In-Vitro, In-Vivo Evaluation of Floating Tablets of Clarithromycin.

 

Manojkumar Patil1*, Audumbar Mali1, Sunayana Mali2

1Department of Pharmaceutics, Sahyadri College of Pharmacy,

Methwade, Sangola-413307, Solapur, Maharashtra, India.

2Department of Quality Assurance, Sahyadri College of Pharmacy,

Methwade, Sangola-413307, Solapur, Maharashtra, India.

*Corresponding Author E-mail: manojpatil83@gmail.com

 

ABSTRACT:

The main purpose of this research work was to design and process optimization of oral floating drug delivery system of Clarithromycin floating tablets by using the hydrophilic polymer Hydroxylpropyl methyl cellulose and gas generating agent sodium bicarbonate and citric acid. A 32 randomized full factorial design was used to study. In this design 2 factors were evaluated, each at 3 levels and experimental trials were performed at all 9 possible combinations. The independent and dependent variables are selected for optimization study. The radio-labelled floating tablets were prepared by adding barium sulphate in the optimized formulations for in- vivo radiographic study. The Results of multiple regression analysis indicated that both factors X1 and X2 significantly affected on the dependent parameters. The formulation was optimized on the basis of floating ability and in-vitro drug release. It should be concluded that as the time increases, the swelling index was increased, because weight gain by tablet was increased proportionally with rate of hydration. In-vivo radiographic studies of the optimized formulations were performed using New Zeal Albino rabbits by X-ray imaging technique. The in-vivo X-ray imaging and radiographic studies clearly indicated that the prepared optimized floating tablets were retained in the rabbit stomach over a prolonged period of time and had good in-vivo performance. Radiological evidences suggest that the formulated floating tablets of antibiotics were well floated more than 6 h in rabbit stomach.

 

KEYWORDS: In-vivo radiographic studies, in-vivo performance, New Zeal Albino rabbits, Clarithromycin floating tablets.

 

 


1. INTRODUCTION:

Gastroretentive drug delivery systems are designed to stay in the stomach for a long period and release their active ingredients, allowing the drug to reach the upper gastrointestinal tract in a sustained and protracted manner. For drugs that act locally in the stomach, have an absorption window in the stomach or upper part of the small intestine, are unstable in the intestinal or colonic environments, or have low solubility at high pH values, a modified release drug delivery system with prolonged residence time in the stomach is of particular interest. Floating drug delivery systems, low density systems, raft systems including alginate gel, bioadhesive or mucoadhesive systems, high density systems, superporous hydrogel, and magnetic systems are now used to develop an effective gastroretentive drug delivery system. The floating dose formulations have been the most widely employed of these.1-4

 

By attaching to the bacterial 50S ribosomal subunit, clarithromycin, a semi synthetic macrolide antibiotic derived from erythromycin, suppresses bacterial protein production. Binding prevents amino acid translocation during translation and protein assembly by inhibiting peptidyl transferase activity. Depending on the organism and drug concentration, clarithromycin can be bacteriostatic or bactericidal.5,6

 

2. MATERIALS AND METHODS:

2.1 Materials: Clarithromycin was used as the active ingredient and provided by Maxwell Life Science, Mumbai (M.S) as a gift sample. HPMC (HPMC K4M, HPMC K15M, and HPMC K100M) were used as the polymers and obtained from Colorcon Pvt. Ltd, Verna Estate, and Goa. Sodium Bicarbonate, Isopropyl alcohol, Hydrochloric acid, PVP K30M, Magnesium stearate and Barium sulphate were procured from S.D. Fine Chemicals Ltd, Mumbai. Citric Acid and Tartaric acid obtained from Poona chemicals laboratory, Pune. And Talc obtained from Loba Chemicals, Mumbai.

