Flaxseed Mucilage Hydrogel based Floating Drug Delivery System:

Design and Evaluation

 

Shreya Ramteke1, Naresh Haigune1, Sachin More2, Shilpa Pise3, Ajay Pise4, Rohini Kharwade5*

1B.Pharm. Final Year Student, Dadasaheb Balpande College of Pharmacy, Besa, Nagpur,

Rashtrasant Tukadoji Maharaj, Nagpur, University, Nagpur, (MS), India.

2Asst. Professor, Pharmacology Department, Dadasaheb Balpande College of Pharmacy, Besa, Nagpur, Rashtrasant Tukadoji Maharaj, Nagpur University, Nagpur, (MS), India.

3Asst. Professor, Regulatory Affair Department, Dadasaheb Balpande College of Pharmacy, Besa, Nagpur, Rashtrasant Tukadoji Maharaj, Nagpur University, Nagpur, (MS), India.

4Professor, Quality Assurance Department, Dadasaheb Balpande College of Pharmacy, Besa, Nagpur, Rashtrasant Tukadoji Maharaj, Nagpur University, Nagpur, (MS), India.

5Asst. Professor, Pharmaceutic Department, Dadasaheb Balpande College of Pharmacy, Besa, Nagpur, Rashtrasant Tukadoji Maharaj, Nagpur University, Nagpur, (MS), India.

*Corresponding Author E-mail: rohinismore1@gmail.com

 

ABSTRACT:

Natural polymer-based plant polysaccharides and proteins have been most widely explored as an adjuvant in the dosage form formulation. Here we design a novel gastro-retentive floating tablet, based on a polysaccharide material from Flaxseed (Linum usitatissimum L.) for Domperidone. After oral administration; Domperidone showed good solubility in acidic pH but significantly reduced solubility in alkaline medium. So that to increase the absorption and bioavailability of Domperidone, it is necessary to increase the retention time in the upper part of the Gastrointestinal tract (GIT) by developing a floating sustained drug delivery system. The directly compressible floating tablets of domperidone were formulated using varying amount of hydroxypropyl methylcellulose K 100 M (HPMC K100 M), Carbopol 934 and Flaxseed mucilage. Hardness, friability, weight variation, thickness, disintegration time of tablet formulations were within acceptable limits. The overall results explained that the optimized formulation F5 prepared by the exact ratio of Flaxseed mucilage, HPMC K100 M, Carbopol, could be more efficient on floating and sustained release of Domperidone in the upper part of GIT as compared to the tablets prepared by using HPMC K100 M and Carbopol 934 only. These findings indicated that Flaxseed can be used to develop novel gastro-retentive sustained release drug delivery system with the double advantage of sustained drug release at the upper part of GIT.

 

KEYWORDS: Floating tablet, Flaxseed mucilage, Sustained release, Gastroretentive, Drug release kinetics.

 

 


INTRODUCTION:

In the orally administered dosage form, the pH of the gastrointestinal tract (GIT) has an important role in its absorption. Most of the drugs absorbed from the upper part of the GIT and rapid gastrointestinal transit could result in incomplete absorption which leads to diminished efficacy of the administered dose.1

 

 

Domperidone is a synthetic benzimidazole compound that acts as a dopamine D2 receptor antagonist. Domperidone is used as a prokinetic agent for the treatment of upper gastrointestinal motility disorders. After oral administration; Domperidone is rapidly absorbed from the stomach and the upper part of the GIT. It is a weak base with good solubility in acidic pH but significantly reduced solubility in alkaline medium. So that to increase the absorption and bioavailability of domperidone is to increase the retention time in the upper part of GIT by developing a controlled or sustained drug delivery system. Therefore different approaches have been proposed to retain the dosage form in the stomach. These include bioadhesive systems, swelling and expanding systems and floating systems.2,3

 

For the formulation of this system, excipients played an important role to convert the drug into suitable dosage form which achieved the targeted action without side effect. Recently researchers have explored the utility of natural polymers based plant polysaccharides and proteins. Naturally occurring polysaccharides exhibited high swelling index at various physiological pH and stimuli-responsive swelling against different solvent systems. Flaxseeds/linseeds are the rich source of polysaccharides.4 Biodegradability, biocompatibility, and edibility properties of flaxseeds mucilage have been proved its potential as an excipient in the pharmaceutical dosage form.5

 

Therefore we aimed to formulate flaxseeds mucilage based sustained release gastro-retentive tablet for Domperidone with the help of gelling agent Carbopol 934 and HPMC K100 M. These systems have sufficient buoyancy to float over the gastric contents and release the drug in the acidic environment with increase bioavailability of Domperidone due to gastro retention at the upper part of GIT.

