INTRODUCTION:

Pulsatile drug delivery systems are characterized by a rapid drug release after a predetermined lag time. These can be classified as single unit (e.g. tablet or capsule) or multiparticulate (e.g. pellets) systems. Multiparticulate also known as multiple unit dosage forms appear to be more reliable for a time controlled adjustment in drug release due to their smaller variation in gastric transit time. Hence multiparticulate dosage forms are gaining considerable importance over single-unit dosage forms. The advantages include low risk of dose dumping, reduced risk of local irritation, increased bioavailability as well as short and reproducible gastric residence time ^1-4.

Majority of the pulsatile drug delivery systems contain a drug reservoir, surrounded by a barrier, which erodes/ dissolves or ruptures.

The major mechanism of controlled drug release from the pellets is dependent on the type of coating; insoluble coating under all physiological conditions, pH-dependent coating and slowly erodible coating. The method of application and processing conditions may influence the porosity of coating and consequently the release mechanism⁵. Thus modified drug release could be achieved by incorporating release rate controlling polymers such as acrylic polymers commonly known as enteric polymers or ethylcellulose⁶. Enteric polymers are frequently used for coating, because they can provide drug release profiles that are triggered by the pH of the surrounding environment along the GI tract. Majority of enteric polymers are insoluble at low pH, they dissolve at pH in the range 4.8-7.0 ^7-10. Controlled release technologies whose release based on pH of the GI tract are designed to release drugs in the GI tract depending on the pH of the GI fluids, which can vary from pH 1.2-3.5 in the stomach to pH 6.0-7.5 in the lower small intestine^{11, 12}. Thus the time-controlled systems or delayed release systems can be prepared easily for delivering weakly acidic drugs, since these are soluble at intestinal pH. Eudragit^® S100 and Eudragit^® RS were frequently used for coating, which are known to be pH-dependent and time dependent polymers respectively^{11, 13}. The pH sensitive multiparticulate systems of diltiazem was demonstrated for colon delivery by some researcher, where they had used microcrystalline cellulose as spheronizing aid, PVP K-30 as binder and coated with Eudragit^® S100 for effective drug release at colonic pH¹⁴.

The aim of the present work was to assess the suitability of such a coating approach in achieving time-specific drug release, using valsartan pellets coated with acrylic polymer dispersions such as Eudragit^® RS and Eudragit^® S100. Valsartan, antihypertensive, a long-acting angiotensin receptor blocker (ARB), has been reported for treatment of early morning surge in blood pressure (BP). In our earlier attempt pulsatile capsule-based drug delivery system was developed successfully for delayed delivery of valsartan¹⁵. In the present study, valsartan pellets were prepared and coated with acrylic polymers and studied for various physicochemical tests and in vitro release studies.

MATERIALS AND METHODS:

Materials:

Valsartan, Avicel PH-101, Lactose, Polyvinyl pyrolidone (PVP K-30), hydroxypropylmethyl cellulose (HPMC E-5), Talc, Aersoil 200, Eudragit^® S100 and Eudragit^® RS are obtained as gift samples from Lupin Research Park, Pune, India. HPLC grade Acetonitrle and Methanol, were purchased from Merck Specialties Ltd., Mumbai. Milli-Q water was produced in the lab using the Milli-Q water generator (Millipore (India) Pvt. Ltd., Bangalore). All other chemicals and reagents were used are of analytical grade, purchased from standard chemical manufacturers.

Methods:

Preformulation studies:

Micromeritic properties of drug and mixture of drug with polymers were determined such as bulk density, tapped density, Carr’s compressibility index and Hausner’s ratio^{16, 17}.

Drug–excipient compatibility studies were carried out by Infrared Spectroscopy and Differential Scanning Calorimetry (DSC). Infrared spectra were recorded by using KBr pellet technique using a Shimadzu FT-IR 8300 Spectrophotometer (Shimadzu, Tokyo, Japan) in the wavelength region of 400 to 4000 cm−1. The procedure consisted of dispersing a sample (drug alone or mixture of drug and excipients or formulation) in KBr and compressing into discs by applying a pressure of 5 tons for 5 min in a hydraulic press. The pellet was placed in the light path and the spectrum was obtained. DSC scans were performed using a DSC-60 (Shimadzu, Tokyo, Japan) calorimeter. The instrument comprised of a calorimeter (DSC 60), flow controller (FCL 60), thermal analyzer (TA 60) and operating software (TA 60). The samples (drug alone or mixture of drug and excipients or formulation) were heated in sealed aluminum pans under nitrogen flow (30 mL/min) at a scanning rate of 5°C/ min from 25 to 150°C with indium as a reference. The heat flow as a function of temperature was measured¹⁵.

