Formulation and Evaluation of Sustained Release Matrix Tablets of Acyclovir

 

Mohammed Asif Hussain*, K. Sravan, Maimuna Anjum, Nusrath Ayesha

Blue Birds College of Pharmacy, Bheemaram (V), Hasanparthy (M), Hanamkonda-506015. (A.P)

*Corresponding Author E-mail: asifhussainp@yahoo.com

 

ABSTRACT:

Sustained release is providing promising method to be able to decrease the unwanted effects of drugs by preventing the fluctuation of the therapeutic concentration of the drugs in the body. The aim of current study was to design and characterization of sustained release matrix tablets of Acyclovir by using Hydroxylpropylmethylcellulose (HPMC K100M, K15M, K4M) and Sodium Alginate, by direct compression method. The matrix tablets were then evaluated for various physical tests like, Thickness, Uniformity of weight, hardness, friability, drug content and in vitro drug release. The calculated  regression coefficient has shown higher r2 values with zero order kinetics and higuchi kinetics. The  ‘n’ values of most of the formulations has shown non-fickian diffusion.

 

KEYWORDS: Acyclovir, sustained release matrix tablet, Direct compression technique, HPMC, Sodium Alginate.

 

 

1. INTRODUCTION:


Over the past 30 years, as the expense and complications involved in marketing new drug entities have increased. With the concomitant recognition of the therapeutic advantages of novel drug delivery, greater attention has been focused on development of sustained or controlled released drug delivery system. There are several reasons for the attractiveness of these dosage forms. It is generally recognized that for many disease states, a substantial number of therapeutically effective compounds already exists. The effectiveness of these drugs however is often limited by side effects or the necessity to administer the compound in a clinical setting.

 

The major goal set in designing sustained delivery is to:

·        Reduce the frequency of dosing

·        Increase the effectiveness of the drug by localization at the site of action.

·        reducing the dose required

·             providing the uniform drug delivery.1,2

 

Modified release delivery systems may be divided into four catagories.3

·        delayed release

·        sustained release

·        site specific targeting

·        receptor targetting

 

Sustained release (SR) dosage forms are developed to achieve, continuous thereapeutic effect through continuously releasing the medication over a good extended interval of time on administration of a single dose. However, this time is actually measured by hours and greatly depends on residence period on the dosage form in a gastro intestinal tract.4

 

Acyclovir is an antiviral drug, belonging to the deoxiguanosine family. It is widely prescribed for the treatment of herpes simplex virus infections, varicella zoster infection, chicken pox and shingles. Recently, acyclovir has been used in combination with AZT to treat AIDS patients. The total bioavailability of acyclovir is estimated between 15% and 30% and decreases with increasing dose. The drug is almost completely unionized and has the maximum solubility (2.5 mg/ml) at pH 7.0. It is slowly and scarcely absorbed from the gastrointestinal tract when administered orally and has maximum absorption in stomach and upper part of small intestine. The recommended adult oral dosage of acyclovir is 200 mg twice daily or 400 mg once daily. The effective treatment of genital herpes simplex requires administration of 1000 mg of acyclovir in 5 divided doses a day. An alternative dose of 800 mg leads to plasma fluctuations; thus a sustained release dosage form of acyclovir is desirable 5, 6. The short biological half-life of drug (~2.0-3 hours) also favors development of a sustained release formulation. A traditional oral sustained release formulation releases most of the drug at the colon, thus the drug should have absorption window either in the colon or throughout the gastrointestinal tract 7, 8. Acyclovir is absorbed only in stomach and the initial part of the small intestine and has 30% absolute bioavailability 9. Conventional drug delivery systems achieve as well as maintain the therapeutically effective range of drug concentration needed for treatment only when taken several times a day. This results significant fluctuations in drug levels and side effects. Hence, clinically acceptable sustained release dosage forms of acyclovir prepared with conventional technology may not be successful. The oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract.14

 

Present research work deals with the preparation and characterization of matrix tablets of acyclovir containing hydroxypropylmethylcellulose (K100 M , K15M & K4 M) and Sodium Alginate  as the polymers and matrix tablets of acyclovir were prepared by direct

compression method.

