2.1 INTRODUCTION TO LITERATURE SURVEYThe literature survey was done with the intention of developing formulations of

Zidovudine and Lamivudine from bulk and pharmaceutical dosages forms. As by Literature

survey it was found that many research works are available for the preparation of these drugs.

2.1.1 REVIEW OF LITERATURE

VNL. Sirisha et.al. 37 formuled and evaluated Lamivudine and Zidovudine extended release

tablets. In her research, Microcrystalline cellulose was used as a diluent, PVPK 90 was used as a

Binder, Sodium starch glycolate was used as a disintegrant, Isopropyl Alcohol was used as a

Solvent, Megnesium stea

rate was used as a Lubricant, Talc was used as a glidant, HPMC was used as a counting saluting.

Lamivudine and Zidovudine tablets were prepared by wet granulation method and coating with

HPMC. After evaluation of physical properties of tablets, the in-vitro release study was

performed in 7.8 pH Phosphate buffer, in phosphate buffer pH 6.8. Based on the observations, it

can be concluded that the attempt of formulation and evaluation of the Lamivudine and

Zidovudine coated tablets was found to be successful in extend the release by effectively coated

with a Hydrophilic Polymer up to a extend period.

Krishna Vamshi Allam et.al. 38 stated his research, Lamivudine as a Nucleoside Reverse

Transcriptase Inhibitor (NRTI), licensed for the treatment of HIV, and chronic Hepatitis B. In his

research, the pharmacokinetic data of Lamivudine shows that, frequent administration for a

prolonged period of time (lifelong in AIDS and for one year in hepatitis patients) is necessary to

maintain constant therapeutic drug levels in the body, in case of AIDS, the dose is 150 mg twice

daily (i.e. multiple times a day) in the form of conventional oral tablets. But the long-term AIDS

therapy with the conventional tablets of Lamivudine found to have some drawbacks, such as

adverse side effects (sometimes severe) resulting from accumulation of drug in multi-dose long-

term therapy; poor patient compliance; and high cost. Designing of controlled and sustained

release once-daily formulations of Lamivudine can overcome these problems, and maintaining of

systemic drug levels consistently above its target antiretroviral concentration throughout the

course of the treatment (which is crucial for the success of AIDS therapy) is also possible with

these approaches. This review briefly discusses about the novel dosage forms like controlled

release matrix tablets, floating tablets, nanoparti4cles, microparticles, liposomes, and niosomes;

which may possibly suitable for the controlled and/or sustained release of Lamivudine and thus,

useful in developing the more effective AIDS therapy with very less or no adverse side effects.

Vikramjit Singh et.al 39 prepared tablets containing Zidovudine and Lamivudine (ZILA) by

direct compression method. Optimization studies were done for the selection of glidant, lubricant

and coating materials. Evaluation of granules was done on the basis of preformulation studies.

The prepared tablets were evaluated for physicochemical properties. The in-vitro release studies

were performed as per USP and compared with marketed product. The release of Zidovudine and

Lamivudine were analyzed by high performance liquid chromatography (HPLC). The ZILA

tablets exhibited better release characteristics than the marketed product. Stabilities studies were

performed in both blister as well as cold form blister packings. Stabilities studies revealed the

suitability of blister package in comparison to the cold form blister packing. From the study it

was concluded that the selected composition can be used for the preparation of tablets that can be

used for the treatment of HIV-1 and Hepatitis-B after performing studies on animals for its

suitability and efficacy.

B. Rajkumar, T. et.al. 40 developed a reverse phase HPLC isocratic method that has been

validated as per ICH guidelines in terms of specificity, accuracy, precision, linearity, robustness,

limit of detection and limit of quantitiation, for the simultaneous quantitative estimation of

Efavirenz, Lamivudine Zidovudine. A good linear relationship was observed for both the drugs

between concentration ranges of 50 and 150 µg/ml. The correlation coefficients were greater

than 0.999 for both the drugs. The inter day and intraday precision results were good enough to

say that the method developed is precise and reproducible. Accuracy studies revealed that mean

recoveries after spiking experiments were between 98 and 102%, an indicative of accurate

method. Accordingly it can be concluded that the developed reverse phase HPLC method is

accurate, precise, linear and robust and therefore the method can be used for the routine analysis

of Efavirenz, Lamivudine and Zidovudine in tablets.

