INTRODUCTION:

The popularity of controlled-release multiple unit dosage forms has increased when compared to single unit dosage forms. Although similar drug release profiles can be obtained with both types of dosage forms, multiparticulate offers several advantages. The coated pellets spread uniformly throughout the gastrointestinal tract and high local drug concentrations can be avoided, along with the risk of a localized toxic reaction due to a restricted tablet in the gastrointestinal tract. Premature drug release from enterically coated dosage forms in the stomach may result in drug degradation or irritation of the gastric mucosa. These problems can be reduced with coated pellets due to the rapid transit time when compared to enterically coated tablets. The better distribution of multiparticulate throughout the GI-tract has, in several instances, improved the drug bioavailability, which potentially could result in a reduction in the side effects and the drug dosage requirements. Inter- and intra-individual variations in bioavailability that may be caused by food effects are often reduced with multiparticulates¹.

An ideal drug delivery system is one which provides the drug only when and where it is needed, within these systems a solute/drug is dispersed within a polymer matrix. When the system is introduced to a good solvent for the polymer, swelling occurs allowing increased mobility of the solute, and it diffuses out of the polymer into the surrounding fluid. Such a system should provide a programmable concentration-time profile that produces optimum therapeutic responses. Recent developments in polymeric delivery systems for the controlled release of therapeutic agents has demonstrated that these systems not only can improve drug stability both in vitro and in vivo by protecting unstable drugs from harmful conditions in the body, but also can increase residence time at the application site and enhance the activity duration of short half-life drugs. Therefore, compounds which otherwise would have to be discarded due to stability and bioavailability problems may be rendered useful through a proper choice of polymeric delivery system².

The combination of hydrophilic gums are used for the controlled release multiparticulate drug delivery system was developed by using hydrophilic gums as release modifier polymers. In this influence of the combination of Xanthum gum, Karaya gum and Gaur gum on swelling and viscosity were investigated. The combination of Captopril and gum blend in ratio 1:1.5 and Hydrochlorthizide and gum in 1:0.5 ratio are optimize. Captopril and Hydrochlorthizide have synergistic antihypertensive action act by inhibiting ACE, block the active re-absorption of sodium (Na⁺) and chloride (Cl^-) with water in the distal tubule respectively^3-5

MATERIALS AND METHODS:

Materials:

Captropil was obtained as gift sample from Lupin pharmaceuticals, Aurangabad, Hydrochlorothiazide from Cipla Pharmaceuticals, Mumbai, Karaya and Xanthan Gum was obtained as gift sample from Crystal Colloids Ltd. Mumbai and Gaur gum purchased from Merck Limited, Mumbai. All the chemicals and reagent used were on analytical reagent (AR) Grade.

Method:

Preparation of drug and polymer loaded nonpareil seeds:

Powder layering method was chosen to load drug on the nonpareil seeds (NPS), NPS was dried at 60-70ºC for 3 hours in hot air oven and sieved through mesh No.20 and 24 respectively to get the desired size (20/24). The pellets were loaded onto conventional coating pan of 6" diameter. The mixture of drug and gum was passed through sieve # 120 and dusted on to non-pareil seeds using 5% solution of PVP K-30 in isopropyl alcohol. A pilot type of spray gun fitted with a 1mm atomizing nozzle was used to spray the solution during drug loading process the drying of nonpareil seeds was provided as required, with proper prevention of drug dusting. After completion of the process, drug loaded pellets was dried at 50-60ºC for 4 hours in hot air oven and then sieved through mesh No. 16 and 20 to get the desired size.

Coating of moisture protecting layer⁶:

The solution of HPMC E6 LV in non aqueous system of DCM: IPA in proportion of 6:4 was used in concentration 3% for moisture protection until weight gain of 1-2 % was observed.

Formulation of controlled release captopril pellet:

Batches were designed in varying drug: gum ratio with optimized gum/gum blend. The controlled release multiparticulate formulation each containing 25mg captopril in controlled release form were designed for twice daily dosing. The formulation was so designed that preparation release about 95% drugs in 12 hours (t₉₅). The drug dose 25mg was contained in about 150-250mg of final pellet formulation so as to enable filling of unit dose in capsule of size ‘0’. Formulation batches of Captopril and Hydrochlorothiazide are shown in table no. 1 and 2 respectively.