 

MATERIALS AND METHODS:

Materials:

Domperidone was generously gifted by Ajanta Pharma Ltd. Mumbai. Flaxseeds were procured from the local market of Nagpur, India. HPMC K100 M, Carbopol 934, microcrystalline cellulose, magnesium stearate, Sodium bicarbonate and talc were purchased commercially from Loba Chemie, Mumbai. All solvents and reagents used were of analytical grade.

 

Method:

Extraction of Flaxseed mucilage:

For isolation of mucilage, Flaxseeds (Linum usitatissimum L.) 500gm were washed thoroughly with deionised water and then soaked in 500mL deionised water. After 48 h, soaked seeds were boiled in deionised water for 15 min to swell the mucilage and the mass was filtered through the muslin cloth. The retained residue was boiled with deionised water for 15 min and the combined liquid was passed through eight folds of muslin cloth to remove marc. The mucilage was precipitated from the filtrate by adding ethanol.6,7

 

Purification of Flaxseeds mucilage:

The crude mucilage (1%) was obtained after extraction which was centrifuged at 1000rpm, decanted and precipitated in acetone following 1:2 mucilaginous solution: acetone ratio washed with isopropyl alcohol with 1:1 volume ratio and finally, it was dried in the oven at 40oC (Hot Techniques, India) till it was completely dried which was indicated by constant weight of mucilage after drying. till it was completely dried which was indicated by constant weight of mucilage after drying. The powdered mucilage was passed through mesh number 80 and stored at ambient temperature in airtight container7

 

Formulation of the floating tablet of domperidone by direct compression:

Floating tablets of domperidone were prepared by direct compression method. HPMC K100M and flaxseed mucilage, Carbopol 934 were used as a release rate controlling polymers. The concentrations of the above ingredients were optimized as shown in table 1. All the ingredients were weighed accurately. The drug was mixed with the release rate retarding polymers and the mixture was blended for 20 min with sodium bicarbonate to have a uniform distribution of the drug in the formulation. The blend was lubricated with talc and magnesium stearate and compressed using 8 station compression machines (Rimek Minipress, Ahmedabad, India). The tablet weighed for compression was adjusted to 400mg.8-10

 

Table 1: Formulation batches of the floating tablet.

Ingredients

Formulation batches

F1

F2

F3

F4

F5

F6

Domperidone

30

30

30

30

30

30

HPMC

K 100 M

235

185

175

170

150

125

Flaxseed Mucilage

-

50

60

70

100

125

Carbopol 934

50

50

50

50

40

40

Sodium bicarbonate

25

25

25

25

25

25

MCC

50

50

50

45

45

45

Magnesium stearate

5

5

5

5

5

5

Talc

5

5

5

5

5

5

Total weight

400

400

400

400

400

400

(All quantities are given in mg)

 

Evaluation of tablets:

Pre-compression parameters and characterization of Domperidone and excipient mixture:

The physicochemical characteristics of Flaxseed mucilage were analyzed. The flow properties of powders including drug and all existents (before compression) were also characterized in terms of bulk density, Hausner’s ratio, angle of repose, Carr’s index..9,11-14

 

Drug exipient compatibility study:

Fourier transform infrared spectroscopy (FTIR) analysis was very helpful to find out compatibility between Domperidone, Flaxseed mucilage, and other excipients. Incompatibility between the drug and excipient can be predicted based on their characteristic wavenumbers. Domperidone, Flaxseed mucilage and excipients including HPMC K100M, Carbopol 934, Microcrystalline cellulose were mixed with 300 mg of potassium bromide, compressed and IR spectrum was observed between 450 and 4000cm-1 by placing  this thin pellet in the light path of FTIR instrument (IR Affinity-1S, Shimadzu, DRS-8000A).15-17

Physical characterization of tablet:

Compressed tablets were then evaluated for shape, diameter and thickness, weight variation, disintegration, hardness, friability study. Diameter and thickness were measured by Vernier Caliper. Hardness was measured by Monsanto type hardness tester. Friability was determined in friabilator (Electrolab EF-2, USP).18

 

Assay of tablets:

Twenty tablets from each batch were weighed and powdered. Powder equivalent to 30mg of domperidone was accurately weighed and transferred into a 100ml volumetric flask and dissolved in a suitable quantity of 0.1 N HCl. The prepared solution was diluted up to 100 ml with 0.1 N HCl and sonicated for 60 min. Five millilitres of the resulting solution was diluted to 100ml with 0.1 N HCl to get a concentration in the range of 15 μg/ml. A portion of the sample was filtered through a 0.45μ membrane filter and analyzed by Shimadzu UV-1700UV/Vis double-beam spectrophotometer (1800 Shimadzu, Japan) at 284nm.2

 

Floating capacity:

The in vitro buoyancy was determined by floating lag times. The tablets were placed in a 100ml beaker containing 0.1 N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time. The experiments were conducted in triplicate. Total floating times were measured during in vitro dissolution.19,20

 

Swelling Index:

The extent of swelling was measured in terms of % of weight gained by the tablet. Three tablets from each formulation were weighed and kept in a petri dish containing 50ml of 0.1 N HCL solution. At the end of specified time interval tablets were withdrawn from the petri dish and excess buffer was blotted with tissue paper and weighed.11,21-24

 

In vitro dissolution studies:

The release rate of domperidone from floating tablets (n=3) was determined using dissolution testing Apparatus 2 (paddle method). The dissolution test was performed using 900ml of 0.1N HCl, at 37±0.5° and 50 rpm. A sample (5ml) of the solution was withdrawn from the dissolution apparatus hourly for 24 h, 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 HCl. The absorbance of these solutions was measured at 284 nm.14-16,25

 

Kinetic Analysis of In-Vitro Release Rate of Floating Tablets of Domperidone:

The rate and mechanism of release of domperidone from the prepared floating tablets were analyzed by fitting the dissolution data into the following equations:

 

Zero-order kinetics F= k0t

First order kinetics (1-F)= -k1t

 

To describe the drug release behaviour from polymeric systems, the dissolution data were also fitted according to the well-known exponential Korsmayer-Peppas equation.

 

Mt/M=Ktn

Where Mt/Mis the fraction of drug release at time t and k is the kinetic constant, n is the release exponent (indicating the general operating release mechanism).12, 17-19

 

Statistical analysis:

To evaluate the contribution of each factor with different levels on responses, two-way analysis of variances (ANOVA) were performed using Sigma Stat software (Sigma Stat 2.03, SPSS, Chicago, Illinois, USA).

 

Stability Studies:

The optimized formulation was kept for the short term stability study. The conditions for stability were 40oC±2oC room temperature and relative humidity of 65% RH ± 5% RH. All tablets were suitably packed in a group of 10 in aluminium foil. At the end of one month, the sealed tablets were opened and evaluated for in vitro release and in vitro floating.26

 

RESULTS:

Physicochemical characteristics of Flaxseed Mucilage:

The % yield of the flaxseed mucilage was 8%. The mucilage was light brown powder. The powder was slightly soluble in water and practically insoluble in organic solvents such as alcohol and ether. The swelling characteristic of the mucilage was studied in different media and it was affected by pH. The study showed the highest swelling index in water (37.27%) then in Hydrochloric acid (18.26 %) and least in phosphate buffer (6.07). The loss on drying(1%), total ash (3.6%), and acid-soluble ash value(0.34 %) of mucilage was low. The value of compressibility index and angle of repose was 23.07 and 27o confirmed its good compressibility and flow property.

 

Precompression Parameters:

The domperidone powder mixtures obtained during the pre-compression process were subjected to different parameters and the results were represented in table 2.


 

Table 2: Precompression parameters of formulations.

Form. Code

The angle of repose (θ)

Bulk Density (g/cc)

Tapped density (g/ cc)

Compressibility     Index

Hausner’s ratio

 

F1

26.32±0.175

0.61±0.042

0.79±0.062

10.54±0.056

1.04±0.031

F2

25.41±0.284

0.64±0.036

0.78±0.092

9.98±0.082

1.09±0.074

F3

25.70±0.731

0.67±0.026

0.80±0.019

10.43±0.028

1.12±0.071

F4

24.74±0.779

0.60±0.061

0.76±0.063

9.23±0.073

1.06±0.015

F5

26.65±0.432

0.61±0.047

0.77±0.074

11.45±0.084

1.15±0.099

F6

25.91±0.756

0.60±0.036

0.78±0.023

12.26±0.035

1.07±0.013

(Mean, ±SD, n= 3, P<0.05)

 


Drug excipients compatibility study:

FTIR study was performed to investigate chemical interaction between the drug and the excipients. The FT-IR of pure domperidone is characterized by N-H stretching: 3026cm-1, C=O stretching: 1869 cm-1, indicating the presence of –CONH group. Asymmetric C-H stretching: 2385cm-1, symmetric C-H stretching: 2819 cm-1, N-H deformation: 1691cm-1 C=C : 1441 cm-1. These characteristics bands were also present in the physical mixture of tablet formulation composition. No new bands have appeared which are shown in Figure 1. From the obtained spectra, it was proved that, no significant changes in the main functional groups of drug formulation, which confirmed the absence of any interaction.20

 

 

Figure 1: FTIR spectra of (A) pure Flaxseed mucilage (B) Pure Domperidone, (C) Physical mixture of Domperidone + Flaxseed mucilage + other excipients

 

Post compression parameters:

Weight variation data of the prepared tablets indicated no significant difference in the weight of individual tablet from the average value. The hardness of the prepared tablets was observed to be within the range of 3.8 to 4.3kg/cm2. The thickness of all the tablets was found in the range of 3.34 to 3.43mm. Friability of all the tablets was found below 1% was shown in table 3.

 

Table 3: Post compression parameters-I of tablets

Form. Code

Weight Variation

Thickness (mm)

Hardness (Kg/cm2)

Friability

F1

399.98±1.174

3.24±0.036

4.40±0.318

0.69±0.315

F2

399.87±2.103

3.38±0.091

3.34±0.269

0.63±0.248

F3

400.61±1.239

3.40±0.073

4.24±0.587

0.79±0.318

F4

400.06±1.137

3.43±0.082

3.78±0.162

0.82±0.419

F5

401.18±2.238

3.45±0.069

3.91±0.085

0.71±0.246

F6

400.63±1.123

3.29±0.089

4.43±0.186

0.68±0.831

(Mean, ±SD, n= 3, P<0.05)

 

The drug content in all the batches of domperidone floating tablets was in the range of 98 to 100% which is within the specified IP limit. This ensured the uniformity of the drug content in the tablets represented in table 4.

 

Table 4: Post compression parameters-II of tablets

Form.Code

Drug content (%)

Floating Lag Time (s)

Swelling Index (%)

Floating Duration (h)

F1

99.23±0.51

76

28.29±0.31

10

F2

98.67±0.56

70

30.78±0.56

12

F3

98.81±0.76

67

32.67±0.82

13

F4

98.84±0.70

64

34.86±0.34

15

F5

98.96±0.91

60

38.96±0.28

18

F6

99.75±0.18

65

35.23±0.34

14

(Mean, ±SD, n= 3, P<0.05)

 

Swelling Index and Floating Lag Time:

The swelling index results were depicted in Table 4. It was observed that the swelling indexes were increased with increasing Flaxseed gum concentration with Carbopol than that of ones containing HPMC K100M alone because the flaxseed and Carbopol are more viscous and showed good swelling properties in the later periods.16-18 However, the excessive quantity of mucilage restricts the swelling index and floating lag time.17 The formulations had desired floating lag time (< the 80s) and total floating time between 12-18h was found to be the function of the concentration of gum (Fig 2).

 

Figure 2: The photograph represents the floating lag time and total floating time of F5 formulation.

 

In-vitro dissolution study:

The % cumulative drug releases of all formulations from F1 to F6 were within the range of 87.31 to 98.52 % for 18 h. From results of in vitro drug release studies, it concludes that F5 had better-sustained release than the other formulation (Fig. 2). To analyze the Domperidone release mechanism, the in vitro release data were fitted into various release equations and kinetic models (first order, zero order, Higuchi, Korsmeyer-peppa’s) as indicated by the value of r2. To explore the release pattern, results of the in vitro release data of all formulations were fitted to the Korsmeyer-peppa’s equation. Results showed that ‘n’ value present between 0.56-0.78 which indicates that, the drug release occurred via non-Fickian diffusion mechanism (Table 6). 20

 

Figure 2: Cumulative in-vitro drug release profile of Domperidone.

(mean, ±SD, n= 3, P<0.05)


 

Table 5:  Dissolution kinetics of domperidone Floating tablet.

Formulation code

Zero order

First order

Higuchi

Kosrmayer-peppas

Drug release mechanism

r2

r2

r2

r2

Slope (n)

 

F1

0.8502

0.9543

0.9307

0.9553

0.5621

First order non fickian diffusion

F2

0.9232

0.9655

0.9036

0.9628

0.5434

First order non fickian diffusion

F3

0.9452

0.9555

0.9087

0.9821

0.5368

First order non fickian diffusion

F4

0.9708

0.8426

0.9421

0.9197

0.5831

zero order non fickian diffusion

F5

0.9734

0.9427

0.9125

0.9884

0.6238

zero order non fickian diffusion

F6

0.9180

0.8632

0.9484

0.9586

0.7892

zero order non fickian diffusion

 


Stability study:

The results of the stability study indicated that there were no significant changes in drug content (98.42±0.51%) , floating lag-time (65 sec), and floating time (12hr).

