier Transform Infrared (FT-IR) Studies.

FT-IR spectra of pure candesartan celexitil and its respective physical mixtures were taken to assure the compatibility between pure candesartan celexitil and excipients. Fig.1,2 shows infrared spectrum of candesartan celexitil and optimized batch by scanning the sample in KBr discs(Shimanzu FT-IR).

 

Differential Scanning Colorimeter (DSC) Studies.

The thermal behavior of Candesartan celexitil were examined by DSC, using Mettler Toledo Technology Differential Scanning Calorimeter (DSC, STAR SW 12.10). In case of Candesartan celexitil a single sharp endothermic effect corresponding to the melting of drug was observed

T_peak= 205.12^oC.

 

Powder XRD Studies.

P-XRD Studies of pure candesartan celexitil and its respective physical mixtures were taken to assure the compatibility between pure candesartan celexitil and excipients. Fig. represents the P-XRD spectra of Candesartan celexitil. The sharp peaks were observed at 2θ values are 5.69, 10.17, 11.76, 12.95, 17.62, 19.02, 20.71, 22.50, 23.69, 25.28 and 29.46. The sharp peaks were indicates the crystalline nature of drug. The XRD spectrum of formulation show peaks of drug with decreased intensity at 2θ values 5.19, 12.45, 13.75, 19.71, 21.10 and 29.86. The XRD spectrum of formulation with diminished intensity of sharp peaks of drug indicates the amorphous nature of drug entrapped in polymer matrix.

 

UV determination of drug

Preparation of standard stock solution

Standard stock solution containing 100ppm of Candesartan celexitil was prepared in 0.1N Methanol. From the stock solution, different aliquots were taken and diluted to 10ml with methanol to obtained series of concentrations. The solution scanned on spectrophotometer in UV range 200-400nm. Candesartan celexitil showed absorbance maxima at 255nm as shown in fig.3.^[8]

 

Pre-compression Parameter

Angle of Repose (θ)

This parameter is useful to measure resistance of particles to movement. The static heap of powder, when only gravity acts upon it, will tend to form a conical round. One limitation exists; the angle to horizontal plane cannot exceed a certain value and this is known as angle of repose. (θ).This parameter is useful to measure flow properties of powders especially for compression. There is an empirical relationship between values of (θ) and the ability of powder to flow. The value of angle of repose can be used guide to type of flow to expect from particular powder blend. Usually values of (θ) range between 20^o to 40^o. At (θ) values above 50^o, powder flows with difficulty.

 

Bulk Density (D_b)  and  Tapped Density (D_t)

Thebulk density and tapped density of the drug was determined by using USP method. The specific weighed quantity of drug was added in the measuring cylinder. Their volume was noted down to calculate bulk density. After tapping the volume was again noted down to calculate the tapped density. The bulk and tapped densities of drug was determined by following formula-

 

Bulk density (gm/cm³) = Weight of powder/Bulk volume.

Tapped density (gm/cm³) = Weight of powder/Tapped volume

 

Compressibility Index

A simple indication of the ease with which a powder can flow is given by application of a compressibility index (I). The compressibility index was determined by the following equation-

I = [1-V/V_o] x 100

Equation 1: Compressibility Index

Where, V_o = Bulk volume; V = Tapped volume.

Values of I, below 15% usually indicates good flow properties, but readings above 25% indicate poor flowability.

Hausner’s Ratio

Hausner ratio is an index of ease of powder flow; it is calculated by the following formula.

 

Hausner’s ratio = D_t/D_o

Where, D_t= Tapped density, D_o= Bulk density.

Evaluation of powder blends is shown in Table no.2

 

Post-compression parameter

Uniformity of Thickness and Diameter

The uniformity of the diameter and thickness was measured using the vernier caliper. The average diameter and thickness of the tablet was calculated. The test passed if none of individual diameter and thickness value deviated by ±5% of the average.

Hardness

 

The resistance of tablets to shipping or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The hardness of tablet was measured by Monsanto hardness tester (Nevtex). The hardness was measured in terms of kg/cm².

 

Friability

Friability is the measure of tablet strength. Rochhe friabilator was used for testing the friability. Twenty tablets were weighed accurately and placed in the tumbling apparatus that revolves at 25 rpm dropping the tablets through a distance of six inches with each revolution. After 4 minutes, the tablets were weighed and the percentage loss in tablet weight was determined.

 

Uniformity of Weight

Weigh 20 tablets at random and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown and none deviates by more than twice that percentage.

 

Determination of Drug Content

For drug content, accurately weighed tablets was selected and ground to fine powder. An amount equivalent to 50 mg drug was dissolved in 0.1N Metanol and filtered through filter paper. The filtered solutions of appropriate dilutions were analyzed at 255 nm using UV spectrophotometer. The amount of Itopride was determined by measuring the absorbance at 255 nm.

