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WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES M. Ranga Priya et al.

World Journal of Pharmacy and Pharmaceutical Sciences

Volume 2, Issue 5, 3818-3828.

Research Article

ISSN 2278 – 4357

FORMULATION AND EVALUATION OF ELEMENTARY OSMOTIC TABLETS OF LAMIVUDINE AND STAVUDINE IN FIXED DOSE COMBINATION M. Ranga Priya*, Mahendra Babu, N.N.Rajendran Department of Pharmaceutics & Research, Swamy Vivekanandha College of pharmacy, Elayampalayam-637205, Tamilnadu, India. Article Received on 05 August 2013,

ABSTRACT

Revised on 25 August 2013, Accepted on 30 September 2013

HIV/AIDS are not much effective as the drugs do not reach the site of

Most of the conventional drug delivery systems for treating the

action in appropriate concentrations. The objective of present study was concerned with formulation and evaluation of an elementary

*Correspondence for

osmotic tablet of lamivudine and stavudine in fixed dose combination

Author:

in order to improve efficacy and better patient compliance. Tablets were prepared by wet granulation method using various proportions of

* Mrs. M. Ranga priya, M.Pharm, (Ph.D),

polymer PEG 4000 along with Kcl as osmotic agent. The granules

Department of Pharmaceutics

were evaluated for angle of repose, bulk density, tapped density and

& Research, Swamy

compressibility index, shows satisfactory results. Compressed tablets

Vivekanandha College of

were evaluated for uniformity of weight, drug content, thickness,

Pharmacy, Elayampalyam -

friability, hardness and in-vitro dissolution studies. From the in-vitro

Tamilnadu , India.

drug release study the osmotic tablets containing PEG 4000 (20mg)

[email protected].

and kcl (40mg) showed 96.06% drug release in 24 hrs which was well controlled in comparison with other conventional preparations. The in-vitro release data from the osmotic tablets showed zero order pattern and the mechanism was non- Fickian. The results also indicate that the osmotic drug delivery system may be successfully utilized for the controlled delivery of Lamivudine and Stavudine up to 24hours. Key

words:

stavudine,

lamivudine,

osmotic

delivery,

fixed

dose

combination,

controlled release, simultaneous delivery.

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M. Ranga Priya et al.


INTRODUCTION The first report of an osmotic effect dates to Abbenollet [1748].But Preffer obtained the quantitative measurement in 1877. Osmosis refers to the process of movement of solvent molecules from lower to higher concentration across a semi permeable membrane. Osmosis phenomenon makes controlled drug delivery a reality. Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic device. Rate of drug delivery from osmotic pump is directly proportional to the osmotic pressure developed due to imbibitions of fluids by osmogent. [1, 2] These systems can be used for both routes of administrations i.e. oral and parenteral. Oral osmotic system is known as gastro-intestinal therapeutic system (GITS) Parenteral osmotic drug delivery includes implantable pumps. Now a day’s various developed and developing countries move towards combination therapy for the treatment of various diseases and disorders requiring long term therapy. Drug combination therapy, commonly termed HAART (highly active antiretroviral therapy), has for some 15 years been considered as the standard treatment for patients with HIV infections, whether antiretroviral drug-naive or drug-experienced. HAART regimens typically are composed of a backbone of two NRTIs (nucleoside reverse transcriptase inhibitors) combined with either a PI (protease inhibitors) or an NNRTI (non nucleoside reverse transcriptase inhibitors). [3, 4] Lamivudine is a potent antiviral agent used in the treatment of AIDS. Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor (NRTI) and it is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine is rapidly absorbed with a bioavailability of over 80% following oral ingestion. It is bound to plasma proteins less than 36%. It can inhibit both types (1 and 2) of HIV reverse transcriptase and also the reverse transcriptase of hepatitis. Conventional oral formulations of Lamivudine are administered multiple times a day because of its moderate half-life of 5 to 7 hours. Treatment of AIDS using conventional formulations of Lamivudine is found to have many drawbacks, such as adverse side effects resulting from accumulation of drug in multidose therapy, poor patient compliance and high cost. Controlled release formulations of Lamuvidine can overcome some of these problems. [5] Stavudine is a potent inhibitor of HIV-1 replication and the first nucleoside reverse transcriptase inhibitor (NRTI) approved in 1994 by Food and Drug Administration (FDA)

