MATERIALS AND METHODS:

Materials:

Nevirapine (Neuland laboratories, Hyderabad), Sodium Starch glycolate, Croscarmellose sodium, Sodium saccharin, Magnesium Stearate, Talc, Mannitol, Microcrystalline cellulose were purchased from SR chemicals Ltd.

Methods:

Tablet formulation:

Fast disintegrating tablets of nevirapine containing different concentrations of super disintegrants were prepared by wet granulation method. All the ingredients without magnesium stearate and talc were sifted through the sieve #40 and admixed for about 15 minutes to make a uniform blend. The mixed powder blend was granulated with water and passed through sieve no.10, granules obtained were dried (air dry) at 40ºc in hot air oven. After drying the granules, these granules are sifted through 44 mesh sieve. Magnesium stearate and talc were passed through sieve # 60 and mixed with the above granules for sufficient time, usually 5-7 minutes.

The prepared granules were evaluated for various parameters like bulk density, tapped density, Angle of repose, Compressibility index and Hausner ratio and compressed using a sixteen-station Rotary tableting machine.

Evaluation of granules:

a) Angle of Repose(θ) :

The powder mixture was allowed to flow through the funnel fixed to a stand at definite height (h). The angle of repose was then calculated by measuring the height and radius of the heap of powder formed by the given formula:

tan (θ ) = h / r

θ = tan-1 (h / r)

b) Bulk Density (Db):

It was measured by pouring the weighed powder into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume. From this the bulk density is calculated according to the formula mentioned below. It is expressed in g/ml and is given by

Db = M/ Vb

Where, M is the mass of powder

Vb is the bulk volume of the powder.

c) Compressibility Index/ Carr’s index

The compressibility index of the granules was determined by Carr’s compressibility index. It indicates powder flow properties. It is expressed in percentage and is given by

I = (Dt– Db ) /Dt × 100

Where, Dt is the tapped density of the powder and

Db is the bulk density of the powder.

d) Hausener's ratio

Hausner ratio =Tapped density /pore density

Table 1: Formulation of Neverapine fast disintegrating tablets using SSG

INGREDIENTS	CATEGORY	BATCH CODE
INGREDIENTS	CATEGORY	F1	F2	F3
Nevirapine	Anti-viral	200	200	200
S.S.G	Super disintegrant	20	25	30
Sodium saccharine	sweetner	25	25	25
magnesium. stearate	lubricant	25	25	25
Talc	lubricant	75	75	75
Mannitol	diluent	75	75	75
M.C.C	diluent	80	75	70
Total weight of tablet(mg)		500	500	500

Table 2 :Formulation of Nevirapine fast disintegrating tablets using CCS

INGREDIENTS	CATEGORY	BATCH CODE
INGREDIENTS	CATEGORY	F4	F5	F6
Nevirapine	Anti-viral	200	200	200
CCS	Super disintegrant	15	17.5	20
Sodium saccharine	Sweetner	25	25	25
Mg. stearate	Lubricant	25	25	25
Talc	Lubricant	75	75	75
Mannitol	Diluents	75	75	75
MCC	Diluents	85	82.5	80
Total weight of tablet(mg)		500	500	500

Evaluation of Fast disintegrating tablets:

a) Average weight: 20 tablets of each formulation were weighed using an electronic balance, and the test was carried according to the Indian Pharmacopoeia.

b) Hardness: Select one tablet from each formulation. Then the tablet was placed in between the angles of equipment, and the pressure required to break the tablet was noted. Hardness of the tablet of each formulation was determined using Monsanto Hardness tester.

c) Friability: Friability of the tablet determined using Roche friabilator. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at height of 6 inches in each revolution. Pre -weighted sample of tablets was placed in the friabilator and were subjected to the 100 revolutions. The friability (F) is given by the formula.

F = W int. -W fin/ W int.

Where, Wint- Weight of tablets before friability.

Wfin- Weight of tablets after friability.

d) Wetting Time: A tablet is placed on a piece of tissue paper folded twice and kept in a small Petri dish (ID = 6.5 cm) containing 6 ml of Sorenson’s buffer p^H6.8 , and the time for complete wetting is measured.

e) Water absorption Ratio: A piece of tissue paper folded twice was placed in a small Petridish containing 6 ml of Sorenson’s buffer p^H6.8. A tablet was put on the paper & the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using following equation,

R = 10 (wa/wb)

Where, wa is weight of tablet before water absorption & wb is weight of tablet after water absorption.

f) Weight variation: Ten tablets were randomly selected from each batch and weighed on an electronic balance and mean weight was taken. Each tablet was then weighed individually and standard deviation in weight was calculated for each batch.

