FORMULATION AND EVALUATION OF IMMEDIATE RELEASE TABLET OF LAMIVUDINE, ZIDOVUDINE AND NEVIRAPINE

FORMULATION AND EVALUATION OF IMMEDIATE RELEASE TABLET OF LAMIVUDINE, ZIDOVUDINE AND NEVIRAPINE

Srikanth Thota*, A. K. Radhalakshmi, D. Krishnanrajan and K. G. Parthiban

Department of Pharmaceutics, JKKMMRF College of Pharmacy, Komarapalayam, Tamil Nadu, India

ABSTRACT

The present study outlines a systematic approach for Formulation and Evaluation of 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 Invitro dissolution profile with that of the Marketed Tablets^. The in vitro release study was performed in 0.1N HCl upto 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.

Immediate release tablet

INTRODUCTION: Oral route is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient acceptance and cost effective manufacturing process ¹.

As a result the demand for the technologies has been increased 3 fold annually. Since the development cost of new chemical entity is very high, the pharmaceutical companies are focusing on the development of new drug delivery systems for existing drug with an improved efficacy and bioavailability together with reduced dosing frequency to minimize the side effects².

Combination therapy: When two or more drugs are used together to treat any disease, treatment is called as combination therapy. Now a day’s various developed and developing countries move towards combination therapy for treatment of various diseases and disorders requiring long term therapy.

Advantages of Combination therapy over monotherapy such as, problem of dose dependent side effects is minimized, a low dose combination of two different agents reduces the dose related risk, the addition of one agent may counteract some deleterious effects of the other, using low dosage of two different agents minimizes the clinical and metabolic effects that occur with maximal dosage of individual component of the combined tablet and thus dosage of the single component can be reduced, dosage form of two or more active ingredients in combination can show Synergistic cumulative effect and/or decreased side effects ³. Fixed dose combinations are multiple antiretroviral drugs combined into a single pill. Combination of antiretrovirals creates multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation, if a mutation that conveys resistance to one of the drugs being taken, the other drugs continue to suppress reproduction of that mutation, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for longer duration, so these agents must be taken in combinations in order to have a long lasting effect ⁴.

As a result, the standard of care is to use combinations of antiretroviral drugs, Current treatment for HIV infection consists of Highly Active Antiretroviral Therapy or HAART ⁵. Current HAART options are combinations consisting of at least three drugs belonging to at least two different classes of antiretroviral agents, typically, these classes are two Nucleoside Analogue Reverse Transcriptase Inhibitors (NARTIs) plus either a Protease Inhibitor ⁶. These different classes of antiretroviral drugs act at different stages of the HIV life-cycle, this three drug combination is commonly known as a triple cocktail.

Highly active antiretroviral therapy for HIV-AIDS. Lamivudine Reverse transcriptase Inhibitor. Zidovudine Nucleoside Reverse Transcriptase Inhibitor (NsRTI). Nevirapine Non-nucleoside reverse transcriptase inhibitor (NNRTI) ⁷. There are two major classes of ARVs based on their mechanism of action ⁸; Reverse Transcriptase Inhibitors (RTIs) and Protease Inhibitors (PIs).

MATERIALS AND METHODS:

Materials: Lamivudine, Zidovudine, Nevirapine (Cipla, India). Collodal silicon dioxide (Beggusa) Cross Carmellose Sodium (FMC biopolymer) Povidone (Aqualon) Sodium starch glycolate (Stepan) Corn starch (JRSPharma) Microcrystalline cellulose (FMC biopolymer) Magnesium Stearate (Ferro) All other solvents and reagents were of analytical grade.

Preparation of Immediate release tablets: Lamivudine, Zidovudine granules are prepared by Direct compression method and Nevirapine granules were prepared by wet granulation process. The composition of each tablet is shown in table 1. Formulations are prepared first Sifting of Lamivudine, Zidovudine, Microcrystalline Cellulose (Avicel PH 102) and colloidal silicone dioxide, Sodium starch glycolate were sifted together and the material were loaded into octagonal Blender And mixed for 10 minutes. The Nevirapine, Microcrystalline cellulose (Vivapur 101), Croscarmellose Sodium and Corn starch were sifted together through mesh #20.

The Binder solution (Povidone) was prepare and granulate with the Nevirapine. The granules was dried at temperature of 60⁰c ±5⁰c in rapid dryer till to get LOD of NMT 3.0% w/w.The dried granules were passed through # 20 and lubricated with magnesium stearate by further blending for 5 mins. Compression was done on10 station Rimek tablet compression machine (M/s Karnawati Engg. Ltd. Ahemadabad) using 19.4×9.2 mm punches.