 

2 MATERIALS AND METHODS:

2.1 Materials

Acyclovir was obtained from as a gift sample from Hetero labs, Andhra Pradesh, India. Hydroxyl propyl methyl cellulose (K100M , K15M & K4M) and Sodium Alginate  purchased from S.D Fine chemicals.

 

2.2 Method of Preparation

Acyclovir 200mg and all the ingredients were accurately weighed. Acyclovir was well mixed with weighed quantity of polymer and then mixed with remaining ingredients i.e  microcrystalline cellulose in geometric proportions. Mixed homogenously in a polybag for about 5-10 min. Then lubricated with the previously weighed and sieved magnesium stearate, talc to obtain the blend for compression. Then the lubricated blend was subjected to compression on a single station rotary tablet punching machine using 10mm circular flat faced punches.

       

2.3 Evaluation of Tablets

a)      Hardness and Friability Test

The crushing strength (Kg/cm²) of tablets was determined by using Monsanto type hardness tester. Friability was determined by weighing 10 tablets after dusting, placing them in the friabilator (Roche Friabilator) and rotating the plastic cylinder vertically at 25 rpm for 4 min. After dusting, the total remaining weight of the tablets was recorded and the percent friability (PF) was calculated using formula. 10, 11

PF = (Weight original – Weight final) / Weight original X 100.

 

b)      Uniformity of weight

 Average weight of the tablet was calculated by weighing 20 tablets individually and all together. The percent weight deviation of each tablet was computed as per official method. The results are given in table 3.12

 

c)       Drug content uniformity of the tablets

Five tablets were powdered in a mortar. From this, powder equivalent to 50 mg of drug was taken in a 100 ml round bottom flask. It is extracted with 20 ml of 1.2 buffer for ½ hour, filtered in a volumetric flask and the filtrate was made up to the mark with pH 1.2 buffer. Further appropriate dilutions were made and the absorbance was measured at 289 nm against blank. The results are given in table 3.13

 

2.4  In Vitro  Release Studies

The release rate of Acyclovir from matrix tablets was determined using United States Pharmacopoeia (USP), Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 ml of 0.1N hydrochloric acid, at 37 ± 0.5°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter and diluted to a suitable concentration with 0.1N hydrochloric acid. Absorbance of these solutions was measured at 255 nm using a Thermospectronic-1 UV/V is double-beam spectro-photometer.  Percentage drug release was calculated using an equation obtained from a standard curve. 14, 15.

 

2.5 Kinetic Studies16

To analyse the release of drug from the tablet the data was fitted into different kinetic models like Zero order by taking time on x axis and cumulative % of drug release on y axis, First order by taking time on x axis and log % of drug release on y axis. To find out the mechanism of drug release the data was fitted into Higuchi by taking square root of time on x axis and cumulative % of drug release on y axis and Peppas by taking log time on x axis and log cumulative % of drug release on y axis.

 


 

Table 1: Composition of Acyclovir Sustained Release Matrix tablets

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

F13

F14

F15

Acyclovir

200

200

200

200

200

200

200

200

200

200

200

200

200

200

200

HPMC K100M

25

50

65

45.5

19.5

 

 

 

 

 

 

 

 

 

 

HPMC K15M

 

 

 

 

 

25

50

75

52.5

22.5

 

 

 

 

 

HPMC K4M

 

 

 

 

 

 

 

 

 

 

50

75

100

70

30

Sodium Alginate

 

 

 

19.5

45.5

 

 

 

22.5

52.5

 

 

 

30

70

Microcrystalline Cellulose

363

338

323

323

323

363

338

313

313

313

338

313

288

288

288

Magnesium Stearate

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

Talc

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

Total Weight

600

600

600

600

600

600

600

600

600

600

600

600

600

600

600

 


