![Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121.
115©Pharmaceutical and Biological Evaluations
Evaluation of Lamivudine controlled release
tablets:
Hardness29
The hardness of the tablets was tested by
diametric compression using a Monsanto
Hardness Tester. A tablet hardness of about 2-4
kg/cm2
is considered adequate for mechanical
stability.
Friability27
The friability of the tablets was measured in a
Roche friabilator (Camp-bell Electronics,
Mumbai). Tablets of a known weight (W0) or a
sample of 20 tablets are dedusted in a drum for a
fixed time (100 revolutions) and weighed (W)
again. Percentage friability was calculated from
the loss in weight as given in equation as below.
The weight loss should not be more than 1 %
Friability (%) = [(Initial weight- Final weight)
/ (Initial weight)] x 100
Content uniformity29
In this test, 20 tablets were randomly selected and
the percent drug content was determined, the
tablets contained not less than 85% or more than
115% of the labelled drug content can be
considered as the test was passed.
Assay
Weighed and finely powdered not less than 20
tablets were taken and transfer an accurately
weighed portion of the powder equivalent to
about 100 mg of lamivudine was extracted with
pH 6.8 buffer and the solution was filtered
through 0.45 μ membranes. The absorbance was
measured at 270 nm after suitable dilution using
UV-visible spectrophotometer.
Thickness29
Thickness of the all tablet formulations were
measured using vernier calipers by placing tablet
between two arms of the vernier calipers.
In-vitro dissolution study:
The In-vitro dissolution study for the lamivudine
controlled release tablets were carried out in USP
XXIII type-II dissolution test apparatus (Paddle
type) using 900 ml of 0.1 N HCl as dissolution
medium for 2 hours followed by phosphate buffer
pH 6.8 for next 10 hours at 50 rpm and
temperature 37±0.5°C. At predetermined time
intervals, 5 ml of the samples were withdrawn by
means of a syringe fitted with a pre-filter, the
volume withdrawn at each interval was replaced
with same quantity of fresh dissolution medium.
The resultant samples were analyzed for the
presence of the drug release by measuring the
absorbance at 270 nm using UV Visible
spectrophotometer after suitable dilutions. The
determinations were performed in triplicate
(n=3).
Kinetic modeling of drug release:
The dissolution profile of all the formulations
was fitted in to zero-order, first-order, Higuchi
and Korsmeyer-peppas models to ascertain the
kinetic modeling of drug release.30-32
Results and Discussion
Controlled release tablets of lamivudine were
prepared and optimized by 32
factorial design in
order to select the best combination of different
rate retarding agents, CARBOPOL974P,
XANTHAN GUM and also to achieve the desired
prolong/sustained release of drug from the dosage
form. The two factorial parameters involved in
the development of formulations are,
concentration of CARBOPOL974P &
XANTHAN GUM polymers as independent
variables (X1, X2), and In vitro dissolution
parameters such as t10%, t50% , t75% & t90% as
dependent variables. Totally nine formulations
were prepared using 3 levels of 2 factors and all
the formulations containing 150 mg of
lamivudine were prepared as a controlled release
tablet dosage form by Direct Compression
technique as per the formulae given in Table 2.
