Fabrication and Evaluation of Mouth Dissolving Strips of Metoclopramide Hydrochloride by Using Novel Film Former

 

Hemant A. Deokule1*, Smita S. Pimple1, Praveen D. Chaudhari1, Ajit S. Kulkarni2

1Department of Pharmaceutics, P.E.Society’s Modern College of Pharmacy, Nigdi – 411044,

Dist-Pune Maharashtra, India.

2Gourishankar institute of Pharmaceutical Education and Research, Satara – 415015,

Dist- Satara Maharashtra, India.

*Corresponding Author E-mail: hemant.pharma31@yahoo.com

 

ABSTRACT:

Fast dissolving strips are used as novel approaches, as it dissolves rapidly in mouth and directly reaches the systemic circulation. In present research work, an attempt has been made to prepare mouth dissolving strips of Metoclopramide hydrochloride by using a novel film former Pullulan by solvent casting method. A33 full factorial design was utilized for the optimization of the effect of independent variables such as the amount of Pullulan, amount of PEF 400, amount of SSG on mechanical properties, and % drug release of strips. The drug compatibility studies using FTIR and DSC studies formulated strips were characterized for their physicochemical parameter like weight variation, visual appearance, folding endurance, thickness, disintegration time, drug content, and in vitro dissolution studies. FTIR and DSC studies revealed that the polymer is compatible with the drug. It was found that the optimum levels of the responses for a fast release strip could be obtained at low levels of Pullulan, PEG400, and SSG. The prepared strip was clear transparent and had a smooth surface. The surface pH was found 4.8 to 5.2 be in the range of to which is close to salivary pH, which indicates that strips may have less potential to irritate the oral mucosa, thereby they are comfortable. The drug release was found to be between 90.94 to 100.5% in 2 min. The in-vitro disintegration time of strips prepared with Pullulan was in the range of 19 to 57 sec. As the concentration of SSG increases the decrease in the disintegration time of strips a decrease. The dissolution rate increased with an increase in the concentration of SSG. Hence, it can be inferred that the fast dissolving oral strips of Metoclopramide hydrochloride may produce rapid action thereby improving bioavailability and enhance the absorption by avoiding the first-pass effect.

 

KEYWORDS: Mouth dissolving strips, Pullulan, Metoclopramide hydrochloride, Solvent casting method.

 

 


INTRODUCTION:

The oral route is the most preferred and most popular route of administration, from the patient compliance aspect. The oral dosage form is a new area of research being explored now days commonly by most of the pharmaceuticals. A relatively novel dosage form explored is oral strip a thin film prepared using hydrophilic polymers that rapidly dissolves on the tongue or in the buccal cavity.

 

The surface of the buccal cavity comprises stratified squamous epithelium which is essentially separated from the underlying tissue of lamina propria and submucosa by an undulating basement membrane1. An interesting fact that the permeability of buccal mucosa is greater than that of the skin but less than that of the intestine makes it an important route of administration of drugs having lower penetration capacity2,3,4. Saliva and salivary mucin contribute to the barrier properties of oral mucosa5. Palatability is the most important factor to be considered in the development of pediatric formulations, oral strips can readily meet this criteria6,7,8.

 

Fast dissolving oral strips are used as an alternative to traditional routes such as liquids, tablets, and capsules because of various benefits shown by strips (fast-dissolving, accurate dosing, safety, efficacious format, convenience, palatable and portable). As the fast-dissolving strip delivers drugs by the sublingual route, rapid absorption into the systemic circulation of the drug is prominent, this leads to the quick onset of drug action9.

 

Recent developments in drug delivery technology have to lead to the development of orally disintegrating strips with improved patient compliance and convenience. Rapid dissolution strips disperse quickly after placement in the mouth without aid10. As soon as the dispersing strips are placed in the mouth, the dosage form disintegrates instantaneously or within a few seconds releasing the contents in saliva. This saliva containing medicament is the swallowed and the drug is absorbed in a normal way. Some fraction of the drug may be absorbed from pregastric sites such as the mouth, pharynx, and esophagus as the saliva passes down into the gastro-retentive platforms for the delivery of both small and large molecules. In the present investigation, we attain to prepare oral strips of Metoclopramide hydrochloride by using a novel strip former employing solvent casting method11.