Preparation of pellets by extrusion/ spheronization method:

The pellets of valsartan were prepared by using Extruder Spheronizer¹⁸ (Umang Pharmatech Pvt. Ltd., UICE-Lab, Mumbai, India). The compositions of core pellets are given in Table 1.

Preparation of dry blend:

Valsartan, lactose, and Avicel PH-101 were weighed accurately mixed in double cone blender (HD-410 AC, Kalweka, Mumbai, India).

Preparation of binder solution:

Polyvinyl pyrolidone (PVP K-30) or hydroxypropylmethyl cellulose (HPMC E-5) solution was prepared by dissolving weighed quantity in distilled water under stirring.

Preparation of wet mass:

The granulating fluid/ binder solution was added in small increments to dry blend until a desirable end point was obtained.

Extrusion:

The wet mass was passed through the extruder equipped with screw and screen with 0.5 mm aperture at 50 rpm. The extrudate was prepared by varying the speed of extruder to get extrudate with good appearance.

Spheronization:

The extruded material was transferred to a spheronizer having plate diameter 2.0 mm and spheronized for 1 min at 800 rpm. The effect of spheronization speed and time were studied to get spherical pellets.

Drying and sieving:

The spheronized pellets were then dried in a vacuum oven at 40°C for 24 h. The sieving analysis was performed using standard sieves. The pellets passed through sieve # 20 and retained on sieve # 40 (0.42–0.84 mm) were used for enteric coating.

Table 1. Composition of core pellets

Ingredients	Concentration (% w/w)
Ingredients	B-1	H-1/P-1	H-2/P-2	H-3/P-3
Valsartan	20.0	20.0	20.0	20.0
Avicel PH-101	40.0	39.5	38.75	37.5
Lactose	40.0	39.5	38.75	37.5
PVP K-30/HPMC E-5	-	1.0	2.5	5.0
Water	qs	qs	qs	qs

Coating of the pellets:

Dried pellets were weighed accurately and lubricated with 0.1% talc. The composition of coating solutions is given in Table 2. Eudragit^® and talc were dispersed/ dissolved separately in solvent mixture and then mixed together. The triethyl citrate solution was mixed with Eudragit^®-talc dispersion using overhead stirrer for 30 min. The coating solution was passed through sieve # 100 to get a clear dispersion and was used for coating. Pellets were coated in a pharma R&D coater (Model: delux, Ideal Cures Pvt. Ltd., Mumbai, India) and operated under the following conditions¹⁸.

Coating conditions:

Inlet air temperature : 30-35°C

Bed temperature : 30°C

Pan speed : 20 rpm

Atomizing air pressure : 1.5 bar

Spray rate : 2-2.5 g/min

Spray nozzle diameter : 0.8 mm

The coating solution was applied when the pellet bed in the coating pan reached 30°C. The coating dispersion was stirred continuously throughout the coating process to prevent sedimentation of insoluble particles. The pellets were coated until the desired film weight was deposited (15% w/w, 20% w/w and 25% w/w). The coating level (based on polymer in coating) was calculated from the weight difference between the coated and the uncoated pellets. The coated pellets were lubricated using Aersoil 200 and talc (0.5% w/w; 1:1).

Table 2. Composition of coating solution

Ingredients	Composition (% w/w)
Ingredients	Eudragit^® S100	Eudragit^® RS
Polymer	3.0	3.0
Triethyl citrate	1.2	1.2
Talc	0.9	0.9
Isopropanol	91.9	56.94
Water	3.0	-
Acetone	-	37.96

Filling of capsules:

The empty hard gelatin capsules size ‘0’ were used and capsules were filled with pellets using a hand filling machine (ProFill 100 System, Torpac Inc., NJ, USA). Unit formulae for 80 mg valsartan capsule filled with coated pellets are given in Table 3.