Table 2: Diffusion exponent and solute release mechanism for cylindrical shape

Diffusion Exponent

Overall solute diffusion mechanism

0.45

Fickian diffusion

0.45<n<0.89

Anomalous (non-fickian) diffusion

0.89

Case II transport

n>0.89

Super Case II transport

 

2.6  Study of physical interaction between drug and polymer

Infrared spectrum was taken by scanning the samples of pure drug and the polymers individually over a wave number range of 4000 to 400 cm–1 using Fourier transform infrared spectrophotometer (FT-IR, Shimadzu 8400S, Shimadzu, Japan). The change in spectra of the drug in the presence of polymer was investigated which indicates the physical interaction of drug molecule with the polymer. DSC measurements were performed using a Mettler TA 4000 apparatus equipped with a DSC 25 cell in order to evaluate the drug-excipient compatibility and to verify the absence of solid-state interactions. The thermal analysis was performed in a nitrogen atmosphere at a heating rate of 100°C /min over a temperature range of 30–3008°C. Alumina was employed as the reference standard.

 

3. RESULTS AND DISCUSSION:

3.1. Physical Evaluation of matrix tablets

a. Dimension (Thickness and Diameter)

Thickness and diameter specifications may be set on an individual product basis. Excessive variation in the tablet thickness and diameter can result in problems with packaging as well as consumer acceptance. There were no marked variations in the thickness and diameter of tablets within each formulation indicating uniform behavior of powder throughout the compression process.

 

The sizes (diameter) of the tablets of all formulations were found to be 5.44±0.03 to 6.24±0.065mm.

 

b. Tablet Hardness

A difference in tablet hardness reflects difference in tablet density and porosity. Which in turn are supposed to result in different release pattern of the drug by affecting the rate of penetration of dissolution fluid at the surface of the tablet and formation of gel barrier. The hardness of tablets was found to be in the range of 6.45±0.14 kg/cm2 to 7.05±0.48kg/cm2. This indicates good tablet strength.

 

c. Weight Variation

A tablet is designed to contain a specific amount of drug. When the average mass of the tablet is 600 mg the pharmacopeial limit for percentage deviation is ± 5 %. The percentage deviation from average tablet weight for all the tablet was found to be within the specified limits and hence all formulations complied with the test for weight variation according to the pharmacopeial specifications.

 

d. Percent Friability

Percentage friability of all the formulations was found between 0.46±0.07 to 0.87±0.04%. This indicated good handling property of the prepared Sustained Release tablets.

e. Drug content of Acyclovir

The content of active ingredients in the formulation was found to be between 96.32±5.92 to 101.11±2.65 % w/w, which is within the specified limit as per Indian Pharmacopoeia 1996 (i.e. 90-110% w/w).

 

3.2 Drug release from matrix tablets containing HPMC K100M alone and in combination with Sodium alginate

Formulations (F1-F5), were subjected to in vitro drug release studies in 6.8 pH phosphate buffer solution.

 

The cumulative percent drug released from the formulation F1 at the end of 8 hrs has shown 100%, F2 at the end of 10 hrs has shown 100% and F3 at the end of 12 hrs has shown 100%. Formulations of Acyclovir F1, F2 and F3 containing HPMC K100M retarded the drug release as a function of polymer concentration. As the concentration of polymer increased drug release decreased. HPMC K100M, a hydrophilic polymer upon contact with aqueous fluid is able to form quite viscous gel, and hence retard the drug release from hydrophilic matrix. Formulations containing the combination of Sodium Alginate and HPMC K100M, F4 and F5 has shown complete drug release at the end of 8 hrs and 10 hrs respectively.  All formulations retained their shape upto 12 hours of dissolution testing.