All the prepared tablets were evaluated for
different post compression parameters, drug
content, mean hardness, friability, mean
thickness as per official methods and results are](https://image.slidesharecdn.com/7-160129084920/85/Design-Formulation-and-Evaluation-of-Lamivudine-Controlled-Release-Tablets-6-320.jpg)
Design, Formulation and Evaluation of Lamivudine Controlled Release Tablets
- 1. 110 PHARMACEUTICAL AND BIOLOGICAL EVALUATIONS August 2015; vol. 2 (Issue 4): 110-121. www.onlinepbe.com ISSN 2394-0859 ©Pharmaceutical and Biological Evaluations Research Article Design, Formulation and Evaluation of Lamivudine Controlled Release Tablets Raghavendra Kumar Gunda1 *, J. N. Suresh Kumar1 , Chandan Kumar Brahma1 , Satyanarayana Viragandham2 1 Department of Pharmaceutics, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur (Dt), Andhra Pradesh, India-522601 2 Department of Pharmacy practice, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur (Dt), Andhra Pradesh, India-522601 *For correspondence Raghavendra Kumar Gunda, Assistant Professor, Department of Pharmaceutics, Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur(Dt), A.P. India-522601. Tel: +91-9666705894 Email: raghav.gunda@gmail.com Received: 12 August 2015 Accepted: 26 August 2015 ABSTRACT Objective: The main objective of present investigation is to formulate the controlled release tablet of Lamivudine using 3² factorial design. Lamivudine, a basic molecule and antiretroviral drug belongs to BCS Class III, having low permeability and high solubility. Methods: The controlled release tablets of lamivudine were prepared employing different concentrations of Carboplol974P and Xanthan gum in different combinations as a rate retarding agent by Direct Compression technique using 32 factorial design. The quantity/ concentration of rate retarders, Carboplol974P and Xanthan gum required to achieve the desired drug release was selected as independent variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution t10%, t50%, t75%,t90% were selected as dependent variables. Results: Totally nine formulations were designed and are evaluated for hardness, friability, thickness, % drug content, in-vitro drug release. From the results it was concluded that all the formulation were found to be with in the pharmacopoeial limits and the in-vitro dissolution profiles of all formulations were fitted in to different Kinetic models, the statistical parameters like intercept (a), slope (b) & regression coefficient (r) were calculated. Polynomial equations were developed for t10%, t50%, t75%,t90%. Conclusions: According to SUPAC guidelines the formulation (F5) containing combination of 10% Carboplol974P and 10% Xanthan gum, is the most similar formulation (similarity factor f2=85.04 & No significant difference, t= 0.20046) to Innovator product (Lamivir). The selected formulation (F5) follows Higuchi’s kinetics, and the mechanism of drug release was found to be Case-II transport or typical Zero order release (Non- Fickian, n= 0.915). Keywords: Lamivudine, Factorial design, Controlled release tablet, Carbopol974P, Xanthan gum, Non Fickian mechanism, Case-II transport
- 2. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 111©Pharmaceutical and Biological Evaluations Introduction Oral administration is the most convenient, widely utilized for both conventional and novel drug delivery systems, Tablets are the most popular oral solid unit formulations available in the market and are preferred by patients and physicians alike. There are many obvious reasons for this, not the least of which would include acceptance by the patient and ease of administration. In long-term therapeutic concern for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses and therefore have several disadvantages1 . However, when administered orally, many therapeutic agents are subjected to extensive presystemic elimination by gastrointestinal degradation and/or first pass hepatic metabolism as a result of which low systemic bioavailability and shorter duration of therapeutic activity and formation of inactive or toxic metabolites.2 Controlled release (CR) tablet formulations are preferred for such therapy because they offer better patient compliance, maintain uniform drug levels, reduce dose and side effects, and increase the safety margin for high-potency drugs.1 Over the past 30 years, as the expense and complications involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of controlled drug delivery, the goal in the designing sustained or controlled delivery system is to reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery.3 Sustained release dosage forms may be defined as any drug or dosage form modification that prolonged but not necessarily uniform release of drug. The goal of a sustained release dosage form is to maintain therapeutic blood or tissue levels of the drug for an extended period. This is usually accomplished by