 

Floating Lag Time

The time taken for dosage form to emerge on surface of medium called Floating Lag Time (FLT) or Buoyancy Lag Time (BLT) and duration of time by which the dosage form constantly emerge on surface of medium called Total Floating Time (TFT).

 

Swelling Study

Swelling of tablet excipient particles involves the absorption of a liquid resulting in an increase in weight and volume. Liquid uptake by the particle may be due to saturation of capillary spaces within the particles or hydration of macromolecule. The liquid enters the particles through pores and bind to large molecule, breaking the hydrogen bond and resulting in the swelling of particle. The extent of swelling can be measured in terms of % weight gain by the tablet. One tablet was weighed and placed in a beaker containing 20 ml of 0.1 N HCL. After each hour the tablet was removed from beaker and weighed up to 5 hours. The % weight gain by the tablet was calculated by the formula, Swelling Index

 

(S.I.) = {(Wt-Wo) / Wo} ×100

 

Where,

S.I. = Swelling index.

Wt = Weight of tablet at time t

Wo = Weight of tablet before immersion

 

In-vitro Release Study

The release of Candesartan celexitil for different formulations of floating tablets was determined using USP dissolution test apparatus (type II). The dissolution medium was 900 ml in 0.1N HCl at 37±0.2°C with a stirring speed of 50 rpm. Aliquots of 5 ml were withdrawn at predetermined intervals of 1 hr., filtered and replaced by equivalent volume of fresh dissolution media. The test sample was filtered through membrane filter, (0.45 μm) and the concentration of drug release was determined by using UV- Visible Spectrophotometer at λ_max 255 nm.

 

Drug Release Kinetics

The dissolution profile of all the batches were fitted to zero order kinetics, first order kinetics, Higuchi, Hixon-crowell, Krosmeyer and Peppas to ascertain the kinetics modeling of the drug release by using a PCP Disso version 2.08 software, and the model with the higher correlation coefficient was considered to be the best model . The observations were summarized in the Table 4.

 

Analysis of Data by Design Expert Software

A 3² full factorial design was selected and the 2 factors were evaluated at 3 levels respectively. (Table7). The percentage of HPMC K15M(X₁) and HPMC K100M(X₂) were selected as independent variables and the dependent variables were lag time, float time, and percentage drug release. The data obtained were treated using Stat Ease Design Expert 8.0.7.1 software and analyzed statistically using analysis of variance (ANOVA). The data were also subjected to 3-D Response Surface Methodology to study the interaction of HPMC K15M (X₁) and HPMC K100M (X₂) on dependent variables.

 

 

Table 1: Formulation of Factorial Design batches.

Name of Ingridient	F1	F2	F3	F4	F5	F6	F7	F8	F9
Candesartan celexitil	32	32	32	32	32	32	32	32	32
HPMC K15M	55	55	45	45	55	55	45	45	50
HPMC K100M	45	45	45	45	55	55	55	55	50
Sodium Bicarbonate	20	20	20	20	20	20	20	20	20
Lactose	97	87	77	77	67	67	87	97	77
MCC	30	20	30	30	20	20	20	30	20
Magnesium stearate	1	1	1	1	1	1	1	1	1

 

Table2: Evalution of Powder blend

 

Table 3: Evaluation of various parameters of Tablet of factorial design batches.

 

Table 4: Data of drug release rate kinetics.

 

 

 

Table 5: Amount of variables in 2³ factorial design batches.

Level	Factors-Actual values
	X1	X2	X3
+1	55	45	20
-1	45	55	30

(where X1-concentration of HPMC K15M,X2-concentration of HPMC K100M,X3- concentration of Sodium bicarbonate,(+1) high level of X1,X2,X3 , (-1) low level of X1,X2,andX3)

 

Table 6: Stability data for optimized formulation (F3)

Sr. No.		Tests	Observation	Result
1		Physical evaluation	-	-
	a.	Appearance	White to off white in color Same as initial tablet color	Passes
	b.	Thickness (n=5)	6.5± 0.1	Passes
	c.	Hardness (n=5)	1.        0.1	Passes
2		Drug Content (%) (n=2)	99. 7  ± 1.01	Passes

 

Table 7 Design Summary

Factor	Name	Units	Type	Low Actual	High Actual	Low coded	High coded
A	HPMC K15M	%	Numerical	80	120	-1	+1
B	HPMC K100M	%	Numerical	80	120	-1	+1

 

Fig. 1: UV spectrum of Candesartan celexitil drug.

 

Fig.2 : Infrared spectra of  Candesartan celexitil drug.

 

Fig. 3.  FTIR Spectra of (A) Pure drug ,(B) drug+HPMC K 15, (C) drug + HPMC K 100.