 

 


 

Table 3: Physical Evaluation of Matrix Tablets

Code

Thickness  (mm)*

Hardness (kg/cm2)*

Weight variation test (%)*

Friability (%)*

Drug content (%)*

F1

5.53±0.24

6.77±0.50

585±2.30

0.63±0.07

97.56±6.64

F2

5.48±0.027

5.60±0.64

582±2.04

0.57±0.05

100.95±2.90

F3

6.24±0.065

5.58±0.37

601±1.90

0.69±0.08

96.32±5.92

F4

5.84±0.064

7.05±0.14

592±2.20

0.46±0.03

97.20±5.79

F5

5.44±0.039

6.66±0.54

605±2.12

0.87±0.05

101.11±2.65

F6

5.54±0.051

5.86±0.40

603±1.92

0.54±0.04

97.99±5.18

F7

5.52±0.039

5.83±0.25

594±2.09

0.63±0.09

99.14±5.37

F8

5.57±0.053

5.96±0.48

597±2.12

0.49±0.04

99.15±4.68

F9

5.51±0.046

5.78±0.37

589±2.03

0.86±0.05

100.11±2.38

F10

6.09±0.032

6.94±0.43

608±2.04

0.75±0.07

97.65±5.37

F11

5.98±0.043

6.45±0.23

603±2.00

0.66±0.04

98.7±3.78

F12

6.02±0.043

5.67±0.14

599±1.92

0.57±0.06

101.3±2.78

F13

5.89±0.045

5.68±0.43

595±2.13

0.67±0.04

98.98±3.98

F14

5.99±0.023

6.67±0.24

602±1.98

0.73±0.06

96.99±3.69

F15

5.98±0.064

6.45±0.34

604±1.76

0.62±0.06

99.56±6.45

*All the values are expressed as mean± SD


Figure 1: Drug Release profiles of Acyclovir from matrix tablets containing HPMC K100M alone and in combination with Sodium Alginate.

 

3.3  Drug release from matrix tablets containing HPMC K15M alone and in combination with Sodium Alginate

Formulations (F6-F10), were subjected to in vitro drug release studies in 6.8 pH phosphate buffer solution.

The cumulative percent drug released from the formulation F6 at the end of 6 hrs has shown 100%, F7 at the end of 8 hrs has shown 100% and F8 at the end of 12 hrs has shown 100%.

 

Formulations of Acyclovir F6, F7 and F8 containing HPMC K15M retarded the drug release as a function of polymer concentration. As the concentration of polymer increased drug release decreased.  HPMC K15M, a hydrophilic polymer upon contact with aqueous fluid is able to form quite viscous gel, and hence retard the drug release from hydrophilic matrix. Formulations containing the combination of Sodium Alginate and HPMC K15M, F9 and F10 has shown complete drug release at the end of 8 hrs and 6 hrs respectively. All formulations retained their shape upto 12 hours of dissolution testing.

 

Figure 2: Drug release profiles of Acyclovir matrix tablets containing HPMC K15M alone and in combination with Sodium Alginate.

3.4  Drug Release from matrix tablets containing HPMC K4M alone and in combination with Sodium Alginate

Formulations (F11-F15), were subjected to in vitro drug release studies in 6.8 pH phosphate buffer solution.

 The cumulative percent drug released from the formulation F11 at the end of 6 hrs has shown 100%, F12 at the end of 10 hrs has shown 100% and F13 at the end of 12 hrs has shown 100%. Formulations of Acyclovir F11, F12 and F13 containing HPMC K4M retarded the drug release as a function of polymer concentration. As the concentration of polymer increased drug release decreased. HPMC K4M, a hydrophilic polymer upon contact with aqueous fluid is able to form quite viscous gel, and hence retard the drug release from hydrophilic matrix. Formulations containing the combination of Sodium Alginate and   HPMC K4M, F14 and F15 has shown complete drug release at the end of 8 hrs and 6 hrs respectively. All formulations retained their shape upto 12 hours of dissolution testing. 

