Int J App Pharm, Vol 11, Issue 4, 2019, 88-91Original Article


DEVELOPMENT OF MUCOADHESIVE TABLET OF PENTOXIFYLLINE USING A NATURAL POLYMER FROM MANILKARA ZAPOTA LINN

GNANASEKARAN JOHN SELVARAJ, ARUL BALASUBRAMANIAN*, KOTHAI RAMALINGAM

Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation (Deemed to be University) Salem 636008, Tamilnadu, India
Email: arul1971@yahoo.com

Received: 26 Jan 2019, Revised and Accepted: 17 Apr 2019

ABSTRACT

Objective: The present study was designed to develop a mucoadhesive tablet of pentoxifylline using the mucoadhesive natural polymer from the plant Manilkara zapota Linn.

Methods: The tablets were formulated with three different concentrations of the isolated polymer and evaluated for thickness, weight variation, friability, hardness, swelling index, mucoadhesive strength and in vitro drug release. The swelling index was indirectly proportional to the mucoadhesive polymer of Manilkara zapota (MAPMZ) concentration.

Results: The tablets formulated with a high concentration of MAPMZ showed good mucoadhesion strength in 5 min contact time. The in vitro drug release studies indicated that the drug release was directly proportional to MAPMZ concentration. The release kinetics indicated that the drug release was followed the zero-order.

Conclusion: The MAPMZ showed the controlled release of pentoxifylline for a period of 12 h.

Keywords: Mucoadhesion, Pentoxifylline, Manilkara zapota

© 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2019v11i4.32177

INTRODUCTION

Mucoadhesive drug delivery system has recently gained more interest in pharma profession [1]. Mucoadhesion is a facet of bioadhesion that is aimed to localize the drugs at a certain mucosal area in the body. Water-soluble polymers, those become adhesive on hydration, has been used to design the formulation. The most important aims of mucoadhesion are drug targeting, sustained/controlled release, increasing of gastric residence time, minimizing the first pass effect and reducing the adverse effects [2, 3]. The polymers chosen for mucoadhesion must be non-absorbable, non-toxic, biocompatible, non-covalent adhesive and economic [4]. These polymers may be either natural (sodium alginate, gelatin and guar gum) or synthetic/semi-synthetic (sodium carboxymethyl cellulose, carbopol 934 and hydroxypropyl methylcellulose) [5–9]. They may be used either alone or blends of two or more adhesive polymers for mucoadhesive systems.

Manilkara zapota Linn. (M. zapota), is an evergreen plant belongs to the family Sapotaceae, grows up to 8-15 m height. It is cultivated throughout Indian subcontinent including Bangladesh, though it is native to Mexico and Central America. The seeds of M. zapota are diuretic tonic aperients and febrifuge. Stem bark is act as an astringent, febrifuge [10] and anticancer [11]. The leaves and bark are used to treat cough, cold, dysentery and diarrhea [12]. Antimicrobial and antioxidant activities are also reported from the leaves of M. zapota [13, 14]. A natural gum from the seeds of the plant was also isolated [15].

Even though many advances have been made in the area of mucoadhesives, still many challenges ahead in this area and also the search for newer mucoadhesives are going on. The objective of this study was to develop mucoadhesive tablets of pentoxifylline using the mucoadhesive polymer from the plant Manilkara Zapota Linn. (MAPMZ) with respect to the in vitro drug release rate and the characterization of the isolated polymer.

MATERIALS AND METHODS

Materials

The seeds of Manilkara zapota were purchased from the local vendors of Chennai, Tamilnadu in the month of December 2017. The collected seeds were identified and authenticated by a botanist Dr. S. Balasubramanian, ABS Medicinal garden, Salem. The voucher specimen (MZG-1) was kept in our museum for future reference. Pentoxifylline was obtained as a gift sample from Shasun Pharmaceuticals, Puducherry. Avicel and magnesium stearate were purchased from Central Drug House (India). Acetone, diethyl ether and petroleum ether were from Qualigens (India) and sodium hydroxide from E-Merck (India). All the chemicals used were of analytical grade

Methods

Isolation of MAPMZ

Three batches of MAPMZ was prepared on a laboratory scale by the method of Rao et al. [16]. 200 ml of cold distilled water was added to 20 g of the seed powder and the slurry was prepared. Then the slurry was added to 800 ml of boiling water and boiled for another 20 min with continuous stirring. The solution was kept overnight to settle the solid matter. The clear solution was centrifuged for 20 min at 5000 rpm. The supernatant fluid was separated and twice the volume of acetone was added with continuous stirring. The formed precipitates were filtered and washed with petroleum ether and diethyl ether and then dried under vacuum at 50-60 °C. The dried materials were sieved through sieve No 80 and used for the formulation of tablets.