Table No 1: Formulation of controlled release captopril pellet

Batch code	Gum/gum blend	Pellets (gm)	Drug: Gum	Talc ( % )	PVP K-30 ( % )
A1	X	30	1 : 1	10	5
B1	K:X (2:8)	30	1 : 1	10	5
C1	K:G (6:4)	30	1 : 1	10	5
A2	X	30	1: 1.5	10	5
B2	K:X (2:8)	30	1: 1.5	10	5
C2	K:G (6:4)	30	1: 1.5	10	5
A3	X	30	1 : 2	10	5
B3	K:X (2:8)	30	1 : 2	10	5
C3	K:G (6:4)	30	1 : 2	10	5

K – Karaya gum, X – Xanthan gum. G – Guar gum

Dissolution profile:

In vitro drug release was studied using USP Dissolution Testing Apparatus I (basket type).at 37.5± 0.5 C for 12 hr, at 100 rpm. 0.1 N HCL (pH 1.2) was used as dissolution medium for the first 2hr. followed by pH 6.8 phosphate buffer for next 10hrs. Percentage cumulative drug release of batch A2, B2, C2 containing drug: gum (1:1) are shown in figure no. 3

Angle of repose^7-8:

Angle of repose was found to be in the range of 23-27 which indicate that material is having good flow this might because of coating on spherical surface of NP seed. All batches are excellent for flow so batch filling will not have the problem while capsule filling and less weight variation will be observed. The angle of repose of all formulation are given in Table no 3

Table No.2: Formulation table for immediate release hydrochlorothiazide pellet

Batch code	Gum/gum blend	Pellet (gm)	Drug : Gum	Talc (%)	PVP K-30 (%)
H1	X	30	1 : 0.25	10	5
H2	K:X (2:8)	30	1 : 0.25	10	5
H3	K:G (6:4)	30	1 : 0.25	10	5
H4	X	30	1 : 0.5	10	5
H5	K:X (2:8)	30	1 : 0.5	10	5
H6	K:G (6:4)	30	1 : 0.5	10	5

K – Karaya gum, X – Xanthan gum. G – Guar gum

Friability of pellets⁸:

Percent friability was found to be 4-6.5 % before HPMC film coat and after film coat it was found in range of 0.04 – 0.09 which indicates that coated film is strong enough to resist the abrasion. The friability of pellets of all formulation are given in Table no 3

Drug content:

Drug content was found to be in range of 24 -28% i.e. 100 mg of pellet contain approximately 24-28 mg of captopril. The drug content for all formulation are given in Table no 3

Scanning electron microscopy:

The SEM of captopril pellet indicates smooth surface and thus good coating of the blend of drug and gum powder. The SEM of Captopril are given in Figure no 1

Dissolution studies:

The release rate of hydrochlorothiazide from immediate release hydrochlorothiazide pellet was determined using USP Dissolution Testing Apparatus I (basket type). The dissolution test was performed using 900ml of 0.1 N HCL, at 37 ± 0.5 C and 100 rpm. In vitro dissolution study Percentage cumulative drug release of batch H4, H5, H6 containing drug: gum (1:0.5) these are shown in figure 4:

Angle of repose

Angle of repose was found to be in the range of 23-26 which indicate that material is having good flow this might because of coating on spherical surface of non pareil seed.