 

2.2 Animals: New Zealand White Rabbit (Oryctolagus cuniculus) (Body weight 2.5- 3 kg) were gifted from APT Research Foundation, Pune, (National Toxicological Center, Pune) (Maharashtra) and maintained under standard laboratory conditions. Institutional Animal Ethics Committee approved the experimental protocol; animals were maintained under standard conditions in an animal house approved by Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA). The study approved by the Institutional Animal Ethical committee (Approval No. SCPM/IAEC/10/2013) (Sahyadri College of Pharmacy, Methwade Sangola)

 

Registration number:

1406/a/11/CPCSEA Date: 03/02/2011

Species/Common name: New Zealand Rabbits (Oryctolagus cuniculas)

Weight:  2.8kg

Gender: Female

 

2.3 Methods:

2.3.1 Pre-formulation Study:7,8 The Pre-formulation studies were performed on the drug, which included melting point determination, solubility and compatibility studies. Also performed solubility and melting point of Clarithromycin. Performed compatibility study in that Fourier Transform Infrared Spectrophotometer, Differential Scanning Calorimetry Study and Powder X-Ray Diffractometry.

 

2.3. 2 Full Factorial design:9-11 The factorial design is a technique that allows identification of factors involves in a process. Construction of a factorial design involves the selection of parameters and the choice of responses. Optimization has been done by using 32 full factorial designs, in this design 2 factors are evaluated, each at three levels and 9 experimental trials are carried out.

 

For Clarithromycin the independent variables are selected that is the amount of citric acid (X1) and amount of HPMC K15M (X2). The dependent variables are chosen (Q6) percentage drug release at 6 h, (Q12) percentage drug release at 12 h and diffusion exponent (n).

 

A statistical model incorporating interactive and polynomial term is used to evaluate the responses.

 

Y = b0 + b1X1 + b2X2 + b11X12+ b22X22 + b12X1X2 . (1)

 

Where Y is dependent variable, b0 is the arithmetic mean response of the nine runs, and bi (b1, b2, b12, b11 and b22 is the estimated coefficient for the factor X1).

 

The main effect (X1 and X2) represents the average results of changing one factor at a time from its low to high values.

The interaction term (X1X2) show how the response changes, when two factors are changed simultaneously.

The polynomial term (X12 and X22) are included to investigate nonlinearity.

 

2.4 Formulation of Clarithromycin Floating tablets:

Clarithromycin floating tablets were prepared by wet granulation method using different concentrations of polymers with sodium bicarbonate and citric acid as gas generating agent. Take required quantity of PVP K30 and isopropyl alcohol in the beaker. Take mortar and pestle and mix the polymer and Clarithromycin in it. The granules are prepared by passing the wet mass through a sieve no 16 #. These granules were dried on hot air oven at a temperature of 600C. The dried granules are passed through sieve no 20 # and lubricated with magnesium stearate and talc before the compression. The lubricated granules are converted into tablets by using 10 station Rotary Tablet Compression Machine (Karnavati Mini press I) using 13 mm punch.9


 

Table 1: Composition of Clarithromycin Floating Tablets.

Ingredients (mg.)

F1

F2

F3

F4

F5

F6

F7

F8

F9

Clarithromycin

500

500

500

500

500

500

500

500

500

HPMC K15M

75

100

125

75

100

125

75

100

125

Sod.  Bicarbonate

70

70

70

70

70

70

70

70

70

Citric Acid

10

10

10

20

20

20

30

30

30

PVP K30M

40

40

40

40

40

40

40

40

40

Mg stearate

10

10

10

10

10

10

10

10

10

Talc

5

5

5

5

5

5

5

5

5

Total weight (mg)

710

735

760

720

745

770

730

755

780

 

 


2.5: Preparation of floating tablet for in- vivo study.

The radio-opaque tablets of optimized batch were prepared. For X- ray opaque purpose barium sulphate is incorporated.