attempting to obtain zero-order drug release from the dosage form. Zero-order release constitutes the drug release from the dosage form that is independent of the amount of drug in the delivery system (i. e., constant release rate). Sustained release systems generally do not attain this type of release and usually try to mimic zero-order release by providing drug in a slow first-order fashion (i. e., concentration dependent). Systems that are designated as prolonged release can also be considered as attempts at achieving sustained release delivery.4,5 Sustained release tablet allowing a 2 fold or greater reduction in frequency of administration of a drug in comparison with the frequency required by a conventional dosage form6,7 . Sustained release products provide advantage over conventional dosage form by optimising biopharmaceutics and pharmacokinetics properties of drug. Sustained release dosage forms have been demonstrated to improve therapeutic efficiency by maintenance of a steady state drug plasma concentration.8,9 Oral controlled drug delivery system represents one of the frontier areas of drug delivery system in order to fulfill the need for a long-term treatment with anti-HIV agents10 . Among the different controlled drug delivery (CDD) systems, matrix based controlled release tablet formulations are the most popularly preferred for its convenience to formulate a cost effective manufacturing technology in commercial scale. Development of oral controlled release matrix tablets containing water-soluble drug has always been a challenging because of dose dumping due to improper formulation resulting in plasma fluctuation and accumulation of toxic concentration of drug11 . The use of polymers in controlling the release of drugs has become an important tool in the formulation of pharmaceutical dosage forms. Over many years, numerous studies have been reported in the literature on the application of hydrophilic polymers in the development of controlled release matrix systems for various drugs.12-14 Since the early 1950s, the application of polymeric materials for medical purposes is growing very fast. Polymers have been used in the medical field for a large extent.15 Natural polymers remain attractive primarily because they are inexpensive, readily available, be capable of chemical modifications, non-
- 3. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 112©Pharmaceutical and Biological Evaluations carcinogenicity, mucoadhesivity, biodegradable, biocompatible, high drug holding capacity and high thermal stability and easy of compression.16 This led to its application as excipient in hydrophilic drug delivery system. The various natural gums and mucilages have been examined as polymers for sustained drug release in the last few decades for example; guar gum, tragacanth gum, xanthan gum, pectin, alginates etc. In the development of a sustained release tablet dosage form. . These dosage forms are available in extended release, targeted release, delayed release, prolonged action dosage form. Some factors like molecular size, diffusivity, pKa- ionization constant, release rate, dose and stability, duration of action, absorption window, therapeutic index, protein binding, and metabolism affect the design of sustained release formulation. The future of sustained release products is promising in some area like chronopharmacokinetic system, targeted drug delivery system, mucoadhesive system, particulate system that provide high promise and acceptability. Developing oral-controlled release formulations for highly water-soluble drugs with constant rate of release has become a challenge to the pharmaceutical technologists. Fast release drug generally causes toxicity if not formulated as extended release dosage form. Among various formulation approaches, in controlling the release of water-soluble drugs, the development of sustained release coated granules has a unique advantage of lessening the chance of dose dumping which is a major problem when highly water-soluble drug is formulated as matrix tablets. Most of the researchers have worked on matrix tablets and multilayered matrix tablets. Among numerous approaches to oral CR formulation, matrix system of dosage form proves to be potential because of its simplicity, ease of manufacturing, low cost, high level of reproducibility, stability, ease of scale up, and process validation.17 Oral controlled release dosage form by direct compression technique is a simple approach of drug delivery systems that proved to be rational in the pharmaceutical arena for its ease, compliance, faster production, avoid hydrolytic or oxidative reactions occurred during processing of dosage forms.18 The selection of the drug candidates for controlled release system needs consideration of several biopharmaceutical, pharmacokinetic and pharmacodynamic properties of drug molecule.19 In the present study, a controlled release dosage