Table No 3: Parameter of controlled release captopril pellet

Formulation	Angle of repose before film coating	Friability before Film coat (%)	Friability after Film coat (%)	Drug content (%)
A1	24 73'	4.98	0.081	26.93
B1	25 93'	4.66	0.072	24.85
C1	23 75'	5.57	0.08	26.73
A2	25 13'	6.32	0.09	27.92
B2	24 79'	4.49	0.07	25.68
C2	26 12'	4.21	0.06	26.42
A3	24 24'	5.25	0.076	24.67
B3	25 32'	6.11	0.054	27.52
C3	25 53'	5.26	0.042	24.32

*Average of three determinations

Table No 4: Parameter of immediate release hydrochlorothiazide pellet

Formulation	Parameter*
Formulation	Angle of repose before film coating	Friability before Film coat (%)	Friability after Film coat (%)	Drug content (%)
H1	26 3'	8.25	-----	10.42
H2	23 19'	9.04	-----	12.7
H3	25 83'	8.78	-----	9.32
H4	26 27'	4.25	0.07	25.53
H5	25 14'	5.04	0.05	29.71
H6	25 42'	4.78	0.12	27.62

* Average of three determinations

Figure No. 1

SEM of drug (captopril) coated pellet of optimized batch C2

Figure No.2

SEM of drug (hydrochlorothiazide) coated pellet of optimized batch H4

All batches are excellent for flow so batch filling will not have the problem while capsule filling and less weight variation will be observed. The angle of repose of for all formulation are given in Table no 4

Friability of pellets:

Percent friability of batch H4, H5, H6 was found to be 4-5% before HPMC film coat. Thus these batches were selected for further film coat to give strength to pellet. Percent friability of batch H4, H5, H6 was found to be 0.05-0.12% after HPMC film coat. It indicates that coated film is strong enough to resist the abrasion. The friability of pellets of all formulation are given in Table no 4

Drug content:

Drug content of batches H4, H5, H6 was found to be in range of 25-30% i.e. 100 mg of pellet contain approximately 25 -30 mg of hydrochlorothiazide. The drug content of for all formulation are given in Table no 4

Scanning electron microscopy:

The SEM of hydrochlorothiazide pellet indicates smooth surface and thus good coating of the blend of drug and gum powder. The SEM of Hydrochlorothiazide are given in Figure no 2

Figure No 3:

In vitro dissolution profile of batch A2, B2, C2 containing drug: gum (1:1.5)

Figure No.4

In vitro dissolution profile of batch H4, H5, H6 containing drug:gum (1:0.5)

RESULT AND DISCUSSION:

Controlled release and immediate release are investigated by using the different combination of gums. From the figure no 3 it was found that when drug and optimized gum blend were coated in the ratio 1:1.5 batch A2 release 100% of drug within six hour, while batch B2 release 98% of the drug in nine hour and batch C2 release 99% of drug in twelve hour. From the graph it was conclude that batch A2, B2, does not satisfy t₉₅but batch C2 satisfy t₉₅for controlled release of drug captopril in 12 hour. The burst effect in first hour in all the three batches might be due to time required for swelling of gum to provide optimum diffusion path. In case of immediate dissolution profile of batch H4, H5, H6 containing drug: gum (1:0.5) From the figure 4 it was found that when drug and optimized gum blend were coated in the ratio 1:0.5 batch H4 release 100% of drug within first half hour, while batch H5 release 100% of the drug in fifty minutes and batch H6 release 99% of drug within one hour. The immediate release from batch H4 might be due to erosion of xanthan gum and due to single gum and may also due to less gum concentration as compared to drug. From the graph it was conclude that batch H4 satisfy t₉₅for immediate release of drug hydrochlorothiazide in half hour.

CONCLUSION:

On evaluation of several gum blends for their ability to demonstrate viscosity synergism, it was found that Karaya: Gaur in 6: 4 Ratio shows promising increasing viscosity. Such system can thus be considered for use in design of swallable oral controlled release formulation.

Looking at the tremendous advantages controlled release multiparticulate formulation offer, designing swallable controlled release multiparticulate formulation appear to be more lucrative since such system would be advantageous as compare to multiparticulte formulation where drug release is controlled primarily by the application polymer membrane as the diffusion barrier. The present study confirmed that swallable controlled release multiparticulate system could be successfully design using synergy gum blends.

ACKNOWLEDGEMENT:

The authors are thankful to the Management and Department of Industrial Pharmacy, Sudhakarrao Naik Institute of Pharmacy, Pusad for providing necessary facility for the research work.

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