D.Ramakanth Reddy et.al.41 developed a simple, accurate, precise and economical procedure

for simultaneous estimation of Zidovudine and Lamivudine in combined tablet dosage form that

utilizes concept of Dual Wavelength method. This method involves selection of two wavelengths

at which the drug has same absorbance. The method is based upon determination of Zidovudine

at 272 nm and 287.2 nm and Lamivudine at 256 nm and 275.2 nm in 0.1N HCl. Different

analytical performance parameters such as linearity, precision, accuracy, LOD, LOQ and assay

were determined according to ICH guidelines. The method was found linear between the range

of 50-425 μg/ml for Zidovudine and 50-275μg/ml for Lamivudine. The results of formulation

given as percentage of label claim were found to be 100.73±0.56 and 101.86±0.68 for

Zidovudine and Lamivudine respectively. Therefore, the proposed methods can be used for the

routine analysis of both drugs in quality control laboratories.

Srikanth Thota et.al. 42 formulated and evaluated immediate release Tablets of Lamivudine and

Zidovudine, Nevirapine - HAART triple therapy. The objective of this regimen is, to delay

disease progression, to increase the duration of survival by achieving maximal and prolonged

suppression of HIV replication, to restorate and preserve immunological function. Combination

therapy is more effective and has less chances of developing resistance than monotherapy. To

achieve this goal various prototype formulation trials were taken and evaluated with respect to

the various quality control tests such as Thickness, hardness, weight variation, dissolution,

disintegration, hardness and assay. The formula was finalized by comparing the in-vitro

dissolution profile with that of the Marketed Tablets. The in-vitro release study was performed in

0.1N HCl up to 60 min. Among all the formulations, formulation F7 release profile was good as

compared to the marketed products. Stability studies (40±2ºC/75±5%RH) for 2 months indicated

that no characteristics changes in formulation. There was no chemical interaction between drug

and excipients.

Joseph J. Eron et.al. 43 prepared a randomized, open-label, multicenter study to establish clinical

equivalence (non-inferiority) of a regimen employing a Lamivudine 150 mg/Zidovudine 300 mg

combination tablet, administered twice daily, plus a marketed protease inhibitor, compared with

a conventional regimen of 150 mg Lamivudine twice daily, 600 mg Zidovudine daily, and a

protease inhibitor, in antiretroviral-experienced patients infected with HIV-1. Adults who were

seropositive for HIV-1 infection with plasma HIV-1 RNA levels < 10,000 copies/ml (Roche

Amplicor polymerase chain reaction assay, lower limit of quantitation (LLOQ) 400 copies/ml)

and CD4+ cell counts ≥ 300X106/l). All patients had been receiving the conventional

Lamivudine/Zidovudine/protease inhibitor regimen for ≥ 10 weeks immediately prior to the

study. The result of the combination tablet regimen was associated with a 3.5% greater success

rate than the conventional regimen (96.4 versus 92.9%), with four and eight patients failing

treatment due to increases in HIV-1 RNA levels, respectively. The lower limit of the associated

confidence interval for the difference was -2.4%, which was well within the -10% margin

predefined as clinically unimportant. This establishes the clinical equivalence (non-inferiority) of

the combination tablet regimen to the conventional regimens regarding virologic response. The

combination tablet and conventional regimens were similar with respect to percentage of patients

maintaining HIV-1 RNA levels, LLOQ at the end of study or improving from baseline to

undetectability (94 versus 91%), overall incidence of drug-related adverse events (21 versus

19%), and mean area under the curve for CD4. cell counts [treatment difference, 5.9 cells (95%

confidence interval, -15.8 to 27.6 3 106 cells). A self-reported adherence questionnaire indicated

that patients in the combination tablet group were less likely to miss doses of nucleoside

analogue medication at weeks 8 and 16.

Sreenivasulu Y et.al. 44 developed a simple, accurate, precise and economical procedure for UV

Spectroscopic estimation of Lamivudine in pure state and in its pharmaceutical formulation. The

developed method is based upon complex formation of the drug with methyl red reagent.