Table 3. Unit formula for 80 mg valsartan capsule

Ingredients	Quantity/capsule (mg)
Ingredients	15%	20%	25%
Valsartan	80.0	80.0	80.0
Avicel PH-101	155.0	155.0	155.0
Lactose	155.0	155.0	155.0
PVP K-30	10.0	10.0	10.0
Eudragit^® S100/RS	35.29	47.06	58.82
Triethyl citrate	14.11	18.82	23.54
Talc	10.6	14.12	17.64

Characterization of extrudates and pellets:

Surface appearance:

Extrudates were kept on dark non-reflective background and the surface of extrudates was observed, whether it was smooth, rough or wrinkled.

Size analysis:

The pellets were sieved through a nested set of sieves (BS410) from sieve # 60 to 10 (0.25 to 2 mm) for 10 min, using mechanical electromagnetic sieve shaker (EMS-8). The pellets retained on each sieve fraction were collected and weighed. From this, graph was plotted as cumulative percentage weight fraction versus size^{19, 20}. Arithmetic mean diameter was calculated using the following formula;

Where, Di = arithmetic mean diameter, Wi = weight retained on the sieve and Xi = Mean diameter of the sieve.

Content uniformity:

Accurately weighed samples of the Eudragit^®-coated pellets (100 mg) were dissolved in methanol, filtered, and analyzed spectrophotometrically (UV-1601PC, Shimadzu, Tokyo, Japan) for valsartan content at 250 nm after suitable dilution with phosphate buffer pH 6.8. The study was performed in triplicate.

Weight variation:

Twenty capsules were selected randomly from the lot and weighed individually to check for weight variation. Percentage deviation from average weight was calculated.

Micromeritic properties:

The packing ability was evaluated from the changes in volume due to rearrangement and packing occurring during tapping process. The Carr’s compressibility index (%) and Hausner’s ratio of the coated pellets were computed on the basis of tapped bulk density and bulk densities^{16, 17}.

Pellet friability:

Friability of pellets was assessed by using friabilator (USP EF-2, Electrolab, Mumbai, India). Pellets were subjected to sieve analysis and friability was evaluated as weight loss²¹.

Wi = the initial weight of the pellets; Wf = the weight of pellets retained over sieve # 40 aperture after friability testing.

Drug content:

The pellets were crushed and 100 mg of powder was dissolved in 100 mL of phosphate buffer pH 6.8 (n=3). The solution was then passed through a Whatmann (no. 1) filter and analyzed by UV–Visible spectrophotometer (UV 1601 PC, Shimadzu, Japan) at 250 nm after sufficient dilution with phosphate buffer pH 6.8.

FTIR and DSC analysis of pellets:

Powdered pellets were analyzed by Infrared Spectroscopy and Differential Scanning Calorimetry for determining the possible interaction between drug and excipients after formulating into pellets as explained above under sub-heading preformulation studies.

Scanning Electron Microscopy:

The shape and surface morphology of the pellets was studied from the micrographs taken with the Scanning Electron Microscope (JEOL, JSM-5610LV, Tokyo, Japan). The samples were mounted on double sided adhesive tape that has previously been secured on copper stubs and then analyzed. The accelerating voltage was 15 kV.

Image analysis:

The pellet shape and size were determined by Feret diameter and aspect ratio of at least 100 pellets of each using an image analysis program. Image analysis was conducted using a system consisting of a Motic BA 400 microscope attached to a computer with software (Motic Incorporation Ltd., Hong Kong). Images of the pellets at a suitable magnification were taken for each pellet and Feret diameters were determined. The ratio of the maximum Feret diameter and the Feret diameter perpendicular to the maximum Feret diameter is used as the aspect ratio²².

In vitro dissolution studies:

The dissolution test was carried out using a USP Type II dissolution apparatus (TDT-06P, Electrolab, Mumbai, India) at 37 ± 0.5°C and a paddle speed of 75 rpm. The study was carried out in 900 mL of 0.1 N HCl for the first 2 h, followed by 900 mL of phosphate buffer pH 6.8 for 3 h and continued with 900 mL of phosphate buffer pH 7.4 ²³. The coated pellets filled into the capsules (size 0) were tied to circular wire mesh of diameter 2 cm and immersed in the dissolution medium. At different time intervals, 5 mL of sample was withdrawn and analyzed by UV–Visible spectrophotometer at 250 nm. At each time of withdrawal 5 mL of corresponding fresh medium was replaced into the dissolution vessel.