g) In vitro dispersion time: In vitro dispersion time was measured by dropping a tablet in a beaker containing 50 ml of Sorenson's buffer pH 6.8. Three tablets from each formulation were randomly selected and in vitro dispersion time was performed. The time required for the tablet to get dispersed in the solution was noted.

h) Disintegration time: Select one tablet from each formulation and placed in a petriplate containing 10 ml of Phosphate buffer (pH 6.8) as a disintegrating medium. The time taken for the tablet to get disintegrate in the medium was noted.

i) Invitro dissolution test: Dissolution test for Nevirapine was carried out as per USP method for dissolution test for tablets and capsules using apparatus II (paddle type). Dissolution medium used was 900 mL of 0.1N Hcl, rotating at 50 rpm at 37±0.50C. An aliquot of 5 mL of samples were withdrawn at different time periods and replaced with fresh solvent. These samples were filtered. Absorbance of the resulting solution was measured at 313 nm (experimental λmax for nevirapine in 0.1N HCl). Percent drug release was calculated.

Standard curve preparation:

100 mg of nevirapine was dissolved in sufficient quantity of buffer of hydrochloric acid to produce 100 ml of solution. The following dilutions are made from the above stock solution.0.5, 1.0, 1.5, 2.0, 2.5 micro grams per ml.

The absorbance at 313 nm is measured in a spectrophotometer meter and a standard curve is plotted by absorbance v/s concentration.

RESULTS AND DISCUSSION:

TABLE-3: PREFORMULATION PARAMETERS

Formulation batch

Bulk Density(g/ml)

Tapped density (g/ml)

Carr’s index (%)

Hausner’s ratio

Angle of repose (θ)

0.726

0.71

0.74

0.69

0.75

0.73

0.756

0.74

0.77

0.73

0.78

0.76

3.96

4.00

3.8

5.4

3.8

3.9

1.04

0.95

1.04

1.05

1.04

26.56

TABLE-4: Evaluation of Fast Disintegrating tablets:

Formulation batch	Thickness Mm	Hardness Kg/cm²	% Friability	% Weight variation	Disintegration Time sec
F1	2.71	4.5	0.08	0.21	28
F2	2.72	4.3	0.07	0.28	32
F3	2.75	5	0.06	0.13	24
F4	2.43	4.5	0.07	0.24	31
F5	2.36	4.7	0.07	0.19	34
F6	2.33	4.5	0.09	0.26	27

TABLE-5: Evaluation of Fast Disintegrating tablets:

Formulation Batch	Dispersion time (Sec)	Wetting time (Sec)	Water absorption ratio
F1	85	36	5.4
F2	80	34	5.32
F3	77	33	4,90
F4	95	35	5.14
F5	110	38	4.35
F6	100	37	4.15

GRAPH-1

TABLE 6:Dissolution profile of SSG based Fast disintegrating tablets:

CUMULATIVE % DRUG RELEASE
TIME	F1	F2	F3
0	0	0	0
5	34.2274	36.838	40.876
10	43.4230	47.774	53.285
15	52.0736	57.608	65.471
20	56.9999	64.0	82.653
25	65.7227	75.387	96.397
30	77.9727	85.370	101.645
60	86.2125	94.245	103.341

GRAPH-2

TABLE 7:Dissolution profile of CCS based Fast disintegrating tablets:

CUMULATIVE % DRUG RELEASE
TIME	F4	F5	F6
0	0	0	0
5	35.967	38.280	40.318
10	45.453	48.934	51.274
15	55.275	62.546	62.269
20	60.509	75.942	77.403
25	67.483	93.478	93.799
30	73.022	96.291	94.876
60	82.121	99.134	98.565

GRAPH-3

Standard curve of Nevirapine:

GRAPH-4

All the pre-formulation parameters conducted, showed values within the limit. Weight variation of FDTs was within 1.91 %. Hardness and friability of all formulations were within acceptable limits. Hardness of tablets prepared by wet granulation method was 4.3 to 5.0 kg/cm2. The friability of all formulations was found to be less than 0.09%.Disintegration time is very important for FDTs, which is desired to be less than 60 seconds. Disintegration time of prepared FDTs was in the range of 14 to 59 seconds. The cumulative % drug release profile of F-3 was found to be maximum when compared with other formulations.

CONCLUSION:

Based on above results and discussion, it is concluded that the formulated FDT tablets of Nevirapine using sodium starch glycolate was capable of exhibiting immediate release properties. Among all the formulations F-3 prepared with sodium starch glycolate (SSG) in conc. 6% as disintegrant exhibit least disintegration time (24 sec.). As the concentration of superdisintegrant in the formulations increased the disintegration time was found to decrease. From the characterization of fast disintegrating tablets of Nevirapine it can be concluded that formulation containing sodium starch glycolate 6% is most acceptable. Fast disintegrating tablets of Nevirapine is a therapeutically effective, economical, commercially feasible approach for the therapeutic benefit of HIV patients.