 

 

Barium sulphate has a high relative density and poor floating properties.  The amount of the X-ray opaque material in these tablets was sufficient to ensure visibility by X-ray, but the same time this amount of BaSO4 was low enough to enable tablet to float. For this purpose, 100 mg of the drug was replaced with barium sulphate (100 mg BaSO4 + 400 mg) and all other ingredients were kept constant.12-14

 

3. Evaluation Parameters:15,16

3.1 In-Vitro buoyancy studies: The test was carried out using USP dissolution test (type II paddle) apparatus (Electro Lab) using 900 ml of 0.1 N HCl at paddle rotation of 50 rpm at 37 ± 0.5o C. Floating lag time is defined as the time required for the tablet to come on the surface of the dissolution medium. Total floating time is the total duration or time for the tablet constantly floated on the dissolution medium.

 

3.2 In-Vitro drug release study: The dissolution test was carried out with 900 ml of 0.1 N HCl dissolution medium, at 37 ± 0.5°C temperature and 50 rpm speed. A 5ml of the sample is removing from the dissolution apparatus hourly for 12h, and the samples are replaced with fresh dissolution medium. The sample were filtered through a 0.45m membrane filter and diluted to a suitable concentration with 0.1N HCl. The absorbance’s of solutions are measure at 760 nm using a Simadzu UV spectrophotometer. The cumulative percentage of drug release was determined with the equation obtained from calibration curve. The data was analyzed by using ‘PCP Disso V-3’ software, India. The graphs of % cumulative release vs time were plotted.

 

3.3 In-vivo radiographic studies: In each experiment, the animals are allowed to fast overnight with free access to water, and a radiograph is made just before the administration of the floating tablet to ensure the absence of radio- opaque material. Barium sulphate is radio-opaque material. It is added in dosage form for visualization of dosage form. The tablet is administered with swallowing 50 ml of water. The radiographic imaging is taken from each animal in a standing position, and the distance between the source of X- rays and the animal should kept constant for all imaging, so that the tablet movement can be easily noticed. Gastric radiography was done at 1hr time intervals for a period of 8 h by using an X- ray machine. (AGFA) All the in-vivo experiments were performed under permission from animal ethical committee. In-vivo study of the optimized batch is carried out by using the New Zealand Albino rabbit by X-ray techniques. The study approved by the Institutional Animal Ethical committee (Approval No. SCPM/IAEC/10/2013) (Sahyadri College of Pharmacy, Methwade Sangola)

 

Registration number:

1406/a/11/CPCSEA Date: 03/02/2011

Species/Common name: New Zealand Rabbits (Oryctolagus cuniculas)

Weight:  2.8kg

Gender: Female

 

3.4 Statistical analysis:

The statistical analyses of formulation are performed with the multiple regression analysis using Microsoft Excel sheet. For the evaluation of contribution of factors with different levels of responses, two way analysis of variance (ANOVA) followed by Turkey test was performed using PCP DISSO software (Bharati Vidyapeeth College of Pharmacy, Pune) and Origin lab software. The P < 0.05 is considered to be significant.

 

4. RESULT AND DISCUSSION:

Melting point of clarithromycin is determined by capillary method. The melting point of clarithromycin was found to be in the range 217-2200C, which complied with the IP standards, indicating the purity of drug sample. The reported melting point value for clarithromycin is 220°C. Clarithromycin is freely soluble in acetone and dichloromethane.

 

 

Compatibility studies were performed using following parameters.

4.1 FTIR: The principle peaks observed at wave numbers 1689.34, 1727.91, 1454.00, 2909.84, 3471.24, 3660.23 cm.

 

Figure 1: FTIR of Clarithromycin + excipients.

 

The FTIR spectrum of pure drug, physical mixture of drug and polymer are study.  This method is used to interpret the interaction occurred between drug and excipients. From figure 1 it was clearly seen that there is no changes in these peaks in FTIR spectra mixture of drug and polymers, which show there is no physical interactions. The peaks obtained in the spectra of each polymer correlates with the peaks of drug spectrum. This indicates that the drug was compatible with the formulation components.

 

Table 2: Interpretation of IR Spectra.