form of Lamivudine has been developed that enables less frequent administering of drug. Acquired immune deficiency syndrome (AIDS) is considered to be an epidemic, and according to estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) AIDS Epidemic Update 2005, 38 million adults and 2.3 million children were living with the human immunodeficiency virus (HIV) at the end of 2005. The annual number of AIDS deaths can be expected to increase for many years to come, unless more effective and patient-compliant anti- retroviral medications are available at affordable prices (Joint United Nations Programme, 2006). As of 2009, AVERT (also known as the AIDS Education and Research Trust) estimated that there are 33.3 million people worldwide living with HIV/ AIDS, with 2.6 million new HIV infections per year and 1.8 million annual deaths due to AIDS. The major drawbacks of antiretroviral drugs for the treatment of AIDS are their adverse side effects during long-term therapy, poor patient compliance, and their huge cost.20,21 Lamivudine is a synthetic nucleoside analog that is being increasingly used as the core of an antiretroviral regimen for the treatment of HIV infection.22,23 In vivo, nucleoside analogs are phosphorylated intracellularly by endogenous kinases to putatively active 5′- triphosphate (3TC-TP) derivatives that prevent HIV replication by competitively inhibiting viral reverse transcriptase and terminating proviral DNA chain extension. Lamivudine belongs to class III of the BCS Classification with High solubility and low permeability. Lamivudine is rapidly absorbed after oral administration with an absolute
- 4. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 113©Pharmaceutical and Biological Evaluations bioavailability of 86% ± 16%, peak serum concentration of lamivudine (Cmax) of 1.5 ± 0.5 mcg/mL and mean elimination half-life (t½) of 5 to 7 hours. It is bound to plasma proteins less than 36%.thus necessitating frequent administration to maintain constant therapeutic drug levels.24 Lamivudine (ß-L-2’, 3’-dideoxy-3’-thiacytidine) (LAM), one of the dideoxycytidine analogue NRTIs, is the first nucleoside analogue approved to treat chronic HBV infection and AIDS. Conventional oral formulations of LAM are administered multiple times a day (150 mg twice daily) because of its moderate half-life (t1/2 = 5-7 hours).Treatment of AIDS using conventional formulations of LAM is found to have many drawbacks, such as adverse side effects resulting from accumulation of drug in multi-dose therapy, poor patient compliance, and high cost. Controlled release once daily formulations of LAM can overcome some of these problems.25 Development of dosage form depends on chemical nature of the drug/polymers, matrix structure, swelling, diffusion, erosion, release mechanism and the in vivo environment. It is an important issue is to design an optimized formulation with an appropriate dissolution rate in a short time period and minimum trials. Many statistical experimental designs have been recognized as useful techniques to optimize the process variables. For this purpose, response surface methodology (RSM) utilizing a polynomial equation has been widely used. Different types of RSM designs include 3-level factorial design, central composite design (CCD), Box-Behnken design and D-optimal design. Response surface methodology (RSM) is used when only a few significant factors are involved in experimental optimization. The technique requires less experimentation and time, thus proving to be far more effective and cost- effective than the conventional methods of formulating sustained release dosage forms. Hence an attempt is made in this research work to formulate controlled release (CR) tablets of LAM using Carbopol974P and Xanthan gum. Instead of normal and trial method, a standard statistical tool design of experiments is employed to study the effect of formulation variables on the release properties. Large scale production needs more simplicity in the formulation with economic and cheapest dosage form. The CR tablets formulation by direct compression method is most acceptable in large scale production. A 32 full factorial design was employed to systematically study the drug release profile. A 32 full factorial design was employed to investigate the effect of two independent variables (factors), i.e the amounts of Carbopol 974P and Xanthan Gum on the dependent variables, i.e. t10%, t50%, t75%, t90%, (Time taken to release 10%, 50%, 75%, 90% respectively). Materials and Methods Materials used in this study were obtained from the different sources. Lamivudine was a gift sample from Aurobindo pharma Ltd, Hyderabad, India. Carbopol974P and Xanthan gum were procured from Loba Chemie Pvt.Ltd, Mumbai. Other excipients such as Aerosil and magnesium stearate were procured from S.D. Fine Chem. Ltd., Mumbai. Formulation development of Lamivudine sustained release tablets: The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition, any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses.26 A selected three level, two factor experimental design (32 factorial design) describe the proportion in which the independent variables HPMC Carbopol974P and Xanthan gum were used in formulation of lamivudine controlled release (CR) Tablets. The time required for 10% (t10%), 50% (t50%), 75% (t75%) and 90% (t90%) drug dissolution were selected as dependent variables. Significance terms were chosen at 95% confidence interval (p<0.05) for Final Equations. Polynomial equations were developed for t10%,
