DESIGN AND EVALUATION OF BILAYER & TRILAYER TABLET COMBINATION OF ANTIRETROVIRAL DRUGS

DESIGN AND EVALUATION OF BILAYER & TRILAYER TABLET COMBINATION OF ANTIRETROVIRAL DRUGS  

R. Natarajan * and R. Sambath Kumar

Department of Pharmaceutics & Research, The Erode College of Pharmacy, Erode, Tamil Nadu, India.

ABSTRACT: A non-nucleoside reverse transcriptase inhibitor (NNRTI) is Nevirapine. Zidovudine and Lamivudine are antiretroviral medications that are members of the nucleoside analogue class. Combination of three drugs commonly used in the management of the Human Immunodeficiency Virus (HIV) infection. Nevirapine exhibits a decent initial release, while Zidovudine and Lamivudine demonstrate sustained release in the produced trilayer and bilayer tablets. The outcome demonstrates that the release profile is not affected by layer separation and is highly dependent on the drug to polymer ratio. The results show that the release can be effectively controlled for up to 12 hours using a 1:1 ratio of zidovudine and HPMC and a 1:1 ratio of lamivudine and ethyl cellulose. It is clear that formulation F1, out of all formulations, has the best sustained release, drug content, and highest regression values. Nevirapine fits best in first order release of Zidovudine in all of the F1–F6 formulations.

Keywords: HIV medication combinations, Immediate release, Sustained release, Bilayer and trilayer tablets and AIDS

INTRODUCTION: The outbreak of acquired immune deficiency syndrome is one of the biggest problems the medical profession is now confronting combinations of three medications that are frequently prescribed to treat HIV infections ^{1, 2}. Nevirapine is the first non-nucleoside reverse transcriptase inhibitor and a strong inhibitor of HIV-1 replication. Nevirapine has a long first-pass metabolism and a about 45-hour relative elimination half-life. With its wide range of applications in treating AIDS, Zidovudine (AZT), the first anti-HIV compound approved for clinical use, is soluble in water, soluble at all pH values, and absorbs throughout the gastrointestinal tract.

For these reasons, sustained release tablets ³ are a better option than conventional dosage forms. A strong antiviral medication called lamivudine is used to treat AIDS ⁴. A strong nucleoside analogue reverse transcriptase inhibitor is lamivudine. After oral consumption, lamivudine is quickly absorbed and has a bioavailability of more than 80%. Because lamivudine ⁵ has a moderate half-life of five to seven hours, it is delivered numerous times a day. Hydroxypropyl Methylcellulose is frequently utilised in controlled drug delivery systems that are hydrophilic. In controlled-release dosage formulations, ethyl cellulose has been widely employed as a release retardant because to its hydrophobic properties ⁶.

METHODS:

Preparation of Standard Curve: Nevirapine obeys Beer-Lambert's law, its spectrophotometric estimate of 312 nm can be obtained using 0.1 N HCL as a medium and falls between 5 and 25 µg/ml. Since zidovudine obeys Beer's-Lambert's law, its spectrophotometric estimate of 267 nm can be obtained using 0.1 N HCL as a medium ⁷ and a range of 5–25 µg/ml. Since lamivudine obeys Beer's-Lambert's law, its spectrophotometric estimation at 270 nm falls between 5 and 25 µg/ml when 0.1 N HCL is used as the medium.

Preparation of the Trilayer Tablets: The composition of Tri layer tablets of the different formulations was given in the Table 1.

Preparation of Nevirapine Immediate Release Layer: Nevirapine, super disintegrant, and excipients make up the instant release layer. One super disintegrant that was used was sodium starch glycolate. Excipients, super disintegrant, and the necessary quantity of medication were taken and mixed. Zidovudine sustained release layer preparation ². The polymer HPMC K100M was utilised to prepare the zidovudine sustained release layer. Zidovudine and HPMC E 15 LV are present in the formulations in the following ratios: 1:0.5,1:0.75, and 1:1. Using a 12 mm curved punch and the wet granulation process, the tablets were made.

Preparation of Lamivudine Sustained Release Layer: The polymer ethylene cellulose was used to create the lamivudine sustained release layer. Lamivudine and ethyl cellulose are present in the formulations in the following ratios: 1:0.5,1:0.75, and 1:1. The tablets were made utilising a 12 mm curved punch and the wet granulation process ⁵.

TABLE 1: COMPOSITION OF TRILAYER TABLETS

Preparation of the Bilayered Tablets: The composition of Bilayer tablets ^{8, 9} of the different formulations was given in the Table 2.

Preparation of Nevirapine Immediate Release Layer: Nevirapine, super disintegrant, and excipients make up the instant release layer. One super disintegrant that was used was sodium starch glycolate. Excipients, super disintegrant, and the necessary quantity of medication were taken and mixed.

Preparation of Zidovudine and Lamivudine Sustained Release Layer: Ethyl cellulose and the polymer HPMC E 15 LV were used to create the sustained release layer for zidovudine ^{3, 10, 11} and lamivudine ^{12, 13}. The formulations include the following ratios: 1:0.5, 1:0.75, and 1:1 for zidovudine and HPMC E 15 LV, and 1:0.5, 1:0.75, and 1:1 for lamivudine and ethyl cellulose. Using a 12 mm curved punch and the wet granulation process, the tablets were made.