Formulation of mucoadhesive tablets

The mucoadhesive tablets (MAT) of pentoxifylline were prepared by using direct compression technique. Accurately weighed quantities of pentoxifylline, mucoadhesive polymer, avicel, magnesium stearate were mixed uniformly and this mixture was compressed into tablets by using Elite multi-station punching machine (Erweka) with 10 mm flat punches. The compression force was adjusted to give tablet hardness in the range of 7 to 11 kp. The constituent of the formulation is presented in table 1.

Swelling study

The formulated MAT’s were individually weighed (W1) and placed separately in an agar gel (2%) plates and incubated at 37±0.5 °C. The tablets were removed from petri dish at regular time intervals of 1 h up to 6 h and the excess water on the surface was removed carefully with filter paper. The swollen tablet was reweighed (W2) and the swelling index was calculated (n=3) by using the formula [17, 18].

Table 1: Formulation of mucoadhesive tablets of pentoxifylline

Ingredients F1 F2 F3
Pentoxifylline 400 400 400
Avicel 152 122 92
MAPMZ 30 60 90
Magnesium stearate 18 18 18
Total weight (mg) 600 600 600

All the quantities are in mg

Mucoadhesive strength

The mucoadhesive strength (MS) of the formulated MAT’s was measured by using a modified 2-arm balance (fig. 1) with rabbit buccal mucosa[19]. The rabbit buccal mucosa was taken as the membrane and phosphate buffer (PB) pH 6.8 as moisturizing liquid. The rabbit buccal mucosa was obtained from the local slaughterhouse and stored in krebs buffer at 4 °C upon collection. The experiment was conducted within 3 h of the procurement of rabbit mucosa. The mucous layer was separated by using a surgical blade and washed with PB pH 6.8. It was then tied on a glass vial using a thread. This set was kept in a glass beaker, which was filled with PB pH 6.8 up to the surface of the buccal mucosa to maintain buccal mucosa viability.

Fig. 1: Mucoadhesive strength measurement apparatus [19]

The MAT was attached to the upper clamp of the apparatus and then the beaker was raised slowly until contact between rabbit buccal mucosa and MAT was established. A weight of 100 g was kept on the clamp for 5 min (pre-load time) to create a strong adhesion between rabbit buccal mucosa and the MAT. The weight (100 g) and pre-load time (5 min) were kept as constant for all the MAT’s. After the pre-load time, the weight was removed from the clamp. Water was added at a rate of 60 drops/min into the beaker until the separation of rabbit buccal mucosa and MAT. The weight of water required to detach the MAT from buccal mucosa was noted as MS and the same was repeated with fresh mucosa (n = 6). The force of adhesion [20-22] was calculated by using MS

In vitro drug release studies

The in vitro dissolution studies were carried out in a USP dissolution test apparatus (Electrolab, India) Type-II, by using 900 ml of phosphate buffer saline (PBS) pH 6.8. The dissolution test was carried out at a speed of 50 rpm and the temperature of 37±0.5 °C. 5 ml of the samples were withdrawn at predetermined time intervals and assayed spectrophotometrically at 274 nm using Shimadzu UV spectrophotometer 1601. All the experiments were done thrice (n=3) and the standard curve specification was y=0.0392X (r2 = 0.9993, n = 10).

Drug release kinetics

The data obtained from in vitro release of drug was plotted in various kinetic models such as zero order (cumulative amount of drug released vs time), first order (log cumulative percentage of drug remaining vs time), and Higuchi’s model (cumulative percentage of drug released vs square root of time) to know the release kinetics [23–25].

Mechanism of drug release

The mechanism of drug release of the prepared mucoadhesive tablet of pentoxifylline was calculated by using Korsmeyer equation (log cumulative percentage of drug released vs log time), and the exponent n was calculated through the slope of the straight line [26].

Statistical analysis

Each experiment was repeated at least three times. The results are expressed as the mean±SD One-way analysis of variance was used to test the statistical significance of differences among groups. Statistical significance of the differences of the means was determined by Student’s t-test.

RESULTS AND DISCUSSION

Natural polymers are preferred over synthetic and semi-synthetic polymers due to their low cost, non-toxic, emollient, free availability and non-irritating nature. Even though many polymers are available, a search for new polymers still interesting to get more efficacious polymers with less toxic. So in this present work, an attempt was made to study the mucoadhesive property of the natural polymer from the plant M. zapota by formulating pentoxifylline mucoadhesive tablets.

The mucilage was isolated from the seeds of M. zapota by the method of Rao et al., [16]. The mucoadhesive tablets of pentoxifylline were formulated by using three different concentrations of MAPMZ.