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M. Ranga Priya et al. for

use

in

combat

World Journal of Pharmacy and Pharmaceutical Sciences of human

immunodeficiency

virus (HIV). Conventional oral

formulations of stavudine are administered twice a day because of its moderate half-life of 0.5-1.5 hours. [6] Lamivudine + Stavudine 150mg/30mg tablets, manufactured at Aurobindo Pharma Limited, Andhra Pradesh, India, was accepted for the WHO list of prequalified products for the treatment of HIV/AIDS and listed on 24 February 2009. MATERIALS AND METHODS Materials Lamivudine and stavudine was obtained as a gift sample from Aurobindo Pharma Ltd, Hyderabad, Potassium chloride and Polyethylene glycol 4000 was supplied by Loba Chemie Pvt Ltd (Mumbai, India). All other reagents and solvents used were of analytical grade. Methods Preparation of core tablets Procedure Accurately weighed quantities of ingredients mentioned in formula were passed through sieve no.65. The entire ingredients, except lubricant (magnesium stearate, glident talc and binder starch) were manually blended homogeneously in a motor by geometric dilution. The mixture was moistened with aqueous solution of 10% (m|v) starch, and granulated through sieve no.18 and dried in a hot air oven at 60 oc for sufficient time (3to4hr) so that the moisture of the granules reached 2-4%. The dried granules were passed through sieve no.25.and blended with talc and magnesium stearate. The homogeneous blend was then compressed into tablets by using concave punches. The compression was adjusted to tablet with approximately 7-8 kg cm2 hardness. [7] Table – 1: Formulae of various formulations Sl. No

Ingredients (mg/tablet)

F1

F2

F3

F4

F5

F6

1 2 3 4 5 6 7

Lamivudine Stavudine Polyethylene glycol(4000) Potassium chloride Magnesium stearate Talc Starch

300 80 20 20 15 15 10

300 80 30 20 10 10 10

300 80 40 20 5 5 10

300 80 20 20 15 15 10

300 80 20 30 10 10 10

300 80 20 40 5 5 10

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Coating of tablet The tablet coatings were applied using dip coating process. The tablet were dip coated in polymer solution consisting of CAP (cellulose acetate phthalate) dissolved in a solutions of acetone and a non solvent, either, formamide or glycerol. Typically, the polymer-coating solution consisted of 15 wt% CAP (cellulose acetate phthalate) and 14 wt% formamide, dissolved in acetone. After the tablets were coated with the polymeric coating solution, they were air-dried for 5seconds and then immersed in a water quench bath for 3min. After removal from the water quench bath the tablets were then air-dried under ambient conditions for at least 12h. [8] Drilling To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system. The typical orifice size in osmotic pumps ranges from 600µ to 1 mm.For coated tablets, a small orifice was drilled through the one side of each coated tablet by standard mechanical micro-drills with various diameters (ranging from 250 to 800 µm). After drilling, the orifice size was controlled and measured microscopically to make sure the right orifice size was used for dissolution studies [9, 10]. EVALUATION OF TABLETS The Physico-chemical properties of the EOP such as Hardness, Friability, Weight variation and drug content uniformity were studied. [11] Thickness The thickness of the tablets was determined by using Vernier calipers, by standard procedure mean and SD was calculated for 3 trials. Hardness test For each formulation, the hardness of 3 tablets were determined by using a Monsanto hardness tester, mean and SD were calculated. Friability test For each formulation, 6 tablets were weighed. The tablets were placed in a friabilator (Roche friabilator) and subjected to 25 rpm in 4 minutes. The tablets were de dusted and reweighed.

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The friability was calculated as the percentage of weight loss. Weight variation test To study weight variation, of tablet of each formulation were weighed using an electronic balance and the test was performed according to the USP official limits of percentage deviation of tablet are presented. IN-VITRO DRUG RELEASE STUDIES [12] Dissolution parameters Medium

: 0.1 N HCl (pH 1.2), Phosphate buffer ( pH 6.8)

Apparatus

: USP, XXIII-type 2 (Paddle)