 

Fig. 4 : DSC Thermogram of Candesartan celexitil.

 

Fig.5 : DSC Thermogram of Final Formulation.

 

Fig.6: P-XRD spectra of Candesartan celexitil

 

Fig.7:P-XRD spectra of formulation

 

Time (Hrs.)

Fig. 8 : Percent Cumulative Release of Formulation F1 to  F9.

 

Fig. 10: Response Surface Plot For Lag Time.

 

Fig.11: Response Surface Plot For Float Time

 

Fig. 12: Response Surface Plot For Percent Drug Release.

 

Fig. 13: Swelling Index of Factorial Design Batches Vs Time

 

Stability Studies:

The optimized formulation was placed into the petri plate and kept in stability chamber at (40 ± 2^oC, 75%  ± 5% RH) for a period of 90 days. Then sample was observed for any physical changes and evaluated for cumulative percentage drug release.

 

RESULT AND DISCUSSION:

Batches of Candesartan celexitil were prepared according to Table no.1 by using HPMC K15M and HPMC K100M by direct compression method. The value of pre-compression parameter evaluated within prescribe limits and indicated good free flowing property data shown in Table no.2

 

Results showed that powder blend have angle of repose from 27.30±1.40, Carr,s index from10.40±0.55,and Hausner’s ratio from 1.176±0.05 ,which indicate good flow  property. The data obtained from post-compression parameters such as weight variation, hardness, friability, dissolution studies, drug content are shown in Table no.3 Hardness, thickness, and friability were found to be in range of 7.6±0.1, 6.33±0.07,0.13±0.03respectively,which is an acceptable criterion in tablet formulations. In all the formulations, hardness taste indicates good mechanical strength; friability is less than 1% which indicates that tablets had a good mechanical resistance. Drug content was found to be high 97% and uniform in all formulations.

 

Floating lag time and Total gastric residence time is shown in table no.3 Total gastric residence time was observed in 12hrs,for all formulations and buoyancy lag time. A lesser floating lag time and desired total floating duration could be achieved by varying the amount of gas forming agent and using different polymer combination.

 

The tablet were subjected to dissolution studies. Fig.8 depicts the dissolution behavior of the tablets. It was observed that when drug and HPMC K15M and HPMC K100M were used as polymer in the concentration of 1:2 desired dissolution behaviors was achieved. The drug released was for 12 h as compared to all formulations and followed Higuchi model for drug release kinetics.

 

The quadratic model obtained from the regression analysis used to build in 3D graphs in which the response were represented by curvature surface as a function of independent variables presented in a Fig.9, 10, 11 .The response surface plots were generated using Design Expert 8.0.1 software to observe the effect of independent variables on the response studied such as floating lag time and percent cumulative release respectively. Graphical presentation of the data helped to show the relationship between the response and the independent variables and optimized batches were studied showing better response for 12 h duration time.

 

CONCLUSION:

The investigation carried out so far has encouraged for drawing the following conclusion: A 3² full factorial design was performed, and the desired release of Candesartan celexitil from the floating tablet was achieved through careful monitoring of the selected formulation variables. Further the release from the floating studies suggested that the desired floating profile of gastro retentive floating drug delivery system could be achieved while maintain the desired release properties of formulation. The statistical approach for formulation optimization is useful tool, particularly when two or more variables are to be evaluated simultaneously. The mathematical model generated by regression analysis can be used to predict and optimize the formulation variables. The prediction from the model confirm to the experimentation results, thus indicating the validity of the model. The variables HPMC K15M and HPMC K100M evaluated in this study exhibited significant effect on the responses FLT. Float Time and Percentage Drug Release of the formulations; however HPMC K15M and HPMC K100M affected the release profile. The formulated formulation leads to the development of sustained release of Candesartan celexitil, avoided dose dumping and extended duration of action with prolonged floating time i.e. 12hrs.  Overall, a sustained release intragastric floating system for Candesartan celexitil has been successfully developed using the 3² full factorial design. The formulation F5 showed desired response with respect to FLT, Float time and Percent drug release. A step by step procedure of the stastical method has been illustrated in this study which can be extrapolated to the development of GRDDS containing other drugs; exhibiting bioavailability problems in proximal G.I.tract. The designed drug system holds promise to further study  i.e. stability and in-vivo studies leading to IVIVC for commercialization.

 

ACKNOWLEDGEMENT:

The authors are thankful to Cadila Health-Care Pvt. Ltd., for gift sample of Candesartan celexitil, Research Lab. Chem Pvt. Ltd for gift samples of HPMC and Sodium bicarbonate, lactose, magnesium stearate, MCC.

 

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Received on 10.08.2014          Modified on 20.08.2014

Accepted on 05.09.2014          © RJPT All right reserved