Linearity was observed in the concentration range of 0.5-5 μg/ml. Calibration curve was

constructed by plotting absorbance values against concentrations, which gave good regression

values. The method was validated statistically and recovery study was performed to confirm the

accuracy of the method.

Mohite P.B et.al. 45 stated that Lamivudine is cytosine and Zidovudine is cytidine and are used as

antiretroviral agents. Both drugs are available in tablet dosage forms with a dose of 150 mg for

LAM and 300 mg ZID respectively. In his research, the method employed is based on first order

derivative spectroscopy. Wavelengths 279 nm and 300 nm were selected for the estimation of the

Lamivudine and Zidovudine respectively by taking the first order derivative spectra. The

concentration of both drugs was determined by proposed method. The results of analysis have

been validated statistically and by recovery studies as per ICH guidelines. Both the drugs obey

Beer’s law in the concentration range 10-50 μg/ml, for LAM and ZID; with regression 0.9998

and 0.9999, intercept – 0.0677 and – 0.0043 and slope 0.0457 and 0.0391 for LAM and ZID,

respectively. The accuracy and reproducibility results are close to 100% with 2% RSD. Finally

the work concludes that simple, accurate, precise, sensitive and economical procedures for

simultaneous estimation of Lamivudine and Zidovudine in tablet dosage form have been

developed.

Manikanta Kumar A. et.al. 46 developed a simple, specific, accurate and precise UV

spectrophotometric method has been for simultaneous estimation of Lamivudine and Efavirenz

in pharmaceutical dosage form. The absorption maxima of the drugs were found to be at 271 and

247 nm for Lamivudine and Efavirenz respectively. Lamivudine and Efavirenz obeyed Beer’s

law in the concentration range of 10-100 μg/ml and 10-70 μg/ml respectively. Different

analytical parameters such as linearity, precision, and accuracy, limit of detection (LOD) and

limit of quantification (LOQ) were determined as per ICH guidelines. Limit of detection and

quantification values for Lamivudine 10 and 3.5 μg/ml and for Efavirenz 10 and 3.0 μg/ml

respectively. The recovery values between prescribed limit of 98-102% shows that method is

free from interference of excipients present in formulation. The developed method was free from

interferences due to excipients present in formulation and it can be used for routine quality

control analysis.

Emmanuel M. Uronnachi et.al. 47 published a research article on Pharmacokinetics and

biodistribution of zidovudine loaded in a solidified reverse micellar delivery system. The aim of

the research was to study the stability, release profile, pharmacokinetic and biodistribution

properties of Zidovudine (AZT)-solidified reverse micellar microparticulate. Lipid matrices

formulated with Phospholipon 90H and goat fat at ratios of 1:1, 2:1, 3:1 and 2:3 were used to

prepare AZT-loaded SLM by melt dispersion followed by lyophilization. In-vitro release studies

of the drug were carried out using a sequential drug release method in both SGF (pH 1.2) and SIF

(pH 7.2) while the in-vivo drug release studies were carried out using Wistar albino rats. The

result of our findings showed that the drug is compatibility with the lipid matrix with the 1:1

showing the most stable microparticle preparation which was then optimized. The formulations

showed a concentration dependent increase in their concentration maximum (Cmax) with values of

116.05 µg/ml, 124.21 µg/ml, 128.95 µg/ml, 138.95 µg/ml and time to reach maximum

concentration (Tmax) values of 5h, 8 h, 8 h, and 5 h for batches B1, B2, B3 and B4 containing 1

%, 2 %, 3 % and 5 % of AZT respectively. The area under curves (AUCs) of the microparticles

formulated showed that the bioavailabilities of the microparticles were comparable to that of the

conventional release tablet. The biodistribution studies of the microparticles in rats showed

highest concentration of the drug in the liver with the least in the brain and higher biodistribution

in various organs than pure AZT. The data suggested that SLM could be a promising drug

delivery system to improve on the shortcomings of pharmacokinetics and bio-distribution

properties of conventional AZT tablets like fluctuation in blood levels of the drug.