Evaluation of Tablets: The prepared tablets can be evaluated for various official and non official specifications.

Thickness: The thickness of the tablet is measured by vernier calipers scale. Thickness of the tablet relate to the tablet hardness and can be used an initial control parameter.                    

Weight variation: Twenty tablets were selected at a random and average weight was calculated. Then individual tablets were weighed and the individual weight was compared with an average weight.

Hardness and Friability: Tablets were evaluated for hardness and friability test using Monsanto hardness tester and Roche Friabilator respectively.

In-vitro drug release study: An in-vitro drug release study was carried out using tablet dissolution test apparatus USP type- II (Paddle) at 50 rpm ^{9, 10}. The dissolution medium consisted of 900ml 0.1N HCl, maintained at a temperature 37.0°C ± 0.5°C. A sample of 5ml was withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced, and then measure absorbance by HPLC technique.

RESULTS AND DISCUSSION: In the present study, Lamivudine, Zidovudine and Nevirapine Immediate release tablets were prepared by direct compression and wet granulation process by using ingredients shown in table 1. A total number of seven formulations were prepared. The data of evaluated tablets such as thickness, weight variation, hardness and friability are shown in table 2. The hardness was found to be in the range of 11kp to13 kp, the normal acceptance criteria for hardness are not more than 15.00kp.

In F1, it was observed that the dissolution profile of the test product was on lower side when compared to the innovator, so in order to increase the dissolution it was decided to do the formulation by increasing the concentration of sodium starch glycolate from 27mg/tab to 37mg/tab, Colloidal silicon dioxide 2.75mg/tab to 3.75 mg/tab and corn starch 30mg/tab to 45mg/tab. In F2 the dissolution profile of the test product was on lower side when compared to the innovator and also Sticking of powder was observed during compression, it was due to insuffient lubrication in efavirenz granules final blend .So it was decided to increase quantity of magnesium stearate from 10mg/tablet to 12.5mg/tablet.

In F3, the dissolution profile of the test product was on lower side when compared to the innovator, so in order to increase the dissolution it was decided to do the formulation by decreasing the concentration of Binder (povidone) from 27mg/tab to 20mg/tab and increasing the concentration of sodium starch glycolate from 37mg/tab to 44mg/tab.

In F4, observed that the decreasing the concentration of binder (povidone) from increasing the concentration of sodium starch glycolate improved the dissolution profile of the test product but it was still on lower side when compared to the innovator. So in order to increase the dissolution further, it was decided to the formulation by decreasing the concentration of povidone from 20mg/tab to 18mg/tab. In F5 that the decreasing the concentration of binder (povidone) improved the dissolution profile of the test product but it was still on lower side when compared to the innovator.

So in order to increase the dissolution further, it was decided to the formulation by decreasing the concentration of povidone from 18mg/tab to 15mg/tab. In F6 observed that the decreasing the concentration of binder (povidone) shows improved in the dissolution profile of the test product but it was slightly higher side when compared to the innovator. So in order to decrease the dissolution, it was decided to do the formulation by decreasing the concentration of sodium starch glycolate from 44mg/tab to 37mg/tab. In F7 observed that the dissolution profile of the test product was matching with the dissolution profile of the innovator it was shown in table 3 and Fig. 1.

TABLE 1: INGREDIENTS FOR ALL FORMULATIONS

  TABLE 2: PHYSICAL PARAMETERS OF LAMIVUDINE, ZIDOVUDINE AND NEVIRAPINE TABLETS OF ALL FORMULATIONS (F1-F7)

  TABLE 3: COMPARISON OF RELEASE PROFILE OF F7(OPTIMIZED)

FIG 1: COMPARATIVE DRUG RELEASE PROFILE OF F7WITH INNOVATORS PRODUCT

CONCLUSION: F7 formulation was concluded as optimized formula based on the drug release profile and other evaluation parameters compared with Innovator product. Finally, the identified formula shall be utilized for the process development studies for successful launching of the product as it was proved to be stable and robust, cost effective.

ACKNOWLEDGEMENTS: The authors are grateful to Cipla India Ltd Hyderabad for providing the drug sample and J.K.K. Munirajah College of pharmacy komarapalayam Tamil Nadu, for providing necessary facilities to conduct the work.

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