- 5. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 114©Pharmaceutical and Biological Evaluations t50%, t75%, t90%, (step-wise backward Linear Regression Analysis). The three levels of factor X1 (Carbopol974P) at a concentration of 5%, 10%, 15%. Three levels of factor X2 (Xanthan Gum) at a concentration of 5%, 10%, 15% (% with respect to total tablet weight) was taken as the rationale for the design of the lamivudine CR tablet formulation. Totally nine lamivudine controlled release tablet formulations were prepared employing selected combinations of the two factors i.e X1, X2 as per 32 Factorial and evaluated to find out the significance of combined effects of X1, X2 to select the best combination and the concentration required to achieve the desired prolonged/ sustained release of drug from the dosage form. Preparation of Lamivudine controlled release tablets: All ingredients were collected and weighed accurately. Sift Lamivudine USP with Avicel PH 102 and polymers through sieve no. 60# and then rinse with remaining excipients. Sift colloidal silicon dioxide (Aerosil-200) and magnesium stearate separately, through sieve no. 60#. Pre- blend all ingredients (except lubricant- magnesium stearate) in blender for 15 minutes. Add magnesium stearate and then again blend for 5-6 minutes. Lubricated powder was compressed by using rotary tablet punching machine (RIMEK), Ahmedabad). Compressed tablets were examined as per official standards and unofficial tests. Tablets were packaged in well closed light resistance and moisture proof containers. Experimental design: Experimental design utilized in present investigation for the optimization of polymer concentration such as, concentration of Carbopol974P was taken as X1 and concentration of Xanthan Gum was taken as X2. Experimental design was given in the Table 1. Three levels were selected and coded as -1= 5%, 0=10%, +1=15%. Formulae for all the experimental batches were given in Table 2.27,28 Table 1: Experimental design layout. Formulation Code X1 X2 F1 1 1 F2 1 0 F3 1 -1 F4 0 1 F5 0 0 F6 0 -1 F7 -1 1 F8 -1 0 F9 -1 -1 Table 2: Formulae for the preparation of Lamivudine sustained release tablets as per experimental design. Name of Ingredients Quantity of Ingredients per each Tablet (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 Lamivudine 150 150 150 150 150 150 150 150 150 Avicel PH 102 120 140 160 140 160 180 160 180 200 Carbopol974P 60 60 60 40 40 40 20 20 20 Xanthan Gum 60 40 20 60 40 20 60 40 20 Aerosil 5 5 5 5 5 5 5 5 5 Magnesium Stearate 5 5 5 5 5 5 5 5 5 Total Weight 400 400 400 400 400 400 400 400 400
- 6. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 115©Pharmaceutical and Biological Evaluations Evaluation of Lamivudine controlled release tablets: Hardness29 The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2-4 kg/cm2 is considered adequate for mechanical stability. Friability27 The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics, Mumbai). Tablets of a known weight (W0) or a sample of 20 tablets are dedusted in a drum for a fixed time (100 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 % Friability (%) = [(Initial weight- Final weight) / (Initial weight)] x 100 Content uniformity29 In this test, 20 tablets were randomly selected and the percent drug content was determined, the tablets contained not less than 85% or more than 115% of the labelled drug content can be considered as the test was passed. Assay Weighed and finely powdered not less than 20 tablets were taken and transfer an accurately weighed portion of the powder equivalent to about 100 mg of lamivudine was extracted with pH 6.8 buffer and the solution was filtered through 0.45 μ membranes. The absorbance was measured at 270 nm after suitable dilution using UV-visible spectrophotometer. Thickness29 Thickness of the all tablet formulations were measured using vernier calipers by placing tablet between two arms of the vernier calipers. In-vitro dissolution study: The In-vitro dissolution study for the lamivudine controlled release tablets were carried out in USP XXIII type-II dissolution test apparatus (Paddle type) using 900 ml of 0.1 N HCl as dissolution medium for 2 hours followed by phosphate buffer pH 6.8 for next 10 hours at 50 rpm and temperature 37±0.5°C. At predetermined time intervals, 5 