Groups Present

Observed values of Peaks (cm-1)

Standard values(cm-1)

Pure Drug

Formulation

c-o-o-c stretch (Ester functional group)

1689.34

1693.03

1650-1800

C=O (Ketone functional group)

1727.91

1732.96

1680 1760

C-H stretch (Aliphatic group)

1454.00

1460.84

1500-1440

c-o-c stretch (Ether functional

2969.84

2978.13

2800-3000

c-o-c bend (Ether functional group)

3471.24

3494.30

3400-3600

O-H stretch (Alcohol functional group)

3660.23

3676.98

3300 2500

 

4.2 Differential Scanning Colorimetry (DSC) study.

 

Figure 2: DSC of optimized batch of Clarithromycin

 

The thermogram of drug and polymer are shown in figure 2. The clarithromycin thermogram show endothermic peak at 220°C. From the endothermic sharp peak it was concluded that clarithromycin is crystalline in nature and it shows melting point at 2200C. While the optimized formulation also shows the endothermic peak at 220°C and 185°C.

 

4.3 Powder X-Ray Diffractometry (PXRD).

This study reveals information about the crystallographic structure and composition of materials. In order to determine the physical state of the drug whether amorphous or crystalline before and after formulation, X-ray was conducted for the pure drug, the polymers and the formulations. The PX-RD pattern of Clarithromycin, physical mixture and optimized formulation F1 has been shown in Fig. 3. It reveals that the intensity of the peaks for the pure drug, polymer and optimized batch was sharp. Major peak observed in the diffractograms of pure drug, physical mixture, optimized formulation and their peak intensities are given in the Table 3.

 

 

Figure 3: Powder X ray diffractograms of Clarithromycin and optimized batch.

 

Table 3: Major peaks obtained in the diffractogram of Clarithromycin and optimized batch F1.

Sr. No.

Angle [o 2θ ]

Peak intensity ( F1Batch)

1

15.04

2503

2

17.72

5416

3

25.78

9657

4

30.05

12472

5

33.24

17256

6

34.33

8346

7

35.03

4804

8

39.10

4742

9

44.27

4079

 

4. 4 Full Factorial Design:

Table 4: Formulation and dissolution characteristics of batches in 32 factorial designs.

 

Batch code

Coded values

Percentage drug release at 6 hr (Q6)

Percentage drug  release at 12hr (Q12)

n value

diffusion exponent

X1

X2

F1

-1

-1

46.038

97.766

0.9996

F2

-1

0

50.324

93.945

0.7706

F3

-1

+1

55.797

83.321

0.5807

F4

0

-1

52.337

89.753

0.8217

F5

0

0

50.215

80.738

0.8127

F6

0

+1

43.993

76.859

0.9324

F7

+1

-1

57.879

85.006

0.5614

F8

+1

0

53.220

78.187

0.6708

F9

+1

+1

51.105

72.675

0.7290

 

Table 5: Multiple Regressions output for dependent variables.

Parameters

b0

b1

b2

b11

b22

b12

R2

Q6

49.7606

2.3276

-0.8932

4.1990

-1.3685

-3.9199

0.75963

Q12

82.4081

-6.5888

-6.6117

2.6386

0.0629

0.3686

0.97623

n value

0.8118

-0.0881

-0.0234

-0.160

0.0657

0.1387

0.87489

 


The formulation and dissolution characteristic of the 32 factorial designs are shown in table No. 4.

The values are clearly indicated that the Q6, Q12 and diffusion exponent (n) are dependent on the selected independent variables.

The fitted equation relating the responses Q6, Q12 and diffusion exponent (n) to the transformed factors are shown in equation 1, 2 and 3 respectively.

