The Orodispersible Tablet Of Ivermectin Biology Essay

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Fast- or mouth dissolving tablets have been formulated for pediatric, geriatric, and bedridden patients and for active patients who are busy or while in travelling and may not have access to water. In the many elderly persons may have difficulties in taking conventional oral dosage forms because of hand tremors and dysphagia . Swallowing problems also are common in childrens because of their underdeveloped muscular as well as nervous systems. Also the patients who are mentally ill, the developmentally disabled, and patients who are uncooperative, on reduced liquid-intake plans, or are nauseated may experiences the problem while taking conventional oral dosage forms. Swallowing the conventional tablets may casuse3d some problems in patients suffering from motion sickness, sudden episodes of allergic attack or coughing, and an unavailability of water.

Fast dissolving tablets are also known as mouth-dissolving tablets, melt-in mouth tablets, Orodispersible tablets, rapimelts, porous tablets, quick dissolving etc, which doesnt required water to disintegrate and/or dissolve in the saliva. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true fast-dissolving tablets. Others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed fast-disintegrating tablets, as they may take up to a minute to completely disintegrate.

This tablet is formulated to allow administration of an oral solid dose form without water or fluid intake. Such tablets readily dissolve or disintegrate in the saliva generally within

Less than 60 secs

The basic approach in development of FDT is the use of superdisintegrants like cross linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate (primogel, explotab), polyvinylpyrollidone (polyplasdone) etc, which provide instantaneous disintegration of tablet after putting on tongue, their by release the drug in saliva. The bioavailability of some drugs may be increased due to absorption of drug in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. More ever, the amount of drug that is subjected to first pass metabolism is reduced as compared to standard tablet.

The technologies used for manufacturing fast-dissolving tablets are freeze-drying, spray-drying, tablet molding, sublimation, sugar-based excipients, tablet compression, and disintegration addition.

Criteria for Fast dissolving Drug Delivery System: 

The tablets should:

Not require water to swallow, but it should dissolve or disintegrate in the mouth in matter of seconds. 

Be compatible with taste masking. 

Be portable without fragility concern. 

Have a pleasant mouth feel.

Leave minimum or no residue in the mouth after oral administration.

Exhibit low sensitive to environmental condition as temperature and humidity. 

Allow the manufacture of the tablet using conventional processing and packaging equipments at low cost. 

The ideal characteristics of a drug for FFDT include:

No bitter taste

Dose lower than 20mg 

Small to moderate molecular weight

Good stability in water and saliva 

Partially non ionized at the oral cavities pH

 Ability to diffuse and partition into the epithelium of the upper GIT (log P>;1, or preferably>2)

Ability to permeate oral mucosal tissue 

 Unsuitable drug characteristic for FDT :

Short half-life and frequent dosing

Very bitter or otherwise unacceptable taste because taste masking cannot be achieved

Required controlled or sustained release

Salient Feature of Fast Dissolving Drug Delivery System:

Ease of Administration to the patient who cannot swallow, such as the elderly, stroke victims, bedridden patients, patient affected by renal failure and patient who refuse to swallow such as pediatric, geriatric & psychiatric patients.

No need of water to swallow the dosage form, which is easy feature for patients are traveling and do not have water.

Pregastric absorption can result in improved bioavailability and as a result of reduced dosage effect.

Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patient.

The risk of chocking or suffocation during oral administration of conventional formulation due to physical obstruction is avoided, thus providing improved safety.

New business opportunity like product differentiation, product promotion, patent extensions and life cycle management.

Beneficial in cases such as allergic attack , motion sickness , where an ultra rapid onset of action required.

An increased bioavailability, particularly in cases of insoluble and hydrophobic drugs, due to rapid disintegration and dissolution of these tablets.

Ivermectin is belongs to anthelmintic group developed for the treatment of Onchoceriasis caused by the parasite onchocera volvulus. It is reported to be a Ivermectin is practically insoluble in water, its poor solubility and wettability lead to poor dissolution and hence, variation in bioavailability.11 Several approaches have been carried out to increase the aqueous solubility of ivermectin using solid dispersion,11�14 complexation with cyclodextrins 15�21 and nanoparticles formation.7 In this study, ODTs containing ivermectin were prepared in order to improve its dissolution rate and hence its oral bioavailability.

Pharmacokinetics Parameters �

Plasma protin binding � High (App 93 %)

Half-life � 22-28

Duration of action � Up to 12 months

Apperant Vol � 46.8 lits

Pka � 13.17

MATERIAL AND METHODS:

Materials

Ivermectin, Mcc ph 102, Magnesium Stearate, Aspartame, and other Excipients obtained from Agio Pharmaceuticals Ltd, Pune.