 

MATERIALS AND METHODS:

Metoclopramide hydrochloride I. P. was obtained as a gift sample from Medioral Pharmaceuticals, Ltd., Satara, India and Pullulan (molecular weight, 8000–2,000,000) was gifted from cipla Ltd Mumbai, Sodium starch glycolate (A.R.), Polyethylene glycol (A.R.) and strawberry flavor were purchased from Rajesh Chem. Ltd., Mumbai, India. All other chemicals used were of analytical grade and were used without further purification. Double-distilled water was used throughout the study.

 

Preparation of oral fast dissolving strips of Metoclopramide hydrochloride: The oral fast-dissolving strips were prepared by dissolving film-forming agent such as pullulan, polyethylene glycol (PEG 400) as a plasticizer and xanthan gum as a stabilizing agent in the water, followed by continuous stirring up to 4 h on a magnetic stirrer and kept for 1 hour to remove all the air bubbles entrapped. Meanwhile, in the separate container, a solution of remaining water-soluble ingredients i.e. aspartame as sweetener, sodium starch glycolate (S.S.G), citric acid as saliva stimulant agent, menthol as a cooling agent, tween 80 as an emulsifier, strawberry as a flavor, and Metoclopramide hydrochloride was prepared with constant stirring for 45 min. Both the solutions were mixed and again, kept for stirring for 1 hr. The solution mixture was kept stationary for 1 hour to let the foam settle down. The resulting formulation was cast on a suitable inert platform and dried to form a strip. The strip was preferably air-dried. The dried strip was checked for any imperfections and cut according to the size required for testing (square strip: 2.5 cm length, 2.5 cm width)12,13,14,15,16,17,18,19.

 

Formulation design of oral fast dissolving strips of Metoclopramide hydrochloride:

Full Factorial Design:

A 33 full factorial design was used to design the experiment. To study all the possible combinations of all factors at all levels, a three-factor, the three-level full factorial design was constructed and conducted in a fully randomized order. The dependent variables measured were disintegration time (Y1) and % drug release (Y2) at 2 minutes in a phosphate buffer solution of pH 6.8. Three independent factors, the concentration of pullulan (X1) the concentration of polyethylene glycol 400 (X2), and the concentration of sodium starch glycolate (X3) were set at three different levels. High and low levels of each factor were coded as +1 and - 1 respectively and the mean value as zero (0) is shown in Table 1. This design was selected as it provides sufficient degrees of freedom to resolve the main effects as well as the factor interactions. Stepwise regression analysis was used to find out the control factors that significantly affect response variables. Formulations were prepared according to Table 2.


 

Table 1: Independents Factors, Concentrations, Level.

Factor

Pullulan (X1)

PEG 400 (X2)

S.S.G (X3)

Concentration

55%

60%

65%

10%

15%

20%

0.25%

0.5%

0.75%

Levels

-1

0

+1

-1

0

+1

-1

0

+1

 


Table 2: Composition for 33 Factorial Design

Formulations

(X1)

(X2)

(X3)

F1

-1

-1

-1

F2

-1

-1

+1

F3

-1

-1

-1

F4

-1

0

-1

F5

-1

0

+1

F6

-1

0

+1

F7

-1

+1

-1

F8

-1

+1

+1

F9

-1

+1

-1

F10

0

-1

+1

F11

0

-1

-1

F12

0

-1

-1

F13

0

0

+1

F14

0

0

+1

F15

0

0

-1

F16

0

+1

+1

F17

0

+1

-1

F18

0

+1

+1

F19

+1

-1

-1

F20

+1

-1

-1

F21

+1

-1

+1

F22

+1

0

+1

F23

+1

0

-1

F24

+1

0

+1

F25

+1

+1

-1

F26

+1

+1

+1

F27

+1

+1

+1

Affect Response Variables Y1 = Disintegration time (D.T.)

