INTRODUCTION:

Modified release dosage forms have acquired a great importance in the current pharmaceutical research and development business. It denotes a formulation of a medicinal agent taken orally that releases the active ingredients over several hours, in order to maintain a relatively constant plasma concentration of the drug.¹

In conventional therapy drug is released immediately after medication. So, the drug concentration in the plasma is raised. The target of drug discovery is to obtain maximum drug efficacy and minimum side effect. With the advancement of technologies in the pharmaceutical field drug therapy has changed its path. In addition, sustained and controlled release devices are not applicable in some cases like time-programmed administration of hormones and many drugs. The living systems are predictable dynamic resonating systems which require different amounts of drug at expected times within the circadian cycle. Pulsatile drug delivery system has fulfilled this requirement. Pulsatile drug release is such a system where drug is released suddenly after well-defined lag time or time gap according to circadian rhythm of disease states.²

Pulsatile drug delivery systems release the drug rapidly and completely after a lag time, thus provide spatial and temporal delivery and increasing patient compliance, have generated increasing interest during recent years for a number of diseases and therapies. ³

These systems are beneficial for drugs having high first-pass effect drugs administered for diseases that follow chronopharmacological behavior; drugs having specific absorption site in GIT, targeting to colon; and cases where night time dosing is required.⁴

Tramadol HCl is centrally acting synthetic analgesic used to treat rheumatoid arthritis. In these patients shows severe pain and muscle-spasm at early morning so the patients should be and provided with the adequate dose of the drug at that particular time. It is not possible to give the drug to the patient’s everyday in the morning and therefore there is no patient compliance

MATERIALS AND METHODS:

Materials:

Tramadol HCl was obtained as a gift sample from Gen pharma, Pune, India. HPMC K4M, Cross carmellose sodium, Lactose, ‘0’ size empty hard gelatin capsules, formaldehyde solution, Talc, Magnesium Stearate, potassium permagnet were obtained from SD fine chemicals. All chemicals and reagents were of analytical grade.

Methods:

Formulation of Tramadol HCl fast dissolving tablet:

Table no. 1: Formulation of core tablet:

Sr.No.	Ingredients	C 1	C 2	C 3	C 4
1	Tramadol HCl	50	50	50	50
2	Cross Carmelose Sodium	1	2	3	4
3	Lactose	46	45	44	43
4	Magnesium Sterate	1	1	1	1
5	Talc	2	2	2	2
	Total	100	100	100	100

All weights in mg

Procedure:

All the ingredients were accurately weighed and passed through # 60 mesh separately The drug and the diluents were mixed in small portion of both each time and blending it to get uniform mixture and set aside. The other ingredients were weighed and mixed in geometrical order, mixed thoroughly with lubricant. The tablets of weight 100 mg were prepared by direct compression technique using 6 mm punch in 8- station rotary tablet compression machine.

Preparation of Hydrogel Plug:

Plug for sealing the capsule body was prepared by compressing HPMC K4M in different concentration ratios using 7mm punches on KBr press.

Table no. 2: Composition of erodible plug:

Batch Code	HPMC K4M Mg	Lactose Mg	Magnesium stearate mg
P1	10	89	1
P2	20	79	1
P3	30	69	1
P4	40	59	1
P5	50	49	1
P6	60	39	1
Total	100 mg

Preparation of Cross-Linked Gelatin Capsules:

The ‘0’ sized hard gelatin capsules; about 100 in number were taken. The bodies of the capsules were then placed on a wire mesh. 25ml of 15% v/v formaldehyde was taken into a desiccators and potassium permanganate was added to it to generate formalin vapors. The reaction was carried out for 12 hours. After which the bodies were removed and dried at 50⁰C for 30 minutes to ensure completion of reaction between gelatin and formaldehyde vapor. The bodies were dried at temperature to facilitate removal of residual formaldehyde.⁵

%Swelling index:

Hydrogel plugs were kept immersed in three different pH conditions. Plugs were taken out carefully at each hour and their weights were determined accurately.4

% Swelling =

Dissolution studies:

The dissolution study of time delayed capsule was carried out using USP Type I (labindia ) at 37 ± 0.5 ^oC and basket speed of 50rpm. First 900ml of buffer pH 1.2 was used as dissolution medium up to 2 hours. There after the dissolution medium was replaced by phosphate buffer pH 7, Followed by 6.8 for subsequent hrs and the dissolution test was continued in the new medium. Aliquots of the dissolution medium were removed at different time intervals and amount released was estimated by spectrophotometrically at 271nm.⁶

RESULTS AND DISCUSSION:

Depending upon concentration of the disintegrant, 4 different formulations were prepared. Formulations C1 to C4 consisted Cross Carmellose Sodium as a disintegrant and the concentration was 1% - 4% respectively. For the dissolution studies it was found that the C4 exhibited faster drug release compared to C1 followed by C2 and C3. Figure no. 1 shows the % cumulative drug release Vs Time profile of all the formulations.

The polymer plugs were prepared by direct compression method. A tight fit between the plug and the impermeable capsule body was very important in order to prevent water penetration to the capsule content and drug release prior to complete erosion of the plug material. In order to identify proper plug materials, they were tested for swelling index in various pH conditions like phosphate buffer pH 1.2, 6.8, 7.4 pH condition.

Swelling study of the plug indicated initial swelling of the polymer due to water uptake and followed by a platue which was observed up to 4,5,5,6,7,8 hrs for batch P1-P6 respectively and finally the erosion of the plug takes place (figure no.2) This indicates that the plug was remaining in the body of the for particular time and was getting ejected from the body of the capsule, paving the way for drug release.

When the capsules were subjected to studies in different buffers, the untreated caps disintegrated within 10 mins in all the media whereas the treated bodies remained intact for about 24 hrs.

From the in-vitro release studies of pulsincaps, it was observed that after exposing the impermeable capsule to the dissolution medium, cap of the capsule eroded within 5 to 10 minutes. Then hydrogel plug was exposed to the dissolution medium, 0.1 N HCl. Because of penetration of dissolution medium in to the hydrogel plug, it started swelling. During dissolution studies it was observed that the plugs provided the, degree of swelling for first few hrs after that polymer started to erode slowly. It means that plugs placed at ends of the capsule ensured a good seal, preventing premature drug release. The lag time of the pusincap system was different for all batches i.e.3 hrs, 4.5 hrs, 5 hrs, 6 hrs, 7 hrs, 8.5 hrs for batch P1-P6 respectively and after that the plug got ejected completely and the actual drug release was started. But batch P5 gives sufficient lag time. Depending upon the concentration of the HPMC K4M formulations were prepared. From the dissolution studies it was found that as concentration of HPMC K4M is increased the lag time increases and as the concentration of fillers increases the lag time decreases. Time vs %cumulative drug release studies are depicted in Figure no.3-8.

CONCLUSION:

The aim of this study was to explore the feasibility of pulsincap of Tramadol HCl to treat the rheumatoid arthritis.

Prepared formulation was mainly comprised of three basic components i.e. impermeable capsule, erodible plugs and drug containing tablet.

To obtain desired lag time selection of proper plug material was most essential. The erodible tablet plugs were prepared by using direct compression method. Various concentrations of HPMC K4M were used (10%-60%). It is clear that an increase in the filler concentration in the plug results in a decrease in lag time. Finally, it is possible to release a drug over a predetermined period of time with specific release rates by manipulating the polymers used to prepare plugs.

Depending and concentration of the disintegrant, 4 different formulations were prepared (batch c1-c4), consisted crosscarmellose sodium (1-4%). The precompressional evaluation studies showed good flow properties. From the dissolution studies it was found that batch c4 (i.e.4 % crosscarmellose sodium) showed faster drug release and as the concentration of disintegrant was increased release rate got increased.

The solubility studies of empty gelatin capsule bodies, which were cross linked with formaldehyde treatment (treated for 12 hrs), revealed that they are intact for 24 hrs, and hence suitable for present formulation.

Hence, finally it was concluded that the prepared pulsatile drug delivery system can be considered as one of the promising formulation technique for chronotherapeutic management of rheumatoid arthritis.