Q6 = 49.76 + 2.32X1 0.89X2 + 4.19X12 - 1.36X22 - 3.91X1X2                         (Eq.1)

 (R2 = 0.7596)

 

Q12 = 82.40 - 6.58X1 - 6.61X2 + 2.63 X12 + 0.06X22+0.36 X1X2                       (Eq. 2)

 (R2 = 0.97623)

 

 

n = 0.81 - 0.08 X1 - 0.02 X2 - 0.16 X12 + 0.06 X22 + 0.13 X1X2                       (Eq. 3)                                       

 

(R2 = 0.87489)

 

The polynomial equation can be used to draw conclusion after considering the magnitude of coefficient and the mathematical sign it carries, (i.e., positive or negative). Positive or negative signs before a coefficient in quadratic models indicate a synergistic effect or an antagonistic effect for the factor. The high values of correlation coefficient for Q6 (R2 = 0.7596), Q12 (R2 = 0.9762), n (R2 = 0.8748) indicate a good fit.

 

Equation No. 1 for Q6  showed b1 and b11 positive but b2, b12 and b22 negative this reveals that up to certain level increases in X1 and X12   from -1 to  + 1 increases Q6 after that point again decreases in Q6 seen. Percentage release at 6 hr (Q6) was found to be 46.038 to 57.879 for batches containing X2 at -1 level, 43.993 to 55.797 to for batches containing X2 +1 level, 50.215 to 53.22 for batches containing X2 at 0 level.

Equation No. 2 for Q12 showed b12, b11 and b22 positive but b1 and b2 negative this reveals that up to certain level increases in X1, X2, X12 and X22 from -1 to + 1 increases Q12. Percentage release at 12 hr (Q12) was found to be 85.006 to 97.766 for batches containing X2 at -1 level, 72.675 to 83.321 for batches containing X2 +1 level, 78.187 to 93.945 for batches containing X2 at 0 level.

 

Equation No. 3 for n showed b12 and b22 positive, but b1, b2 and b11 negative this reviles that up to certain level increases in X12 and X22   from -1 to + 1 increases n. The value of diffusion exponent (n) was found to be 0.5614 to 0.9996 for batches containing X2 at -1 level, 0.5807 to 0.9324 to for batches containing X2 +1 level, 0.6708 to 0.8127 for batches containing X2 at 0 level.

 

The equation for Q6 (Eq 1) suggest that the factor X1 has more significant effect on drug release at Q6, therefore high level of factor is not selected for increasing drug release. From equation 2 it can conclude that single factor X1 not more effect on Q12, but factor in combination X1 and X2 shows positive effect. It means that the when the value of X2 increases Q12 decreases. From equation 3 negative sign of X1 it concludes that diffusion exponent not depend on value of X1 but the magnitude of coefficient indicates that the factor X2 has more favorable effect on the dependent variables.

 

Granules were evaluated for the angle of repose. The angles of repose of all the batches are within the range of 240.22' to 270.75'. Compressibility index was carried out, it show between 9.52% and 15.90% indicating the powder blend has the required flow property for compression. The Hausner’s ratio was found between 1.10 and 1.18

 

4.5 In-Vitro drug release study:

All the floating tablets remained floated until the complete drug release. This study is performed up to 12 hrs. The formulation shows the drug dissolution from 97.76 to 72.67% because of increase in concentration of polymer (HPMC K15M). High drug release is observed in F1 batch because of less amount of polymer. The dissolution profiles of all formulations are shown in figure No. 4.

 

Figure 4: In -Vitro Release Profile of Clarithromycin floating tablet (all Formulation)

 

4.6 In-Vitro Buoyancy Studies:

In this study as the mass of the tablet below 1, the tablet becomes float. The floating lag time of all batches from 20 sec to 45 sec. and the total floating time are more than 12 hours. All the batches show good in-vitro buoyancy time, also the tablet remained buoyant for 12 hours, but the tablet actually floated throughout the study.

 

4.7 Swelling Index Study:

In the swelling indexes polymer matrices are porous in nature. The liquid diffuses through the polymer matrix at a constant velocity. This mechanism gives the idea regarding the water uptake study of various grades of polymer. This phenomenon is attributes to that the swelling is more due to water uptake and then gradually decreased due to erosion.