The dissolution of optimized formulation was studied in simulated gastric fluid for 2 h, and then in simulated intestinal fluid up to 12 h. The amount of drug released was analyzed by validated HPLC method using following conditions.

Stationary phase : BDS Hypersil Phenyl C₁₈ column (250 mm × 4.6 mm, 5 µm)

Mobile phase : 10 mM phosphate buffer pH 3.0: Acetonitrile (50:50)

Detection wavelength : 250 nm

Flow rate : 0.8 mL/min

Injection volume : 20 µL

Temperature : 25°C

Sample temperature : 4 ± 2°C

Stability Studies:

The optimized pellets were filled in capsules and charged for the accelerated stability studies according to ICH guidelines Q1C (40 ± 2°C/75 ± 5% RH) for a period of 6 months in humidity chambers (Thermolab, Mumbai, India). They were placed in USP Type-1 flint vials and hermetically sealed with bromobutyl rubber plugs and aluminum caps. The samples (n=3) were taken out at 0.5, 1, 2, 3 and 6 months and evaluated for the drug content and in vitro release studies.

RESULTS AND DISCUSSION:

The drug loaded pellets were produced by extrusion spheronization technique using microcrystalline cellulose (Avicel PH-101) as a spheronizing aid with different binders. Different coat weights of Eudragit^® (RS and S100) were applied to the drug loaded pellets to produce the pH sensitive pellets.

Preformulation studies:

As a part of preformulation studies, micromeritic properties of drug and excipients were studied. The results of micromeritic properties are given in Table 4. The Carr's index (20.26 ± 1.06%) and Hausner’s ratio (1.254 ± 0.017) of valsartan were high, this may not be ideal, whereas, the prepared formulation mixtures showed good flow properties as indicated by low values of Carr's index and Hausner’s ratio. This might be due to the mixing of valsartan with excipients having considerable flowability.

The possible interaction between the drug and the excipients were studied by FTIR spectroscopy and DSC. The carbonyl absorption bands of valsartan at 1730 and 1603 cm⁻¹ remained unchanged in the physical mixture. Also, there was negligible change in the melting endotherm of the drug when combined with excipients. The drug showed melting peak at 97.61°C.

Table 4. Micromeritic properties of drug-excipient mixtures and core pellets (Mean ± SD)

Formulations	Carr’s Index (%)	Hausner’s ratio	Friability of core pellets (%)
Drug	20.26 ± 1.06	1.254 ± 0.017 0.017	- 0.017
B-1	15.28 ± 0.18 0.28	1.18 ± 0.06 0.004	6.9 ± 0.57 0.004
H-1	13.75 ± 0.14 0.28	1.159 ± 0.012 0.004	3.8 ± 0.22 0.004
H-2	14.29 ± 0.24 1.45	1.17 ± 0.01	2.92 ± 0.14
H-3	15.84 ± 0.17 1.45	1.19 ± 0.008	0.93 ± 0.26
P-1	15.38 ± 1.05 1.45	1.18 ± 0.016	2.42 ± 0.13
P-2	15.80 ± 0.72	1.19 ± 0.0072	1.63 ± 0.74
P-3	16.13 ± 0.05	1.19 ± 0.003	0.54 ± 0.11

Optimization of extruder-spheronization process parameters:

All steps involved in the preparation of pellets are to be given equal attention as these parameters control the quality of pellets. The mass prepared for pellets should be homogeneous throughout so that the extrudates formed should not show any signs of adherence to each other. Speed of extruder was found to be critical parameter in controlling the properties of extrudates. When speed of extruder was increased to 80 rpm, extrudates formed were too small and when speed was 30 rpm extrudates formed were large with rough surface. 50 rpm was found to be optimized to produce extrudates with sufficient length and surface smoothness without wrinkles. Similarly, the rotation speed of spheronizer also had influence on properties of pellets. When 1000 rpm was used, clumps or doublets pellets were produced with more fines. At 600 rpm, size of pellets was not uniform. At higher spheronization time, at 2 min and 3 min pellets formed were in the form of lumps. Thus spheronization at 800 rpm for 1 min was found to be suitable for producing spherical pellets.

Characterization of core pellets:

Practical yield and drug content:

The practical yield of pellets was found to be 95 ± 2.5%. Drug content of all the formulations was found to be 98 ± 1.72%. Drug was found to be uniformly distributed among the pellets as evident from content uniformity study.

