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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2022 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                                                            Research Article 

Development and Characterization of Floating Microspheres of Dexrabeprazole Sodium for the Treatment of Peptic Ulcer

Ragini Sahu, Sarang Jain

Rajiv Gandhi College of Pharmacy, Rajharsh Colony, Kolar Rd, Sankhedi, Bhopal, MP, 462042, India

INTRODUCTION

Oral rout of administration is the most convenient and widely used method of drug administration and the development of stomach specific oral controlled-release drug delivery systems is a challenging job due to the variation of pH in different segments of the gastrointestinal tract, the fluctuation in gastric emptying time and the difficulty of localizing an oral delivery system in a selected region of the gastrointestinal tract. Rapid gastrointestinal transit can prevent the absorption of complete drug in the absorption zone and reduce the efficacy of the administered dose since the majority of drugs are absorbed in stomach or the upper part of small intestine^1,2. To overcome the above discussed issues, many types of oral controlled drug delivery systems having prolonged gastric residence times have been reported such as: floating drug dosage systems (FDDS)^3-7, swelling or expanding system⁸, mucoadhesive systems^9,10, modified-shape systems¹¹, high-density systems and other delayed gastric emptying devices¹². FDDS have lower density than gastric fluids and thus remain buoyant in the stomach fluid without affecting the gastric emptying for a prolonged period of time. While the system is floating in the gastric fluid, the drug is released slowly from the system at a desired rate. Materials used for FDDS include carbon dioxide gas-forming agents (carbonate or bicarbonate compounds) ^{8, 13}, highly swellable hydrocolloids and light mineral oils^{14, 15}. Multiple unit systems and floating systems prepared by solvent evaporation methods have also been developed^{12, 16-20}. However, it has been shown that products based on a multiple unit system comprising many small units have advantages over single -unit preparations such as matrix tablets²¹. The gastric emptying of multiple unit dosage forms occur gradually, in a more consistent manner, with less individual variation^{2, 22}. Multiple unit dosage forms also have the potential to distribute widely over a large area in the stomach and small intestine, thus yielding a more predictable drug release by suppressing the effect of many variables in the gastrointestinal environment. As multiple unit dosage forms consist of many small units, less risk of dosage dumping is expected²³. Chemically, Dexrabeprazole sodium is R (+)-isomer of rabeprazole (2-[[[4-(3-methoxypropoxy)- 3-methyl-2-pyridinyl]-methyl] sulfinyl] 1Hbenzimidazole). It is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the gastric H+ K+ ATPase enzyme system at the secretory surface of the gastric parietal cell^{24, 25}. Floating microspheres are one of the multiparticulate delivery system and are prepared to obtain prolonged or controlled drug delivery to improve bioavailability and to target drug to specific sites. Microspheres can also offer advantages like limiting fluctuation within therapeutic range, reducing site effects, decreasing dosing frequency and improving patient compliance²⁶.

MATERIAL AND METHODS

Material

Dexrabeprazole sodium was generously supplied as a gift samples by Bioplus Life Science, Bangalore. Ethyl Cellulose and H.P.M.C. K4 were the gift samples obtained from Mapromax, Life sciences Pvt. Ltd., Dehradun (India). Dichloromethane, ethanol and isopropyl alcohol were purchased from E. Merck (India) Ltd., Mumbai.  Double distilled water was prepared freshly and used whenever required. All the chemicals used in this work were of analytical grade.

Methods

Preformulation studies

Determination of λ _max of DEX 

Accurately weighed 10 mg of drug was dissolved in 10 ml of Distilled water in 10 ml of volumetric flask. The resulted solution 1000µg/ml and from this solution 1 ml pipette out and transfer into 10 ml volumetric flask and volume make up with Distilled water. Prepare suitable dilution to make it to a concentration range of 5-25μg/ml. The spectrum of this solution was run in 200-400 nm range in U.V. spectrophotometer (Labindia-3000+). 

Fourier Transform Infrared (FTIR) spectroscopy

The physical properties of the physical assortment were comparing with those of DEX pure drug. Samples was assorted comprehensively through 100mg potassium bromide IR powder as well as compacted under vacuum at a pressure of concerning 12 psi for 3 minutes. The ensuing disc was mounted in an appropriate holder in Brukers Alpha IR spectrophotometer and the IR spectrum was recorded from 3500 cm to 500 cm. The resultant spectrum was compared for any spectrum changes.

Preparation of floating microsphere of DEX                                                                                                 

Floating microsphere containing DEX was prepared using emulsion solvent diffusion technique. The drug to polymer ratio used to prepare the different formulations was 1:7. The polymer content was a mixture of ethyl cellulose and hydroxypropylmethylcellulose (HPMC) as shown in table 1. The drug polymer mixture is dissolved in a mixture of ethanol (8 ml) and dichloromethane (8 ml) was dropped in to 0.75% polyvinyl alcohol solution (200 ml). The solution was stirred with a propeller-type agitator at 40°C temperatures for 1 hour at 300 rpm. The formed floating microspheres were passed through sieve no.12 and washed with water and dried at room temperature in a desiccator²⁷. 

Table 1 Formulations of the floating microspheres of DEX

Evaluation of microspheres

Particle size determination 

The particle size of formulation was determined by optical microscopy using a calibrated ocular micrometer.