Table no. 4: Evaluation of tramadol tablet

Batch Code

Friability (%)

Hardness (Kg/cm²)

Weight variation (mg)

disintegration time (sec)

Drug content (%)

0.6978

(± 0.0901)

3.3333

(± 0.2886)

100.5

(± 0.8408)

173.3

(± 0.520)

98.96

(± 0.4040)

0.5982

(± 0.0570)

3.5

(± 0.5)

99.90

(± 0.1780)

147

(± 0.132)

99.69

(± 0.5447)

0.6291

(±0.00267)

3.6667

(± 0. 2886)

101.3

(± 0.0027)

134

(± 0.3020)

97.87

(± 0.7320)

0.6759

(± 0.0172)

3.3333

(± 0.5773)

100.1

(± 0.6635)

126.3

(± 0.5237)

99.41

(± 0.27538)

Figure no. 5: Drug release profile of P3 Formulations

Figure no. 6: Drug release profile of P4Formulations

Table: no.5: Evaluation of erodible tablet plug

Batch Code

Friability

(%)

Hardness

(Kg/cm²)

Weight variation

(mg)

0.5668

(±0.0692)

3.6667

(±0.2886)

100.3

(±2.0575)

0.5350

(±0.0239)

4.5

(±0.5)

100.00

(±2.6256)

0.6495

(±0.0030)

4.8333

(±0. 2886)

100.80

(±2.0439)

0.4900

(±0.0358)

4.5

(±0.5)

100.5

(±1.900)

0.7250

(±0.0073)

4.6667

(±0.2886)

100.4

(±2.665)

0.5456

(±0.0239)

4.1607

(±0.2886)

100.1

(±2.3781)

Table no. 6: Solubility studies of treated capsules body

Time of exposure in hrs	Observation
2	Shaped out in 3 hr
4	Shaped out in 6 hr
6	Shaped out in 12 hr
8	Softened in 16 hr
12	Intact up to 24 hr

Figure no. 7: Drug release profile of P5 Formulations

Figure 8: Drug release profile of P6 Formulations

REFERENCE:

1. Charman, SA and Charman, WN Oral modified release delivery systems. In Rathbone, M., Hadgraft, J., Roberts, M. (Eds.), Modified-Release Drug Delivery Technology. New York, Marcel Dekker. 1st Ed. 126: 1 - 10.

2. A.S. Mandal et.al. Drug delivery system based on chronobiology-A review Journal of Controlled Release. 147: 2010; 314–325.

3. Ramesh D. Parmar et al. Pulsatile Drug Delivery Systems: An Overview, International Journal of Pharmaceutical Sciences and Nanotechnology. 2(3); 2009: 605-614.

4. M. Sukanya et al. Design and development of chronopharmaceutical drug delivery of simvastatin Journal of Chemical and Pharmaceutical Research. 4(6); 2012:3195-3200.

5. Bhat et al formulation and evaluation of chronopharmaceutical drug delivery of theophylline for nocturnal asthma international journal of pharmacy and pharmaceutical sciences. 3(2); 2011:183-185.

6. Mahajan AN at.el Formulation and Evaluation of Timed Delayed Capsule Device for Chronotherapeutic Delivery of Terbutaline Sulphate ARS Pharmaceutica 50(4); 2010: 215-223.

Received on 27.07.2013 Modified on 03.08.2013

Research J. Pharm. and Tech. 6(10): October 2013; Page 1137-1140

Batch	Bulk density (g/ml)	Tapped density (g/ml)	Angle of Repose ( θ⁰)	Carr’s Compressibility Index (%)	Hausner’s Ratio
C1	0.4852± 0.040	0.5312± 0.030	29.98 ± 0.20	8.65 ± 0.5	1.10 ± 0.060
C2	0.4943 ± 0.015	0.5868 ± 0.031	30.98 ± 0.78	7.90 ± 0.89	1.08 ± 0.010
C3	0.5123 ± 0.009	0.5765 ± 0.014	27.03 ± 0.29	10.20 ±0.58	1.11 ±0.0037
C4	0.5083 ± 0.0072	0.5495 ± 0.079	29.85 ± 0.54	7.50 ± 0.18	1.08 ±0.0021