Y2 = % Drug release (D.R.) at 2 min

 

Evaluation of Fast Dissolving Strips20,21:

Weight of strips:

Oral fast-dissolving strips are weighed on an analytical singe pan balance (Shimadzu AX 120). All determinations were performed in triplicate.

 

Thickness of strips:

Strip thickness was measured by using a micrometer screw gauge. All determinations were performed in triplicate.

 

Folding endurance of strips:

Folding endurance was measured manually for the prepared strips. A strip of a film (2.5 X 2.5 cm) was cut evenly and repeatedly folded at the same place till it breaks. The number of times the strip could be folded at the same place without breaking gave the exact value of folding endurance. All determinations were performed in triplicate.

 

pH value of strips:

The pH value was determined by dissolving one oral strip in 2ml distilled water and measuring the pH of the obtained solution. All determinations were performed in triplicate for each batch.

 

Disintegration time of strips:

The strip is examined using the USP XXIV disintegrating test apparatus type II. The Disintegrating time was carried out in 900 ml phosphate buffer (pH 6.8) at 37±0.5 0C at 50 rpm. All determinations were performed in triplicate.

 

In Vitro Dissolution Studies:

The dissolution study was conducted in 300 ml of phosphate buffer (pH 6.8) using U.S. Pharmacopoeia (USP) XIV paddle apparatus II at 370±0.5°C and 50 rpm. Each square cut strip sample (dimension: 2.5 cm x 2.5 cm) was submerged into the dissolution media and samples (4 ml) were withdrawn at 0, 0.5,1,1.5, 2, 2.5, 3, 3.5, 4, and 5 minute time intervals. Volume was made up to 5 ml with the help of PBS of pH 6.8. The sample was filtered through 31 µm Whatman filter paper and analyzed spectrophotometrically at 309 nm (Model UV-1700 UV-Visible spectrophotometer, Shimadzu, Japan). Sink conditions were maintained throughout the experiment. The absorbance values were transformed to concentration by reference to a standard calibration curve obtained experimentally (r2 = 0.9994). The dissolution test was performed in triplicate for each batch.

 

RESULTS AND DISCUSSIONS:

Evaluation of Oral Fast Dissolving Strips of Metoclopramide Hydrochloride:

Determinations of weight, visual appearance, pH value, thickness, and folding endurance values for the strips of formulations are shown in Table 3. The visual appearance of the strips was transparent and free of bubbles, which is necessary for the aesthetic appeal of the strips. Table 3 shows the evaluation studies of all batches. The weight of the strip was in the range of 36.3 to 46 mg. Folding endurance was found to be between 130 to193. pH value was found to be between 4.8 to 5.2.

 

The above-evaluated parameter indicated that the strips have desired characteristics like aesthetic appeal, strength.


 

Table 3. Evaluation of Oral Fast Dissolving Strips of Metoclopramide Hydrochloride

Formulations

Visual appearance

Wt of strips(mg)

Thickness of strips (mm)