The evaluation of tablets showed a satisfactory report on hardness (92.572±3.641 Neutons), friability (0.325±0.005%), weight variation (0.6106 mg±3.24%) and drug content (101.97±1.62%).

An appropriate swelling index is mandatory for the uniform and sustained release of the drug and effective mucoadhesion [27]. The swelling study showed that the rate of swelling was indirectly proportional to the MAPMZ content of tablets. F1 batch (lower concentration of MAPMZ) had a high swelling index (4.292±0.10), and F3 the lowest (3.10±0.07) swelling index. Batch F2 and F3 didn’t show any significant change in their shape and form of tablets for a period of 6 h, when they kept in the agar gel (2%) plate. But the F1 batch had completely changed the shape and form.

MS of MAT’s of Manilkara zapota with rabbit buccal mucosa is shown in fig. 2. The mucoadhesion was occurred in three different stages: wetting, interpenetration, and mechanical interlocking between mucus and polymer. The MS is affected by various factors such as polymer’s molecular weight [28], swelling rate, contact time with mucus, and the biological membrane used for the study [29]. Tablets formulated with a high concentration of MAPMZ showed good MS in a contact time of 5 min. This high mucoadhesive strength of MAPMZ may be due to the formation of secondary bioadhesion bonds with mucin and interpenetration of the polymer chains in the interfacial region. However, the formulations F1, F2 and F3 exhibited MS of 10.302±0.241, 33.752±0.246 and 36.762±0.134 gm, respectively, with rabbit buccal mucosa.

Fig. 2: Mucoadhesive strength of tablets formulated with MAPMZ mean±SD, n=6

The in vitro release studies (fig. 3) revealed that the release rate was indirectly proportional to the MAPMZ concentration. The F1 batch, which has a high swelling index, leads to more % of drug diffused from the polymer matrix [30]. The gradual decrease in the % of drug release from F1 (98.05±2.51) to F3 (60.16±2.64), in 5 h, may be due to the increase in the concentration of MAPMZ. It may be due to the in situ gelling property of MAP, which slows the dissolution rate of the drug pentoxifylline. Tablets of batch F2 and F3 were remaining intact during the entire 12 h study period and the batch F1 was up to 5 h.

Fig. 3: The cumulative release profile of mucoadhesive tablets of pentoxifylline formulated with MAPMZ mean±SD, n=3

The zero order release described that the release rate is dose-independent, which shows the cumulative amount of drug release vs time for zero-order kinetics. The first order release described the release rate is dose-dependent, which shows the log cumulative percent drug remaining vs time [31]. Higuchi’s model described the release of drugs from an insoluble matrix as a square root of a time-dependent process based on Fickian diffusion. Higuchi square root kinetics, showing the cumulative percent drug release vs the square root of time[32]. The release constant was calculated from the slope of the appropriate plots, and the regression coefficient (r2) was determined (table 2). It was found that the in vitro drug release of mucoadhesive tablets of pentoxifylline was followed zero order release, as the plot showed the highest linearity (r2=0.9552, 0.9262 and 0.9585 for the formulations, F1, F2 and F3 respectively), and Higuchi’s (r2=0.9916, 0.9845 and 0.99), which indicates the release rate independent.

Table 2: Release kinetics of mucoadhesive tablets of pentoxifylline

Formulation First order Zero-order Higuchi Korsmeyer Peppas
Slope r2 Slope r2 Slope r2 Slope r2
F1 0.3357 0.9186 19.891 0.9552 57.128 0.9916 0.8854 0.9716
F2 0.1675 0.9205 9.2043 0.9262 38.352 0.9845 0.9163 0.9920
F3 0.1594 0.8538 8.9379 0.9585 37.419 0.99 0.9887 0.991

The corresponding Korsmeyer-Peppas [30] plot (log cumulative percent drug release vs time) indicated good linearity (r2=0.9716, 0.992 and 0.991) and showed the matrix release pentoxifylline.

CONCLUSION

Reducing the frequency of the administration of the drug pentoxifylline will increase patient compliance and also reducing the dose-related side effects. The MAT’s formulated with MAPMZ controlled the release of pentoxifylline for 12 h; hence, the formulation may be considered as a once-daily sustained-release tablet of pentoxifylline. The in vitro dissolution studies indicated a sustained-release pattern of the drug pentoxifylline for 12 h of study. The results of this study revealed that increasing the concentration of the polymer leads to a decrease in the release rate and also increases the adhesion strength of the formulation. Drug release kinetics indicated that drug release was followed zero-order equation, as the plot showed the highest linearity.

AUTHORS CONTRIBUTIONS

All authors have contributed equally

CONFLICTS OF INTERESTS

All authors have none to declare

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