                                                                              

Figure 3: Drug Release profiles of Acyclovir matrix tablets containing HPMC K4 alone and in combination with Sodium Alginate

 

3.5  Kinetics

Data obtained from in vitro dissolution studies of formulations (F1-F5) fitted to zero order, first order, higuchi, korsemeyer-peppas equation and results shown in table 4.  From  regression coefficient in vitro drug release from formulations F1 to F15 explained as zero order kinetics, as plot showed highest linearity when compared to First order plot. All the formulations F1 to F15 has shown good correlation in Higuchi kinetics clearly indicating drug release mechanism was predominantly diffusion controlled. To confirm the exact mechanism of drug release from formulations F1 to F15 the data were fitted to koresmeyer –peppas equation. The standard ‘n’ value for all formulations F1 to F15 showed that they followed non-fickian diffusion.

 

To compare dissolution profile of developed formulations with theoretical drug release profile, statistically derived mathematical parameter, “similarity factor(f2)” was employed. The similarity factor (f2) values for the formulations F1 to F15 were calculated and results are shown in table 4. The f2 value of  the formulations F2, F3, F4, F8, F12, and F13 were above 50, indicating the sameness of release profile. Whereas F3 was considered as the most optimized formulation based on its highest “f2” value (79.67).

 


 

 

Table 4: Drug Release kinetics of Ayclovir sustained release tablets

Formulations

Zero order

First order

Peppas

Higuchi

Similarity factor

R2

K0

R2

K1

R2

n

R2

F1

0.9889

11.854

0.6443

0.941

0.9656

0.7161

0.9305

42.44

F2

0.9855

9.8263

0.6410

0.707

0.9683

0.7389

0.9337

52.086

F3

0.9783

7.6128

0.5732

0.526

0.9903

0.6497

0.9688

79.679

F4

0.9813

9.8496

0.6259

0.698

0.9917

0.8248

0.9417

51.270

F5

0.9913

11.907

0.6441

0.940

0.9743

0.7350

0.9351

42.304

F6

0.9618

15.938

0.7065

1.367

0.9970

0.6560

0.9826

27.818

F7

0.9858

11.925

0.6565

0.945

0.9789

0.7044

0.9520

40.368

F8

0.9869

7.9715

0.5978

0.540

0.9953

0.7533

0.9620

71.769

F9

0.9783

11.806

0.6446

0.937

0.9732

0.7154

0.9447

40.913

F10

0.8485

16.163

0.8446

1.459

0.9641

0.5206

0.9796

20.288

F11

0.8301

16.041

0.8625

1.472

0.9588

0.4929

0.9764

19.586

F12

0.9495

8.9518

0.6042

0.678

0.9928

0.6237

0.9825

50.400

F13

0.9361

7.5070

0.5883

0.529

0.9632

0.6730

0.9807

59.793

F14

0.9905

12.099

0.6619

0.951

0.9142

0.9882

0.9442

40.507

F15

0.9079

15.884

0.7568

1.393

0.9916

0.5409

0.9942

23.742

 

 

3.6 Identification and Drug polymer interaction Study

a) FTIR Spectroscopy:

Figure 4: FTIR Spectrum of pure drug  Acyclovir

 

The  drug  was  confirmed  as  Acyclovir  with  results  obtained  from  FTIR spectrum analysis.

 

Figure 5: FTIR Spectrum of Acyclovir with HPMC K100M

 

Figure 6: FTIR Spectrum of Acyclovir with Sodium Alginate

 

 


FTIR spectroscopy was used to ensure that no chemical interaction between the drugs and polymers had       occurred.

       

4. CONCLUSION

Sustained release matrix tablets of Acyclovir were successfully prepared by direct compression method. All the matrix formulations were subjected to quality control tests such as hardness, thickness, drug content, weight variation, friability and in-vitro drug release studies. All the physical parameters complied with pharmacopoeial specifications and the   in-vitro drug release data was fitted to drug release kinetics. Similarity factor analysis was carried out for all the formulations with similarity factor (f2) values greater than 50 were considered as optimized formulations. Among the optimized formulations of Acyclovir formulations F3, F8 and F13 sustained the drug release for 12 hrs. FTIR studies proved that no physical incompatability existed between the drug and excipients. The efficacy and safety of Acyclovir tablet dosage form are expected to offer optimum therapeutic efficacy and improved patient compliance.