ml of the samples were withdrawn by means of a syringe fitted with a pre-filter, the volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at 270 nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate (n=3). Kinetic modeling of drug release: The dissolution profile of all the formulations was fitted in to zero-order, first-order, Higuchi and Korsmeyer-peppas models to ascertain the kinetic modeling of drug release.30-32 Results and Discussion Controlled release tablets of lamivudine were prepared and optimized by 32 factorial design in order to select the best combination of different rate retarding agents, CARBOPOL974P, XANTHAN GUM and also to achieve the desired prolong/sustained release of drug from the dosage form. The two factorial parameters involved in the development of formulations are, concentration of CARBOPOL974P & XANTHAN GUM polymers as independent variables (X1, X2), and In vitro dissolution parameters such as t10%, t50% , t75% & t90% as dependent variables. Totally nine formulations were prepared using 3 levels of 2 factors and all the formulations containing 150 mg of lamivudine were prepared as a controlled release tablet dosage form by Direct Compression technique as per the formulae given in Table 2. All the prepared tablets were evaluated for different post compression parameters, drug content, mean hardness, friability, mean thickness as per official methods and results are
- 7. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 116©Pharmaceutical and Biological Evaluations given in Table 3. The hardness of tablets was in the range of 4.75-6.25 Kg/cm2 . Weight loss in the friability test was less than 0.52%. Drug content of prepared tablets was within acceptance range only. In-vitro Dissolution studies were performed for prepared tables using 0.1 N HCl as a dissolution media for first 2 hours followed by phosphate buffer pH 6.8 for next 10 hours at 50 rpm and temperature 37±0.5°C. The comparative In-vitro dissolution profiles of tablets are shown in Fig.1 and the dissolution parameters are given in Table 5. Table 3: Post-compression parameters for the formulations. S.No. Formulation Code Hardness (kg/cm2 ) Diameter (mm) Thickness (mm) Friability (%) Drug conent (%) 1 F1 4.75 9.51 4.81 0.467 94.79±1.31 2 F2 5.65 9.50 5.220 0.473 97.41±1.12 3 F3 5.05 9.51 4.85 0.353 97.30±1.0 4 F4 4.85 9.50 5.03 0.414 96.35±1.46 5 F5 5.95 9.50 5.47 0.409 99.25±1.45 6 F6 6.25 9.51 5.18 0.338 99.81±1.13 7 F7 6.15 9.50 5.17 0.340 99.30±1.0 8 F8 5.35 9.50 5.01 0.358 97.19±1.31 9 F9 5.05 9.51 5.00 0.353 95.64±1.64 Table 4: Regression analysis data of 32 factorial design formulations of lamivudine. S.No Formul ation Code Kinetic Parameters Zero Order First Order Higuchi Korsmeyer-Peppas a b r a b r a b r a b r 1 F1 9.22 7.02 0.99 2.08 0.08 0.95 8.64 26.65 0.97 1.01 0.90 0.96 2 F2 10.34 7.06 0.99 2.08 0.08 0.95 7.85 26.90 0.97 1.02 0.90 0.96 3 F3 5.07 6.88 0.99 2.06 0.07 0.97 12.08 25.98 0.97 0.87 1.02 0.98 4 F4 9.12 7.19 0.99 2.12 0.09 0.91 8.99 27.23 0.97 1.01 0.92 0.96 5 F5 10.14 7.27 0.99 2.16 0.11 0.88 8.34 27.59 0.97 1.02 0.92 0.96 6 F6 10.28 7.20 0.98 2.10 0.09 0.91 9.00 27.76 0.98 0.94 1.01 0.96 7 F7 6.29 6.91 0.99 2.06 0.07 0.97 11.16 26.19 0.97 0.90 1.00 0.98 8 F8 9.36 7.13 0.99 2.08 0.08 0.94 9.63 27.44 0.98 0.92 1.02 0.96 9 F9 4.21 7.36 0.99 2.14 0.09 0.89 13.16 27.34 0.95 0.91 0.98 0.98 10 IP 3.08 8.10 1.00 2.27 0.13 0.84 16.11 30.15 0.96 0.88 1.06 0.99 F1 to F9 are factorial formulations, r-correlation coefficient, a-Intercept, b-Slope and IP-Innovator Product. Much variation was observed in the t10%, t50%, t75% and t90% due to formulation variables. Formulation F5 containing 40 mg of CARBOPOL974P, 40 mg of XANTHAN GUM showed promising dissolution parameter (t10%= 0.428 h, t50% = 2.816 h, t75% = 5.633 h, t90% = 9.359 h). The difference in burst effect of the initial time is a result of the difference in the viscosity of the polymeric mixtures. Dortunc and Gunal have reported that increased viscosity resulted in a corresponding decrease in the drug release, which
- 8. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 117©Pharmaceutical and Biological Evaluations might be due to the result of thicker gel layer formulation.33 Table 5: Dissolution parameters of lamivudine controlled release tablets 3² full factorial design batches. The In -vitro dissolution data of lamivudine CR formulations was subjected to goodness of fit test by linear regression analysis according to zero order and first order kinetic equations, Higuchi’s and Korsmeyer-Peppas models to assess the mechanism of drug release. The results of linear regression analysis including regression coefficients are summarized in Table 4 and plots shown in Fig. 1-4. It was observed from the above, that dissolution of all the tablets followed zero order kinetics with co-efficient of determination (R2 ) values above 0.984. The values of r of factorial formulations for Higuchi’s equation