TABLE 2: COMPOSITION OF BILAYER TABLETS

In-vitro Drug Release Studies:

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 ±0.5°C

Volume: 900 ml

Procedure: Utilizing a USP dissolving paddle assembly at 50 rpm and 37 o ±0.5 °C, the release of nevirapine, zidovudine, and lamivudine from the trilayer and bilayer tablets was investigated for up to two hours in 900 ml of 0.1 N HCl and 900 ml of phosphate buffer pH 6.8 for up to twelve hours as the dissolution medium. Using a UV Visible spectrophotometer set to 312 nm, 267 nm, and 270 nm, the drug content of nevirapine, zidovudine, and lamivudine was measured after an aliquot (1 ml) was extracted at predetermined intervals and diluted to 10 ml with the dissolving media.

To maintain the dissolution volume, an equivalent volume of new dissolving medium was added. For duration of 12 hours, three dissolution investigations were conducted, and the mean value was determined ^{14, 15}.

Statistical Analysis: The Tucky post test and one-way analysis of variance (ANOVA) were used to statistically evaluate the various attributes of the formulations. Version 3.0.1 of the GraphPad Instat programme was used for this. The threshold for statistical significance was set at p < 0.05.

Kinetic Analysis of In-vitro Release Rates of Formulations: The results of in-vitro release profile obtained for all the formulations were plotted in modes of data treatment as follows:

1. Zero-order kinetic model-cumulative percentage drug release versus time.
2. First- order kinetic model-log cumulative percentage drug release remaining versus time.
3. Higuchi's model-cumulative percentage drug released versus square root of time.
4. Korsmeyer’s equation/peppa's model-log cumulative percentage drug released versus log time.

TABLE 3: MECHANISM OF DRUG RELEASE AS PER KORSEMEYER EQUATION/PEPPA'S MODEL

RESULTS: Nevirapine dissolves in two hours in all formulations because sodium starch glycolate, a super disintegrant, is present. In contrast, Zidovudine and Lamivudine showed drug release for up to twelve hours in Formulations F1 and F4, ten hours in Formulations F2 and F5, and eight hours in Formulations F3 and F6. The findings imply that the ratio of medication to polymer has a more significant impact on zidovudine and lamivudine release patterns. Compared to formulations generated with ratios of 1:0.75 and 1:0.5, it was noted that the formulation developed with the drug and polymer ratio of 1:1 could control the release for up to 12 hours. The release data is not significantly affected by the layer separation; that is, the release patterns of formulations with trilayer and billayers do not differ significantly. Nevirapine fits best in first order release in all six formulations, while Lamivudine and Zidovudine fit best in zero order models. Every formulation follows a non-fickian release process, depending on the values of 'n'.

TABLE 4: COMPARATIVE IN-VITRO DRUG RELEASE OF ALL TABLET FORMULATIONS OF NEVIRAPINE

FIG. 1: COMPARATIVE IN-VITRO DRUG RELEASE OF NEVIRAPINE IN ALL FORMULATION

TABLE 5: COMPARATIVE IN-VITRO DRUG RELEASE OF ALL TABLET FORMULATIONS ZIDOVUDINE

FIG. 2: COMPARATIVE IN-VITRO DRUG RELEASE OF ZIDOVUDINE IN ALL FORMULATIONS

TABLE 6: COMPARATIVE IN-VITRO DRUG RELEASE OF ALL TABLET FORMULATIONS OF LAMIVUDINE

FIG. 3: COMPARATIVE IN-VITRO DRUG RELEASE OF LAMIVUDINE IN ALL FORMULATIONS

TABLE 7: KINETIC VALUES OF NEVIRAPINE IN ALL FORMULATIONS

TABLE 8: KINETIC VALUES OF ZIDOVUDINE IN ALL FORMULATIONS

TABLE 9: KINETIC VALUES OF LAMIVUDINE IN ALL FORMULATIONS

CONCLUSION: Nevirapine exhibits a decent initial release, while Zidovudine and Lamivudine demonstrate sustained release in the produced trilayer and bilayer tablets. The drug to polymer ratio has a significant impact on the release profile, which is not affected by layer separation. This suggests that the release can be effectively controlled for up to 12 hours using a 1:1 ratio of zidovudine and HPMC and a 1:1 ratio of lamivudine and ethyl cellulose. It is clear that Formulation F1 is the best formulation out of all of them due to its higher regression values, higher drug content, and better sustained release. It is clear that the bilayer and trilayer tablets containing zidovudine, lamivudine, and nevirapine are a viable alternative to the traditional dose form. Nevirapine fits best in first order release in all of the F1–F6 formulations, while Lamivudine and Zidovudine fit best in the zero order model. Every formulation follows a non-fickian release process based on the values of 'n'.

ACKNOWLEDGEMENT: I would like to thank our Chairman & Secretary, Prof. Dr. M. Karunanithi, B.Pharm, M.S, Ph.D., D.Litt. Vivekanandha Educational Institutions, for providing all the necessary facilities and support for the research work and also I thank our Secretary & Correspondent Thiru. A. Natarajaan, the Erode College of Pharmay.

CONFLICTS OF INTEREST: Nil

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    How to cite this article:

    Natarajan R and Kumar SR: Design and evaluation of bilayer & trilayer tablet combination of antiretroviral drugs. Int J Pharm Sci & Res 2024; 15(9): 2852-57. doi: 10.13040/IJPSR.0975-8232.15(9).2852-57.

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