 

4.8 In- vivo Study:

4.8.1 In -vivo radiographic studies:

The prepared floating tablets of Clarithromycin containing hydroxyl propyl methylcellulose (HPMC) (F1) were selected for evaluation of gastric retention using X-ray imaging. It was observed that tablets showed good floating property and sufficient integrity of Clarithromycin floating tablets. The presence of the floating tablet in the upper gastrointestinal tract was clearly observed in these X-ray images. The optimized floating tablet was retained in the stomach for a prolonged period of time and had well in- vivo performance. Radiological evidences suggest that the formulated floating tablets of Clarithromycin (F1) was well floated more than 6 h in rabbit stomach; hence, we can conclude that the floating tablets was satisfactory floated to the rabbit stomach (Fig. 5).

 

 

X-ray after 8 h

Figure 5: X-ray photographs at different time intervals of floating tablets of Clarithromycin.

 

5. SUMMARY AND CONCLUSION:

The aim of present work is to design and process optimization of floating tablet of Clarithromycin. Optimization has been done by using 32 factorial designs. The amount of citric acid (X1) and amount of HPMC K15M (X2) have effectively affected on Q6, Q12, and diffusion exponent (n). From the experimental study result, it concluded that optimized batch releases drug slowly and completely for 12 hours. Tablet remains in floating condition throughout dissolution study. Hence it concluded that prepared formulation can be remain floated in stomach without its early passing to lower GIT side. The prepared floating tablets also characterized by FTIR spectroscopy, differential scanning calorimetry and powder X-ray diffraction to find out compatibility study between Clarithromycin and polymers. Angle of repose of granules was less than 30, Hausner’s ratio was less than 1.18, and Carr’s index was less than 15.90. The results of micromeritic studies indicated an excellent flow property of granules to formulate them in to tablet by compression. The floating tablet was evaluated for in-vitro drug release and in-vitro buoyancy study. The formulation is optimized on the basis of in-vitro release study (97.76%), floating ability (20 sec) and matrix integrity. Thus F1 batch was considered as optimize. In the swelling characteristics (water uptake study), it should be concluded that as the time increases, the swelling index is also increased. The optimize formulation (F1) was keep for stability study at 40ºC / 75% RH condition for a period of 3 months. During the stability study after 3 months, there is no significant change in drug release.  Both factors X1 and X2 significantly affect the diffusion exponent (n) and percentage drug release at 6 (Q6) and 12 (Q12) h.

The in-vitro dissolution profiles of all the prepared clarithromycin floating tablet was found to extend release from 10 to 12 h. From the result it was observed that drug and polymer ratio influence the in-vitro release of drug and in-vitro buoyancy study of clarithromycin floating tablets. Hence, the floating system of Clarithromycin is expected to provide clinician with a new choice of safe and more bioavailable formulation in the management of Helicobacter pylori infection which is causative organism for peptic ulcer. The study reveals satisfactory results with a further scope of pharmacokinetic and pharmacodynamic evaluation.

 

In-vivo radiographic study of the final formulation (F1) was performed by using New Zeal Albino rabbits by X-ray imaging technique. The X-ray images clearly indicated that the prepared floating tablet was retained in the rabbit stomach over a prolonged period of time and had good in-vivo performance. Radiological evidences suggest that the formulated floating tablet of Clarithromycin (F1) was well floated more than 6 h in rabbit stomach. Thus the main objective of this work is achieved with success to minimize peptic ulcer.

 

6. ACKNOWLEDGEMENTS:

The authors are thankful to Sahyadri College of Pharmacy, Methwade, Sangola, and Solapur for providing facilities for completion of this project work successfully.

 

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Received on 20.01.2022         Modified on 23.03.2022

Accepted on 28.04.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech. 2022; 12(3):225-231.

DOI: 10.52711/2231-5713.2022.00037