Folding Endurance

pH Value

F1

Transparent

36.3±1.52

9.3±0.5

191±2.51

5.2±0.05

F2

Transparent

37.3±1.52

9.3±0.5

189±2.08

4.8±0.1

F3

Transparent

36.6±1.52

9.6±0.5

193±1.52

5.2±0.05

F4

Transparent

39±1

9.3±0.5

188±2.51

5.1±0.1

F5

Transparent

39.6±1.52

9.3±0.5

174±3.51

5.1±0.1

F6

Transparent

39.3±1.52

9.6±0.5

180±3

4.8±0.1

F7

Transparent

40.3±1.15

9.6±0.5

135±3.05

4.8±0.05

F8

Transparent

40±1.73

9.3±0.5

130±2

4.8±0.1

F9

Transparent

40±1

9.6±0.5

130±1.52

4.8±0.05

F10

Transparent

41±1

11.3±0.5

189±6.65

4.8±0.1

F11

Transparent

41±2

11.6±0.5

188±2.08

5.1±0.1

F12

Transparent

42±2.64

11.6±0.5

192±1.52

4.8±0.1

F13

Transparent

42.6±2.08

11.6±0.5

187±1.52

4.8±0.05

F14

Transparent

42.3±1.52

11.6±0.5

181±3.05

5.1±0.1

F15

Transparent

42±1

12.3±0.5

188±3.05

4.9±0.1

F16

Transparent

43.6±0.57

11.3±0.5

135±3.05

5±0.05

F17

Transparent

44±1

11.6±0.5

131±2.64

5.1±0.1

F18

Transparent

43.6±0.57

11.3±0.5

130±1.52

5±0.1

F19

Transparent

44±1

13±0.5

190±1.52

5.1±0.1

F20

Transparent

43.3±1.52

12.3±0.5

189±2.08

4.9±0.1

F21

Transparent

43±1

13.3±0.5

198±3

4.8±0.1

F22

Transparent

43.3±0.57

13±0.5

188±2.51

5.1±0.1

F23

Transparent

44±1

13.3±0.5

175±3

5.1±0.05

F24

Transparent

43.6±0.57

12.3±0.5

180±3

5±0.1

F25

Transparent

45.6±0.57

13±0.5

134±2

5±0.1

F26

Transparent

46±1

13.3±0.5

133±2.64

5±0.1

F27

Transparent

45.3±0.57

13±0.5

130±1.52

5.1±0.1

n = 3

 

Data Analyses:

The data obtained were treated using Stat-Ease Design Expert 8.0.0.6 Software and analyzed statistically using analysis of variance (ANOVA)22.

 

Table 4: Response Summary

Response

Name

Unit

Observations

Analysis

Minimum

Maximum

Y1

Disintegration time

Sec

27

Factorial

19

57

Y2

Drug release

%

27

Factorial

90.94

100.5

 


The drug release and disintegration time for 27 batches (F1-F27) showed a wide variation (i.e. disintegration time was found to be between 19 to 57 sec and drug release was found to be in between 90.94 to 100.5% in 2 min). The responses of formulations prepared by 33 full factorial designs are indicated in Table 4.

 

Responses and Desirability Function of all Formulations:

The responses and desirability function of all formulations are shown in Table 5. Disintegration time was found to be very less, which resulted in the faster dissolution of the drug. Disintegration time was found in the range of 19(sec) to 57(sec) and in vitro drug release within 2 min was found to be in the range of 90.94% to 100.5%.

 

Table 5: Drug release, disintegration time and desirability

Formulations

Disintegration time (Sec) (Y1)

% Drug release in 2 min(Y2)

Desirability

F1

52(sec) ±2

94.85% ±2.87

0.214

F2

30(sec) ±2

97.43% ±3.23

0.697

F3

19(sec) ±1

100.52%±4.16

1.000

F4

48(sec) ±1

94.90% ±1.44

0.301

F5

31(sec) ±1

96.54% ±5.36

0.640

F6

25(sec) ±1

100.22%±2.79

0.895

F7

51(sec) ±1

94.74% ±1.91

0.235

F8

31(sec) ±1

95.58%±1.38

0.591

F9

23 (sec) ±1

100.4% ±3.31

0.934

F10

51(sec) ±2

95.6% ±5.69

0.256

F11

25(sec) ±3

96.3% ±1.53

0.707

F12

21(sec) ±1

99.73% ±1.76

0.935

F13

56(sec) ±2

95.13% ±1.81

0.088

F14

35(sec) ±2

96.87% ±4.18

0.596

F15

20(sec) ±1.73

100.1% ±3.59

0.967

F16

54(sec) ±2.64

94.57%±4.99

0.155

F17

35 (sec) ±2

94.87% ±0.57

0.500

F18

25(sec) ±2.64

100.1% ±2.84

0.890

F19

56(sec) ±1

90.94% ±0.80

-

F20

34(sec) ±2

96.83%±1.19

0.610

F21

23(sec) ±2

100.06%±1.47

0.920

F22

57(sec) ±1

93.59% ±1.17

-

F23

34(sec) ±1

96.27% ±2.26

0.584

F24

23(sec) ±1

100.05%±3.83

0.919

F25

52(sec) ±1

93.24% ±1.73

0.170

F26

33(sec) ±2

93.61% ±1.40

0.445

F27

25(sec) ±1

100.24%±3.44

0.896

Formulation F3 was found to be the optimized formulation among at all 27 formulations (Desirability function = 1)

 

The data indicated that the % drug release and disintegration time were strongly dependent on the selected independent variables. The equations related to responses to the transformed factors are as shown in equations 1 and 2.