Method

Manufacturing design and development of dispersible tablets:

Effect of superdisintegrants and Diluents in tablet on disintegration time and friability -

Disintegration Time of formulations at 30 sec was Friability 0.20% when disintegrates were used at lower concentration levels. On increasing the MCC pH 102 levels, DT were significantly reduced to 9 sec was Friability 0.10%. With other two factors at their lower levels, higher level of CCS produced more pronounced effect on DT. Friability was found to be below 0.5% for all the formulations studied and hence was not considered as critical. It can be seen from the contour plot in that tablets with DT of less than 120 s can be made in large area of the design space and various combinations of disintegrates and diluents will satisfy the requirement.

Fig.1.Interaction profile for DT with varying diluents concentration.

PREPARATION OF ORODISPERSIBLE TABLETS OF IVERMECTIN:

FABRICATION OF ORODISPERSIBLE TABLETS

Preformulation Studies

Preformulation studies are an investigation of physical and chemical properties of drug substance alone and in combination with excipients. It is the first step in the rational development of dosage form.

1. Drug-Excipients compatibility studies

About 20mg of Ivermectin with various excipients in 1:1 ratio in glass vials were taken and kept at various accelerated condition (300 C/65 RH, 400 C/75% RH and 600 C/80%RH) in stability chamber (Thermolab stability chamber, India).It is carried out for one month in open and closed glass vials. Sample were withdrawn at the intervals of 1, 2, 3, 4, 5, 6, 7, 14, 21,and 30,days and physical characteristics like colour change if any was recorded. Finally the mixtures with no colour changes were selected for formulation development. No reaction takes place in drug and excipients.

2. Angle of Repose

Angle of Repose is defined as the maximum angle that can be obtained between the free standing of a powder heap which is given by the equation.

������=tan−1 (ℎ/𝑟)

Ѳ= Angle of Repose

h= Height of the pile

OPTIMIZATION OF MCC PH 102 AND CROSCARMELLOSE SODIUM:

A 32 factorial design was selected. The 2 factors were evaluated each at 3 levels and experimental trials were performed for all 9 possible combinations as reflected from Table 1. The amount of superdisintegrant, croscarmellose sodium (X1) and the amount of MCC pH 102 (X2) were selected as independent variables. In vitro disintegration time (DT) and friability were

selected as dependent variables. The actual formulation design of Quick-dispersible tablets of

Ivermectin according to factorial design (32) layout is shown in Table 2. The data was interpreted using response surface methodology (Design Expert 8.0.4 Software).The resulting uniform blends of composition per tablet as mentioned in Table 2 were directly compressed using 8 mm, round convex faced tooling to make the tablets using 12 stations CADMECH compression machine. The tablet compression setting was kept constant across all formulations.

Table 1: Formulation design of Orally-dispersible tablets of Ivermectin as per 32 factorial design

layout

Sr No.

Ingredients

Exp No

Exp No 

Exp No 

Exp No 

Exp No 

Exp No 

Exp No 

Exp No 

Exp No 

 

1

2

3

4

5

6

7

8

9

1

Ivermectin

6

6

6

6

6

6

6

6

6

2

MCC PH 102

105

115

125

105

115

125

105

115

125

3

DCL

41

31

21

37

27

17

33

23

13

4

CCS

9

9

9

13

13

13

17

17

17

5

Aspartame

8.5

8.5

8.5

8.5

8.5

8.5

8.5

8.5

8.5

6

Aerosil

1

1

1

1

1

1

1

1

1

7

Mag stearate

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

0.5

8

Banana Flavour

7

7

7

7

7

7

7

7

7

9

Quinoline yellow

2

2

2

2

2

2

2

2

2

 

 

 

 

 

 

 

 

 

 

 

 

TOTAL WT ( mg )

180

180

180

180

180

180

180

180

180

 

 

 

 

 

 

 

 

 

 

% Friability

0.275

0.221

0.291

0.287

0.381

0.401

0.187

0.178

0.102

DT ( sec )

24

30

35

10

15

20

11

13

9

Factor

 

LEVEL 1

LEVEL2

LEVEL3

MCC Ph 102

105

115

125

CCS

9

13

17

Characterization of the prepared orodispersible tablets:

1. Uniformity of weight-

Ten tablets from each formula were individually weighed and the mean weight was calculated.

2. Uniformity of ODTs thickness and diameter -

The diameter and thickness of 10 tablets were measured using a digital Valiner caliber (India) at three different positions.

3. Friability test -

Ten pre-weighed tablets from each formula were tested, accurately placed in the drum of the friabilator and rotated at 25 rpm for a period of 4 min, then reweighed. The percentage loss in weights was calculated and taken as a measure of friability.