was found to be in the range of 0.953- 0.983, which shows that the data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation, the slope (n) values ranges from 0.873- 1.019 that shows Non-Fickian diffusion mechanism (Case-II transport or typical Zero order release). Polynomial equations were derived for t10%, t50%, t75% and t90% values by backward stepwise linear regression analysis. The dissolution data of factorial formulations F1 to F9 are shown in Table 5. Figure 1: Comparative Zero Order Plots of F1- F9. Figure 2: Comparative First Order Plots of F1- F9. Polynomial equation for 3² full factorial designs is given in Equation Y= b0+b1 X1+b2 X2+b12 X1X2+b11 X1²+b22 X2²… Where, Y is dependent variable, b0 arithmetic mean response of nine batches, and b1 estimated co-efficient for factor X1. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. S. No Formu lation Code Kinetic Parameters t10% (h) t50% (h) t75% (h)) t90% (h) 1 F1 0.572 3.764 7.529 12.509 2 F2 0.545 3.584 7.167 11.908 3 F3 0.705 4.638 9.276 15.411 4 F4 0.490 3.227 6.454 10.723 5 F5 0.428 2.816 5.633 9.359 6 F6 0.505 3.322 6.645 11.040 7 F7 0.678 4.457 8.915 14.812 8 F8 0.557 3.662 7.324 12.169 9 F9 0.510 3.356 6.711 11.151 10 IP 0.348 2.287 4.574 7.600
- 9. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 118©Pharmaceutical and Biological Evaluations The interaction term (X1X2) shows how the response changes when two factors are simultaneously changed. The polynomial terms (X1² and X2²) are included to investigate non- linearity. Figure 3: Comparative Higuchi Plots of F1-F9. Fig.4 Comparative Korsmeyer-Peppas Plots F1-F9. The equations for t10%, t50%, t75% and t90% developed as follows, Y1= 0.555+0.013X1+0.003X2-0.075X1X2+0.120 X1 2 +0.067X2 2 (for t10%) Y2= 3.647+0.085X1+0.022X2-0.494 X1X2+0.789 X1 2 +0.44 X2 2 (for t50%) Y3= 7.295+0.170X1+0.044X2-0.988X1X2+1.577 X1 2 +0.880X2 2 (for t75%) Y4= 12.120+0.283X1+0.074X2- 1.641X1X2+2.619 X1 2 +1.462X2 2 (for t90%). Figure 5: Linear contour Plot for t10%. Figure 6: Contour Plot for t10%. The positive sign for co-efficient of X1 in Y1, Y2, Y3 and Y4 equations indicates that, as the concentration of CARBOPOL974P increases, t10%, t50%, t75% and t90% value increases. In other words the data demonstrate that both X1 (amount of CARBOPOL974P) and X2 (amount of XANTHAN GUM) affect the time required for drug release (t10%, t50%, t75% and t90%). From the results it can be concluded that, and increase in the amount of the polymer leads to decrease in release rate of the drug and drug release pattern
- 10. Gunda RK et al. Pharmaceutical and Biological Evaluations 2015; vol. 2 (4): 110-121. 119©Pharmaceutical and Biological Evaluations may be changed by appropriate selection of the X1 and X2 levels. The final best (Optimised) formulation (F5) is compared with Innovator product (Lamivir) shows similarity factor (f2) 85.454, difference factor (f1) 2.392 (There is no significant difference in drug release because tcal is<0.05). Figure 7: Linear Contour Plot for t50%. Figure 8: Contour Plot for t50%. Conclusions The present research work envisages the applicability of rate retarding agents such as Carbopol974P and Xanthan Gum in the design and development of controlled release tablet formulations of lamivudine utilizing the 32 factorial design. From the results it was clearly understand that as the retardant concentration increases the release rate of drug was retarded and both of these release retardants can be used in combination since do not interact with the drug which may be more helpful in achieving the desired controlled release of the drug for longer periods. The optimized formulations followed Higuchi’s kinetics while the drug release mechanism was found to be Non Fickian, Case-II transport or typical Zero order release type, controlled by diffusion through the swollen matrix. On the basis of evaluation parameters, the Best formulation F5 may be used once a day administration in the management of AIDS, other Viral Diseases. Acknowledgements The author would like to thank Management, Principal, Teaching, Non-teaching Staff of Narasaraopeta Institute of Pharmaceutical Sciences, Narasaraopet, Guntur (D.t), A.P., India for providing support for successful completion of research work. Funding: No funding sources Conflict of interest: None declared References 1. Jain S, Mehra NK, Singhai AK, Saraogi GK. Development and evaluation of sustained release matrix tablet of lamivudine. IJPSR. 2011;2(1):454-61. 2. Singh RR. Design, Formulation and In Vitro Evaluation of Lamivudine HCl Sustained Release Tablets. International Journal of Research in Pharmaceutical and Nano Sciences. 2014;3(2):113–21. 3. Y. Ganesh kumar, J Sreekanth, D Satyavati. Formulation development and in vitro evaluation of sustained release matrix tablets of bosentan by using synthetic polymers. Int J Pharm Pharm Sci. 2014;6(11):111-8.
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