REFERENCES:

1. Orenstein R, Tsago N. Looking beyond HAART: drug-related hepatotoxicity in patients with human immunodeficiency virus infection. Pharmacotherapy 2002;22:1468-78.

2. De Maat MM, Ter Heine R, Van Gorp EC, Mulder JW, Mairuhu AT, Beijnen JH. Case series of acute hepatitis in a non-selected group of HIV-infected patients on nevirapine containing antiretroviral treatment. AIDS 2003;17:2209-14.

3. Wit FW, Weverling GJ,Weel J, et al. Incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002;186:23-31.

4. Stern J, Robinson P, Love J, et al. A comprehensive hepatic safety analysis of nevirapine in different population of HIV infected patients. J Acquir Immune Defic Syndr 2003;34(Suppl 1):S21-33.

5. Reisler R, Servoss JC, Sherman KE, et al. Incidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment trials: ACTG Liver Diseases Focus Group (abstract 43). In: Program and abstracts of the 1st International AIDS Society Conference on HIV Pathogenesis and Treatment (Buenos Aires)

6. Gifford aL, bormann JE, Shivley MJ, et al. Predictors of selfreported adherence and plasma HIV concentrations in patients on multidrug antiretroviral regimens. J acquir Immune defic Syndr. 2000;23: 386–95

7. Ammassari a, Murri R, Pezzotti P, et al. Self-report symptoms and medication side effects influence adher-ence to highly active antiretroviral therapy in persons with HIv infection. J acquir Immune defic Syndr. 2001; 28: 445–9.

8. Trotta MP, ammassari a, Melzi S, et al. treatment-relat-ed factors and highly active antiretroviral therapy adher-ence. J acquir Immune defic Syndr. 2002; 15: 31(suppl3), S128-131.

9. Portsmouth Sd, osorio J, Mccormick k, gazzard bg, Moyle gJ. better maintained adherence on switching from twice-daily to once-daily therapy for HIv: a 24-week randomized trial of treatment simplification using stavudine prolonged-release capsules. HIV Med. 2005; 5:185-190.

10. Stone vE, Hogan Jw, Schuman P, et al. antiretroviral regimen complexity, self-reported adherence, and HIv patients' understanding of their regimens: Survey of women in the HER study. J acquir Immune defic Syndr. 2001; 28: 124-131.

11. Cooper cL, van Heeswijk RP. once-daily nevirapine dos-ing: a pharmacokinetics, efficacy and safety review. HIV Med. 2007; 8: 1-7.

12. Van Heeswijk RP, veldkamp aI, Mulder Jw, Meenhorst PL, wit fwnM, Lange JMa, danner Sa, foudraine na, kwakkelstein Mo, Reiss P, beijnen JH, Hoetelmans RMw. aIdS. 2000; 14: 8,f77-f82.

13. Kappelhoff bS, Huitema ad, van Leth f, Robinson Pa, Macgregor tR, Lange JM, beijnen JH; 2nn Study group. Pharmacokinetics of nevirapine: once-daily versus twice-daily dosing in the 2nn study. HIv clin trials. 2005; 6: 254-261.

14. Van Leth f, Phanuphak P, Ruxrungtham k, baraldi E, Miller S, gazzard b, cahn P, Lalloo ug, van der west-huizen IP, Malan dR, Johnson Ma, Santos bR, Mulcahy f, wood R, Levi gc, Reboredo g, Squires k, cassetti I, Petit d, Raffi f, katlama c, Murphy RL, Horban a, dam JP, Hassink E, van Leeuwen R, Robinson P, wit fw, Lange JM; 2nn Study team. Lancet. 2004; 17;363(9417): 1253-63

15. Keiser P, nassar n, yazdani b, armas L, Moreno S. HIV clin. trials. 2003; 4(5): 358-360.

16. Clotet b. once-daily dosing of nevirapine in HaaRt. J antimicrob chemother. 2008;

17. Siegfried nL, van deventer PJ, Mahomed fa, Ruther-ford gw. Stavudine, lamivudine and nevirapine combina-tion therapy for treatment of HIv infection and aIdS in adults. Cochrane database Syst Rev. 2006 apr 19;(2):cd004535.

Received on 15.09.2014 Accepted on 23.09.2014

Asian J. Pharm. Res. 4(3): July-Sept. 2014; Page 129-134

*Corresponding Author E-mail: mamathak84@gmail.com