 

5. ACKNOWLEDGMENT:

The authors are thankful to Hetero labs from Andhra pradesh for providing gift sample of Acyclovir. The authors are thankful to Blue Birds College of Pharmacy Hanamkonda, warangal for providing all the requirements to carry out our research.

 

6. REFERENCES:

1.       Chien YW. Novel drug delivery systems. 2nd ed. New York: Marcel Dekker Inc; 1992.

2.       Lachman L, Lieberman HA, Kanig JL, editors. The theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghese Publishing House; 1987. 

3.       Lee TWY, Robinson JR. Controlled release drug delivery systems. In Gennaro AR, editor. Remington: the science and practice of pharmacy. 20th ed. Easton, Pennsylvania: Mac Publishing Company; 2001.

4.       Remington. The science and practice of pharmacy. New Delhi: Wolters Kluwer; 2005.

5.       Sweetman SC (Ed.), Martindale, the Complete Drug Reference, 33th ed., Pharmaceutical Press. London, 2002; p.612.

6.       Groning R, Berntgen M, Geogarakis M. Acyclovir serum concentrations following per oral administration of magnetic depot tablets and the influence of extra corporal magnet to control gastrointestinal transit. Eur J Pharm Biopharm 1996; 46:28591.

7.       Lewis L, Fowle A, Bittiner S, Bye A, Isaacs P. Human gastrointestinal absorption of acyclovir from tablet, duodenal infusion and sipped solution. Br J Clin Pharmacol 1986; 21:45962.

8.       Gambhire M N, Ambade K W, Kurmi S D, Kadam V J, Jadhav K R, Development and in vitro evaluation of an oral matrix matrix tablet formulation of Diltiazem hydrochloride, AAPS PharmSciTech 2007; 8(3): article 73, 1-16.

9.       Vergin H, Kikuta C, Mascher H, Metz R. Pharmacokinetics and bioavailability of different formulations of acyclovir. Arzneim Forsch 1995; 45:50815.

10.     Banker GS, Anderson NR. Tablets. In: Lachman L, Liberman HA, Kanig JL, Eds. The Theory and Practice of Industrial Pharmacy, Mumbai, India, Varghese Publishing House, 3rd Edition. 1991:297303.

11.     Rosa JC M, Zia H, Christopher Rhodes. Design and testing in vitro of bioadhesive and matrix drug delivery systems for oral application. Int. J. Pharm 1994; 105:6570.

12.     British Pharmacopoeia-2009, London, Vol-I and II, 1973-1977.

13.     Government of India, Ministry of health and family welfare, Indian Pharmacopoeia. The controller of Publications Ghaziabad, Vol-II, 423-424,2007.

14.     Patel F V, Patel M N, Yeole G P, Studies on formulation and evaluation of ranitidine matrix tablets, Indian J, Pharm, Sci,, 2005; 67(6): 703-9.

15.     Gambhire M N, Ambade K W, Kurmi S D, Kadam V J, Jadhav K R, Development and in vitro evaluation of an oral matrix matrix tablet formulation of Diltiazem hydrochloride,  AAPS PharmSciTech 2007; 8(3): article 73, 1-16.

16.     Clark Analysis of Drugs and Poisons. Anthony C, Mofft M, David Osselton, and Brain Widdep, editors. 3rd edition. Great Britain:Pharmaceutical Press; 2004. 763-64

 

 

 

 

Received on 28.11.2013       Modified on 26.12.2013

Accepted on 02.01.2014      © RJPT All right reserved

Research J. Pharm. and Tech. 7(2): Feb. 2014; Page 125-130