Fig. 1. Particle size distribution of coated pellets

Particle Size:

The method of sieving measures the minimum width of the particle, which may not be its actual diameter in the case of ellipse or dumbbells. In the case of round pellets the sieving measurement would be the diameter. This method of size assessment gives a rough idea of the size of the pellets. The majority of pellets were of near-spherical shape. The particle size distribution data of the core pellets indicated that majority of the pellets fall in the size range 0.42–0.84 mm. Mean diameter of pellets (H and P) was found to be 0.63 mm. Whereas, mean diameter of pellets without binder was 0.36 mm. The particle size distribution is shown in Fig. 1. Those which were retained on sieve # 10 (2 mm) were the doublets and triplets, whereas those that passed through sieve # 60 (0.25 mm) were the fines with spherical shape. High spheronization (1000 rpm) speed yielded wider size distribution and large amount of fines were generated. At lower speed (600 rpm), arithmetic mean diameter was at higher side (1.42 mm). At medium speed narrow size distribution neither agglomeration nor fines were generated.

Friability:

Percentage friability of core pellets is given in Table 4. Friability was found to be very high for B-1, pellets were irregular and fragile, due to absence of binder. Addition of binder improved the characteristics of pellets as shown in Table 5. Least friability was observed with pellets containing 5.0% PVP K-30.

Table 5. Micromeritic properties of coated pellets (Mean ± SD)

Formulations

Carr’s Index (%)

Hausner’s ratio

Friability (%)

Eudragit^®RS

15%

20%

25%

13.85 ± 0.24

13.43 ± 0.19

14.11 ± 0.13

1.161 ± 0.04

1.155 ± 0.05

1.164 ± 0.08

0.40 ± 0.17

0.43 ± 0.07

0.32 ± 0.12

Eudragit^® S100

15%

20%

25%

13.69 ± 0.14

14.29 ± 0.26

14.75 ± 0.18

1.159 ± 0.02

1.167 ± 0.08

1.173 ± 0.06

1.01 ± 0.05

0.65 ± 0.11

0.55 ± 0.08

Optimization of core pellets:

Type and concentration of binder:

Binders are usually added either dry or in liquid form during granulation process. Modified natural polymers such as methylcellulose, HPMC and hydroxypropyl cellulose act as binders as well as adhesives. PVP is a synthetic polymer used as an adhesive. The effect of different concentrations of HPMC E-5 and PVP K-30 on appearance and performance of pellets was studied. Strength of extrudate was not considerable and the shape of pellets was not spherical due to lack of binder (B-1). Accordingly, H-1 to H-3 batches were prepared using HPMC-E5 as binder. Higher concentration of binder produced dumbbell shaped pellets. However, lower concentration of binder produced pellets with more fines and size distribution was not uniform. At medium concentration of binder, pellets with uniform size distribution were obtained. Compared to HPMC, the pellets prepared with PVP K-30 (2.5% w/v), were obtained in near-spherical shape with good appearance.

Scanning electron microscopy:

SEM images of HPMC and PVP pellets are shown in Fig. 2. Surface morphology revealed that pellets were of near-spherical shape. Surface of H-3 pellets was rough whereas, surface of pellets containing PVP K-30 (P-2) was smooth in appearance. Pellets were found to be discrete and devoid of cracks.

Image analysis:

The quality of the pellets was analyzed by the shape using aspect ratio. An aspect ratio lower or equal to 1.1 was considered good for pharmaceutical pellets²². All formulations were nearly spherical and the aspect ratio varied between 1.02 and 1.40. The pellets prepared using PVP K-30 as binder P-2 showed satisfactory aspect ratio 1.12 ± 0.12 and pellets containing HPMC E-5 binder H-2 showed aspect ratio of 1.23 ± 0.16.

In vitro release studies;

Dissolution profile of core pellets containing different binders was studied (Fig. 3). All pellets showed 100% release at the end of 45 min. Initial release was slow with pellets containing PVP K-30 compare to HPMC E-5. In the case of HPMC, as the concentration of binder was increased release of valsartan from pellets was improved. As the concentration of PVP increased, release of valsartan was decreased.

Based on in vitro release studies and SEM analysis, pellets containing 2.5% PVP K-30 were found to optimized for coating with methacrylate polymers. In addition these pellets showed good micromeritic properties with less friability. The results were supported by the study carried out by Garekani et al., wherein PVP K-30 found to be better binder than different grades of HPMC⁶.