 

Disintegration time = 32.55556 + 1.50000 (X1) + 1.00000 (X2) -15.16667 (X3) - 0.58333 (X1X2) - 0.83333 (X1X3) + 1.00000 (X1)2 + 0.16667 (X2)2 -1.00000 (X3)2 + 5.83333 (X1) + 0.12500 (X1X2X3)           (1)

 

% Drug release = 96.5629- 0.57389 (X1) - 0.27167 (X2)

+ 2.99111 (X3) + 0.1100 (X1X2) + 0.49583 (X1X3) – 0.059167 (X2X3) – 0.36389 (X1)2 – 0.43056 (X2)2 + 1.13111 (X3)2 – 0.26625 (X1X2X3)                                                                              (2)

 

Response Surface and Contour Plot:

The quadratic surface model obtained from the regression analysis was used to build up 3-D surface and contour plots in which the responses were represented by curvature surface as a function of independent variables. The relationship between the response and independent variables can be directly visualized from the response surface plots. The response surface plots were generated using Design Expert 8.0.0.6 software and are presented in Figures 1 and 2. These were used to observe the effects of independent variables on the studied responses such as % drug release respectively. Graphical presentation of the data helped to show the relationship between the response and the independent variables. The information generated from the graph was similar to that of the mathematical equations obtained from statistical analyses.

 

Fig. 1: Response 3-D surface plot showing the influence of pullulan and S.S.G on % drug release

 

Fig. 2: Contour plot showing the relationship between various levels of pullulan and S.S.G on drug release

 

Figure 1 shows the response surface plot showing the influence of pullulan and S.S.G on % drug release. From the plot, it can be seen that as the concentration of S.S.G was increased drug release was increased and the concentration of pullulan was increased drug release was decreased. Figure 2 shows the contour plot showing the relationship between various levels of two polymers.

 

 

Fig. 3: Response 3-D surface plot showing the influence of pullulan and PEG 400 on % drug release

 

Fig. 4: Contour plot showing the relationship between various levels of pullulan and PEG400 on % drug release

 

Contour plot showing the relationship between various levels of pullulan and PEG 400 on drug release Figure 3 shows the response surface plot showing the influence of pullulan and PEG 400 on % drug release. From the plot, it can be seen that as the concentration of PEG 400 was increased, drug release was decreased and the concentration of pullulan was increased, drug release was decreased. Figure 4 shows the contour plot showing the relationship between various levels of two polymers.

 

 

Fig. 5: Response 3-D surface plot showing the influence of S.S.G and PEG 400 on % drug release

 

Fig. 6: Contour plot showing the relationship between various levels of S.S.G and PEG 400 on % drug release

Figure 5 shows the response surface plot showing the influence of S.S.G and PEG 400 on % drug release. From the plot, it can be seen that as the concentration of PEG 400 was increased, drug release was decreased and the concentration of S.S.G was increased, drug release increased. Figure 6 shows the contour plot showing the relationship between various levels of two polymers.

 

CONCLUSION:

These strips can be real alternatives to oral fast dissolving tablets and can be helpful for the prevention of nausea and vomiting where quick bioavailability of the drug is desired. This would improve patient compliance and disease management. Pullulan proved to be the best strip forming agent.

 

ACKNOWLEDGMENT:

The authors are grateful to authorities of the institute and industries.

 

CONFLICTS OF INTEREST:

We declare no conflict of interest of any kind with anybody.

 

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Received on 20.08.2020            Modified on 18.09.2020

Accepted on 20.10.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(10):5515-5520.

DOI: 10.52711/0974-360X.2021.00962