4. Hardness -

The average breaking strength of tablets was determined by tablethardness tester (Dr. Schlenger pharmaton, USA).23 Fromeach formula, 10 tablets were tested for their hardness.

5. Content uniformity

Ten tablets were used in this test, where each one was crushedand transferred into a 100 ml volumetric flask. The flasks were brought to volume by phosphate buffer pH 0.01. The flasks were placed onto a sonicator till complete dissolution; 1 ml of the solution was filtered through a Millipore filter of 0.45 lm pore size then introduced into a 25 ml volumetric flask

which was completed to volume by phosphate buffer. The absorbance of the solution was measured using a UV spectrophotometer against the blank phosphate buffer (pH 0.01) at 359 nm. The tablets meet the test if the mean drug content lies within the range of 85�115% of the labeled potency.

6. In vitro disintegration time -

The test is carried out on six tablets using the apparatus 900 ml Purified Water at

37± 0.5 _C was used as a disintegration medium and the time taken for complete disintegration in the apparatus was measured in seconds.

7. In vitro dissolution studies -

The dissolution profiles of ivermectin from ODTs were determinedin a dissolution tester, apparatus II . All tests were conducted in 900 ml phosphate buffer (pH = 0.01) at a temperature of 37± 0.5 _C with a paddle rotation speed at 50 rpm. At specified time interval45 min; 5 ml of dissolution medium was withdrawn and replaced with an equal volume of medium to maintain a constant total volume. Samples were filtered through a 0.45 lm Millipore filter and assayed for drug content spectrophotometrically at 359 nm.

8.Wetting Time �

Ten milliliters of water soluble dye eosin solution is added to petri dish containing five circular filter papers of 10 cm diameter. Tablets were carefully placed on the surface of the filter paper and the time required for water to reach upper surface of the tablet was noted as the wetting time.

9. Moisture uptake studies -

Ten tablets from each formulation were kept in a desiccators over calcium chloride at 37 _C for 24 h. Then the tablets were weighed and exposed to 75% relative humidity (using saturated

sodium chloride solution) at room temperature for 2 weeks. One tablet without superdisintegrant as control was kept to assess the moisture uptake due to other excipients. Tablets were weighed and the percentage increase in weight was recorded.

RESULTS AND DISCUSSION

The dissolution profile of ivermectin formulae 1�9 compared to the market product scavista 6 DT is graphically illustrated in Fig. 2. Remarkable differences in the dissolution profiles of the prepared ODTs and those of scavista 6 DT are observed. The extent of dissolution of ivermectin from the marketed product scavista 6 DT was 87. 04 % in 45 min. All formulae showed acceptable dissolution rate, where more than 85% of the labeled dose is dissolved at 45 min. These results indicate that sublimation process used to prepare the ODTs enhanced the extent and rate of dissolution of ivermectin. Formula 9 containing CCS 17mg showed the highest dissolution rate where 94.3% of the labeled dose is dissolved at 45 min; this may be due to faster uptake of water owing to the porous structure formed thus facilitating the disintegrant to bring about faster disintegration and also improving dissolution.

Formulation

Weight

Variation

(mg) ± S.D

Hardness

(Kg/cm2)

(kg) ± S.D

Friability

(%)

Wetting time

(Sec.) ± S.D

Disintegration time

(Sec.)

In-Vitro Drug Release(%)

Increase in weight (after 2 weeks)

F1

180.2±0.51

3.9±0.37

0.27

30±0.8

24

87.67

1.2

F2

181.2±0.29

4.3±0.31

0.22

42±1.3

30

86.78

1.7

F3

180.1±0.28

3.7±0.29

0.29

43±1.9

35

85.74

2.1

F4

179.8±0.35

4.3±0.47

0.28

13±1.1

10

91.94

1.4

F5

182.1±0.12

4.2±0.29

0.38

22±1.8

15

87.83

1.6

F6

180.3±0.23

4.5±0.24

0.40

23±1.4

20

88.46

1.4

F7

180.2±0.46

4.7±0.25

0.18

15±0.8

11

92.17

1.6

F8

180.4±0.15

4.1±0.26

0.17

12±1.0

13

89.94

2.3

F9

180.5±0.32

4.4±0.15

0.10

10±0.8

9

94.30

1.5

DRAW GRAPH OF DISSO PROFILE

CONCLUSION -

From the study, it can be concluded that direct compression methods could be applied effectively in preparing ODTs with better disintegration and drug release properties.

The prepared ODTs disintegrate within few seconds without need of water; thereby enhance the absorption leading to increased bioavailability of ivermectin.

CONFLICT OF INTEREST �

The authors have no conflict of interest to declare.

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