Methacrylate coated pellets:

The optimized pellets were coated with Eudragit^® RS and Eudragit^® S100 at different coating levels (15%, 20% and 25%).

Characterization of coated pellets:

FTIR and DSC:

IR spectra of valsartan and the prepared core pellets are shown in Fig. 4. The results revealed no considerable changes in the IR peaks of valsartan in the prepared formulation when compared to pure drug. The results of DSC studies are given in Fig. 5.

Fig. 3. In vitro release profile of core pellets containing different binders: a) HPMC E-5; b) PVP K-30

Fig. 4. IR spectra: a) Drug; b) and c): Pellets coated with Eudragit RS and Eudragit S100

Pure valsartan showed a sharp endotherm at 97.61°C corresponding to its melting point, whereas the coated pellets showed melting endotherm of 98.42°C and 96.93°C for Eudragit^® RS and S100 respectively. There was no appreciable change in the melting endotherm of the valsartan when compared to the coated pellets. This observation further supported by the IR spectroscopy results, which indicated the absence of interactions between drug and selected excipients used in the formulation of pellets.

Fig. 5. DSC Thermograms: a) Drug; b) and c): Pellets coated with Eudragit RS and Eudragit S100

Micromeritic properties:

The pellets exhibited good flow properties and packability as evident from the micromeritic properties. The micromeritic properties of different coated pellets are given in Table 5.

Scanning electron microscopy:

The SEM photomicrographs of coated pellets are given in Fig. 6. The surface morphology of coated pellets showed good sphericity and smooth surface after coating.

Fig. 6. SEM images of Eudragit S100 (25%) coated pellets a) 35X; b) 500X

In vitro drug release of coated pellets:

In vitro dissolution studies of the coated pellets performed using pH progression method. For simulating conditions of the GI tract, dissolution studies were carried out in media with 0.1N HCl pH 1.2, phosphate buffer pH 6.8 and phosphate buffer pH 7.4 ^23,
24. Study showed that the drug release depended on the coat weights applied and pH of the dissolution media. The dissolution profile of coated pellets is shown in Fig. 7. None of the formulations shown release in buffer pH 1.2, even though the capsule was dissolved. This is due to resistance of these polymers in dissolution media with lower pH. As Eudragit^® S100 is soluble at above pH 7, when media was changed from pH 6.8 to 7.4, outer coat of pellet was dissolved and drug was released. At 15% and 20% coating level about 17.9 ± 2.64 and 10.5 ± 1.8% drug was released at the end of 5 h. Whereas, less than 2% drug was released with 25% coating and showed 5 h lag time. Eudragit^® RS 20% and 25% coated pellets showed lag time of 5 ± 0.5 h, but release was very slow after the lag time. Pellets with 15% coat weight showed fast release, but lag time was only 3 h. The dissolution study revealed that pellets coated with Eudragit^® S100 with 25% weight gain can be optimized and used for further study.

Stability Studies:

Accelerated stability studies were carried out according to ICH guidelines for optimized formulation. The results indicated that coated pellets (Eudragit^® S100-25%) did not show any physical changes (appearance) during the study period and the drug content (n=3; mean±SD) was found above 97.0% at the end of 6 months. There was no significant change in the release profile of the pellets stored under accelerated conditions. Log % drug remaining was plotted against time and shelf life of the formulation was calculated (Fig. 8). Shelf life was found to be 2.11 year for Eudragit^® S100-25% coated pellets.

Fig. 7. In vitro release profile of coated pellets: a) Eudragit S100; b) Eudragit RS

Fig. 8. Accelerated stability studies of Eudragit S100 pellets at 40°C/ 75%RH

CONCLUSION:

Valsartan pellets were successfully prepared and characterized for various parameters. This delayed release multiparticulate pellets, triggered the release of the valsartan due to the pH of the release media. Eudragit^® S100 coated valsartan pellets showed complete drug release after a specified lag time, found to be potentially useful formulation for chronotherapy of hypertension which can control the time and duration of drug release better than conventional formulation.

ACKNOWLEDGEMENTS:

Authors are thankful to Department of Science and Technology, New Delhi India for providing financial support to carry out the research work.

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Received on 05.12.2012 Modified on 18.12.2012

Research J. Pharm. and Tech. 6(1): Jan. 2013; Page 96-104