RPM

: 50

Temperature : 37o ±0.5o C Volume

: 900 ml

Procedure The release of osmotic tablets was studied up to 2 hrs in 900 ml of 0.1 N HCl. and 900 ml of phosphate buffer pH 6.8 up to 24 hrs as dissolution medium using a USP dissolution paddle assembly at 50 rpm and 37o ±0.5o C. An aliquot (1 ml) was withdrawn at specific time intervals, and diluted to 10 ml with the dissolution medium, and drug content of Lamivudine stavudine was determined by UV Visible spectrophotometer at 265 nm. An equal volume of fresh dissolution medium was replaced to maintain the dissolution volume.Dissolution studies were performed 3 times for a period of 24 hrs and the mean value were taken. Cumulative percentage of drug release was calculated using an equation obtained from a standard curve. Release kinetics In order to understand the mechanism and kinetics of drug release, the results of the in-vitro drug release study were fitted to various kinetics equations like zero order (%cumulative drug release vs. time), first order (log %cumulative drug remaining vs. time), Higuchi matrix (% cumulative drug release vs. square root of time)89,90,91. In order to define a model which will represent a better fit for the formulation, drug release data were further analyzed by Peppas equation, Mt/M∞ = ktn, where Mt is the amount of drug released at time t and M∞ is the amount released at ∞, Mt/M∞ is the fraction of drug released at time t, k is the kinetic constant and n is the diffusional exponent, a measure of the primary mechanism of drug

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release. R2 values were calculated for the linear curves obtained by regression analysis of the above plots. Statistical analysis The release data were subjected to ANOVA with Tukey-Kramer multiple comparision test. This test was used to compare different formulations, and a P value of 0.05 was considered to be significant. RESULTS AND DISCUSSION The compatibility of the drugs and polymer was studied by FTIR. The IR spectra of drugs and polymer mixture shows the major characteristic absorption bands of the polymer polyethylene glycol (4000) with negligible difference of absorption band values. So, FTIR spectra show there is no change in the nature and position of absorption bands which proves that there is no chemical reaction between lamivudine and stavudine and polyethylene glycol.

Fig – 1: FT-IR spectra of Lamivudine + Stavudine + PEG The results of the dissolution studies indicate that the influence of osmotic agent as well as the polymer shows the controlled release of drugs from the tablets. The results suggest that the ratio of drug to polymer has greater influence on the release pattern of Stavudine and Lamivudine. The drug release pattern showed a lag time of 1hour for all the formulations which is the basic character of the osmotic drug delivery systems. It is observed that the all formulations are able to control the drug release up to 24 hours. The cumulative percentage

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drug release from the formulations met the standard criteria of drug release from extended release formulations as specified by the US-FDA which is around 20% within the first 4 hrs, 50 – 70 % at 12 hrs and > 85% after 24 hrs. Table – 2: Comparative In- vitro drug release data of all formulations Time (hrs)

Cumulative % drug release* F1

F2

F3

F4

F5

F6

0

0.0

0.0

0.0

0.0

0.0

0.0

1

0.43±0.152

0.6±0.173

0.83±0.115

0.46±0.208

0.53±0.230

1.16±0.251

2

2.23±0.321

2.96±0.152

4.73±0.642

3.36±0.450

3.66±0.450

5.06±0.556

3

10.2±0.500

11.36±0.152

11.16±0.251

10.2±0.400

11.03±0.351

12.73±0.503

4

15.26±0.450

16.01±0.300

17.03±0.251

15.93±0.251

15.36±0.305

19.86±0.305

5

19.8±0.800

22.03±0.251

22.8±0.600

21.33±0.351

21.9±0.458

26.33±0.472

6

26.7±0.458

38.09±0.500

29.63±0.493

26.66±0.750

27.83±0.404

31.93±0.251

7

30.96±0.802

34.13±0.404

36.0±0.655

34±0.360

35±0.300

40.02±0.558

8

36.6±0.793

38.93±0.416

41.63±0.750

40.33±0.351

41.09±0.264

47.96±0.378

9

43.76±0.776

45.06±0.305

47.0±0.721

44.66±0.709

49.25±0.503

55.03±0.650

10

49.15±0.650

52.16±0.667

55.43±0.832

51.63±0.702

55.06±0.251

62.03±0.321

12

55.73±1.002

59.86±0.378

60.04±0.818

57.04±0.360

61.93±0.321

70.76±0.602

14

62.01±0.755

67.46±0.832

67.01±0.700

64.04±0.321

70.8±0.400

78.56±0.288

16

67.04±0.400

72.56±0.611

76.23±0.450

71.16±0.971

76.09±0.458

83.86±0.493

20

75.3±0.500

82.08±1.153

82.96±0.611

76.66±0.776

81.73±0.589

89.04±0.360

24

83.03±0.404

87.03±0.458

91.05±0.700

82.63±0.665

90.03±0.793

96.06±0.360

* Mean ± SD, n=3. Table – 3:

F.Code

Kinetic data of all Formulations Zero order plot

First Higuchi’s order plot plot

KorsemeyerPeppa’s plot

Mechanism of drug release

R2

R2

R2

n

R2

F1

0.979

0.969

0.981

0.975

0.987

Non-Fickian release

F2

0.976

0.989

0.982

0.987

0.947

Non-Fickian release

F3

0.980

0.976

0.903

0.977

0.948

Non-Fickian release

F4

0.968

0.986

0.987

0.966

0.934

Non-Fickian release

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F5

0.990

0.981

0.977

0.996

0.964

Non-Fickian release

F6

0.980

0.961

0.972

0.914

0.957

Non-Fickian release

Fig – 2: Comparative In- vitro drug release of all tablet formulations The drug release was influenced by the concentration of the polymer as well as the osmotic agent. When the concentration of the osmotic agent was increased, there was an increase in the percentage drug release. As seen in the in-vitro drug release data, the formulation F6 showed 96% of cumulative drug release. This might be attributed to the lower concentration of the polymer. When the polymer concentration is increased there is a considerable increase in the percentage drug release and vice versa.

Fig – 3

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Fig – 3 All the six formulations follow the zero order drug release pattern. Based on the ‘n’ values all the formulations follow Non-Fickian release mechanism. It is evident that Formulation F6 shows better controlled release, drug content and highest regression values considered as best formulation among all formulations.

Fig – 4: SEM image of EOP with orifice diameter (800µm)

Fig – 5: SEM image of coating membrane before dissolution

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CONCLUSION The developed of elementary osmotic tablet shows a controlled drug release of Lamivudine and Stavudine combination. The results demonstrate that release profile is strongly dependent on the concentration of the polymer and osmogent. The results also indicate that the osmotic drug delivery system may be successfully utilized for the controlled delivery of Lamivudine and Stavudine up to 24hours. It can be conclusively stated that an elementary osmotic tablet of Lamivudine and Stavudine in fixed dose combination is a promising approach to alternate the conventional dosage forms. Further investigations of the different formulation variables may throw light in the advantages of this drug delivery system. REFERENCE 1. Nagaraju R, Rajesh Kaza. Formulation and Evaluation of Bilayer Sustained Release Tablets of Salbutamol and Theophylline. International Journal of Pharmaceutical Sciences and Nanotechnology 2009; 2(3): 638-646. 2. Remya P.N, Damodharan N, Sulakshan Kumar C.V. Formulation and Evaluation of Bilayer Tablets of Ibuprofen and Methocarbamol. International Journal of PharmTech Research 2010; 2:1251-1255. 3. De clercq, Erik. Antiretroviral drugs. Current Opinion in Pharmacology.2010; 10:507– 515. 4. Michael J, Mugavero, Charles B, Hicks. HIV resistance and the effectiveness of combination antiretroviral treatment. Drug Discovery Today: Therapeutic strategies 2004; 1(4):529-535. 5. Jr Grangeiro S, Strattmann R.R, Alburquerque M.M, Araujo A.A.S, Matos J.R. In vitro Evaluation of Dissolution Profiles and Thermal Properties of Some Commercial Formulations of Nevirapine Tablets. Acta Farm. Bonaerense.2006; 25 (1):76 -82. 6. Josephine LJ. Formulation and in vitro evaluations of floating microsphere of anti retro viral drug as a gastro retentive dosage. IJRPC 2011, 1(3). 7. Sameer sheaikh, Nirali Dave, Anil chandewar and Udhav koli. Characterization of oral osmotic tablet contacting pantoprazole vol.4.145-150. 8. S.M. Herbig, Jr. cardinal, R.W. Korsemeyer, k.L. smith. Asymmetric-membrane tablet coating for osmotic drug delivery (1995).127-136. 9. Stuti Gupta, Ravindra Pal Singh, Rohitashva Sharma, Renu Kalyanwat and Priyanka Lokwani osmotic pump review (2011) vol.02, 1-6.

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10. Longxiao lui, Gilson khang, john m, Rhee. Hai bang lee monolithic osmotic tablet system for Nifedipine delivery (2000) 309-322. 11. Mothilal M, DamodharanN, Lakshmi K.S, Saranya.V ,Bharatharaj .Srikrishna.T, Formulation and in vitro evaluations of osmotic drug delivery system of metoprolol succinate ,Vol 2, Issue 2, 2010 (64-67). 12. Dr. Alexander Pontius Setting specifications for dissolution testing of modified release formulations February 23-24, 2011(1-37).

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