 

DISCUSSION:

From the Physicochemical characteristics of flaxseed mucilage revealed that swelling characteristics of this mucilage was depending on pH. Highest swelling in water and moderate in acidic pH therefore it does not doubt that mucilage based tablet easily swells in the upper part of GIT.13,21 From precompression parameter of the tablet and other micromeritic properties indicate that the tablet easily floatble in gastric fluid.

 

The result of floating lag time (the 60s for F5) demonstrate that the tablets containing  Flaxseed mucilage alone showed longer floating lag time as the tablets tend to disintegrate due to the fast release of CO2 gas. This may be because at lower concentrations, the gum has a lesser ability to form a gel. This was mainly due to the evolution of CO2 entrapped into the matrix of the swollen polymer of the matrix and well protected by gel formation by the hydrated polymer resulting from the interaction between the gas generating agent (sodium bicarbonate) and dissolution medium (0.1N HCl with pH 1.2) that leads to lowering the density and enabling the tablet to float.22,23

 

The results revealed that as the amount of Flaxseed increased, the % swelling increased. This result may be explained by the hydrophilic nature mucilage. When the mucilage was added at optimum concentration with HPMC K 100 M, tablet rapidly hydrates with leading to expansion and consequently an ordering of the polymer chains. Tablets containing Carbopol 934 as copolymer and gelling agent (especially F5) showed higher % swelling with good stability. It was reported that Carbopol swells in simulated gastric fluid, pH 1.2. The amount of effervescent mixture exerted a significant effect on the swelling properties of the tablet. This may be due to the increased reaction of sodium bicarbonate with the dissolution medium that increased the release of CO2 and consequently the number of pores and swelling index.24

 

In-vitro dissolution data of formulation (F1 to F6) reported in fig. 2. The overall drug releases from these tablets are governed by burst effect followed by gel layer formation, drug diffusion into the gel layer and to the dissolution media. These considerations indicate that hydrophilic polymers have the potential to sustain release drug from the tablet. Polymer HPMC K100 and sodium bicarbonate yielded a faster initial burst effect with desirable drug release. The additional use of Carbopol 934 and Flaxseed mucilage decreased the release of Domperidone from the tablet by gel layer formation.25,26 Likely because Carbopol and Flaxseed are cross-linked polymers when contacted with water, it would swell and hold water inside its microgel network and capillaries. By increasing the mucilage percentage, a viscous gel layer is formed and diffusion of the drug is controlled primarily by the gel viscosity. The viscosity of mucilage solutions strongly increases with increasing concentration of the mucilage. Therefore the excessive concentration of mucilage suddenly decreases the release of the drug.26 The behaviour is attributable to the intermolecular interaction, effective macromolecule dimensions and molecular weight of all excipients. In zero order plot, the r2 value was 0.9734 and first order gave 0.9672 which describing the drug release rate relationship with the concentration of the drug. The best linearity was found in the first-order plot in log cumulative % drug remaining Vs time-based on non Fickian diffusion.25,26

 

CONCLUSIONS:

In the present study flaxseed mucilage based gastro-retentive floating tablets of Domperidone were successfully prepared by direct compression method with HPMC K100 and Carbopol 934. Fabricated tablets showed acceptable weight variation, hardness, and uniformity of drug content. The overall results explained that the tablets prepared by combination of Flaxseed mucilage, HPMC K100 M, Carbopol and gas-generating agent sodium bicarbonate, could be more efficient on floating and sustained release of Domperidone in the upper part of GIT as compared to the tablets prepared by using HPMC K100 M and Carbopol 934 only. In the optimized formulation, Polymer HPMC K100 and sodium bicarbonate yielded a faster initial burst effect with desirable drug release. The additional use of Carbopol 934 and Flaxseed mucilage decreased the release of Domperidone from the tablet by gel layer formation. Thus, proper selection of the ratio of all excipients, achieved the desired drug release with good stability.

 

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Received on 01.10.2020            Modified on 22.04.2021

Accepted on 06.07.2021           © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(4):1549-1554.

DOI: 10.52711/0974-360X.2022.00258