Floating behavior of floating microsphere 

100 mg of the floating microsphere were placed in 0.1 N HCI. The mixture was stirred with paddle at 100 rpm. The layer of buoyant microspheres was pipetted and separated by filtration at 1, 2, 4 and 6 hours. The collected microspheres were dried in a desiccator over night. The percentage of microspheres was calculated by the following equation:

% floating microsphere    = Weight of floating microsphere/ Initial weight of floating microsphere x 100

Drug entrapment

The various formulations of the floating microspheres were subjected for drug content. 50 mg of floating microspheres from all batches were accurately weighed and crushed. The powdered of microspheres were dissolved with 10ml ethanol in 100ml volumetric flask and makeup the volume with 0.1 N HCl. This resulting solution is than filtered through whatmann filter paper No. 44. After filtration, from this solution 10 ml was taken out and diluted up to 100 ml with 0.1 N HCl. The absorbance was measured at 260.0 nm against blank.  The percentage drug entrapment was calculated as follows.

% Drug entrapment =Calculated drug concentration/ Theoretical drug concentration x 100

Percentage yield

The prepared microspheres with a size range of 609-874 µm were collected and weighed from different formulations. The measured weight was divided by the total amount of all non-volatile components which were used for the preparation of the microspheres.                          

Shape and surface morphology

In order to examine the surface morphology, the formulations were viewed under scanning electron microscopy. The samples for SEM were prepared by lightly sprinkling the floating microspheres powder on a double adhesive tape, which stuck to an aluminum stub. The stubs were then coated with gold to a thickness of about 300Å using a sputter water. The samples were then randomly scanned for studying surface morphology but show the images of coating to prove internal surface²⁸. 

In-vitro release studies 

The drug release rate from floating microspheres was carried out using the USP type II (Electro Lab.) dissolution paddle assembly. A weighed amount of floating microspheres equivalent to 100 mg drug were dispersed in 900 ml of 0.1 N HCI (pH 1.2) maintained at 37 ± 0.5°C and stirred at 100 rpm. One ml sample was withdrawn at predetermined intervals and filtered and equal volume of dissolution medium was replaced in the vessel after each withdrawal to maintain sink condition. The collected samples were treated with methyl orange and analyzed spectrophotometrically at 260 nm to determine the concentration of drug present in the dissolution medium. Percentage cumulative drug release was calculated²⁹.

Drug release kinetic data analysis

Several kinetic models have been proposed to describe the release characteristics of a drug from matrix. The following three equations are commonly used, because of their simplicity and applicability. Equation 1, the zero-order model equation (Plotted as cumulative percentage of drug released vs time); Equation 2, Higuchi’s square-root equation (Plotted as cumulative percentage of drug released vs square root of time); and Equation 3, the Korsemeyer-Peppas equation (Plotted as Log cumulative percentage of drug released vs Log time).

To study the release kinetics of Famotidinefrom the Floating microspheres the release data was fitted to these three equations

Zero order equation: When a graph of the cumulative percentage of the drug released from the matrix against time is plotted, zero order release is linear in such a plot, indicating that the release rate is independent of concentration.

Q_t = k₀.t ……………………… (1)

Where Q_{t is} the percentage of drug released at time t and k₀ is the release rate constant;

First order equation:-

In (100-Q_t) = In 100- k_I.t ………………….. (2)

 Where k_I is the release rate constant;

 Higuchi’s equation (Wagner, 1969):-

Q_t = k_H.t^1/2    ……………………….. (3)

Where K_H is the Higuchi release rate constant

Korsemeyer-Peppas:-

The curves plotted may have different slopes, and hence it becomes difficult to exactly pin-point which curve follows perfect zero order release kinetics. Therefore, to confirm the kinetics of drug release, data were also analyzed using Korsemeyer’s equation.

 Q_t/Q_∞ = k_KP.tⁿ

Where Q_t/ Q_∞ is the fraction of drug released at time t, k_KPa constant compromising the structural and geometric characteristics of the device and n is the release exponent.

The slope of the linear curve gives the ‘n’ value. Peppas stated that the above equation could adequately describe the release of solutes from slabs, spheres, cylinders and discs, regardless of the release mechanism. The value of ‘n’ gives an indication of the release mechanism. When n = 1, the release rate is independent of time (typical zero order release / case II transport); n = 0.5 for Fickian release (diffusion/ case I transport); and when 0.5 < n < 1, anomalous (non-Fickian or coupled diffusion/ relaxation) are implicated. Lastly, when n > 1.0 super case II transport is apparent.  ‘n’ is the slope value of log M_t/M_∞   versus log time curve^30-32.

RESULTS AND DISCUSSION

Solubility of DEX was freely soluble in ethyl acetate, chloroform and ethanol, insoluble in n- hexane and ether, soluble in water and methanol. The melting point and partition coefficient of DEX was found to be 220-223°C and 1.17 respectively. λ _max of DEX was found to be 260.0 nm by using U.V. spectrophotometer (Labindia-3000+) in linearity range 5-25µg/ml Fig.1. Identification of DEX was done by FTIR spectroscopy with respect to marker compound. It was identified from the result of IR spectrum as per specification Fig. 2. The floating microspheres of DEX were prepared by solvent diffusion-evaporation method. Percentage yield of different formulation was determined by weighing the microspheres after drying.  The percentage yield of different formulation was in range of 56.84 - 82.87% Table 2. The drug entrapment efficacies of different formulations were in range of 48.47-76.19 % w/w as shown in Table 2. Drug entrapment efficacy slightly decrease with increase HPMC content and decreased EC ratio in Microspheres.  This is due to the permeation characteristics of HPMC that could facilitate the diffusion of part of entrapped drug to surrounding medium during preparation of DEX microspheres.  F1 microspheres entrapped maximum amount of the drug. Particle size was determined by optical microscopy method. It plays important role in floating ability and release of drug from microsphere. If size of microspheres is less than 500 mm release rate of drug will be high and floating ability will reduce, white microspheres ranging between 200mm- 500mm, the floating ability will be more and release rate will be in sustained manner. The mean particle size of DEX microsphere was in range 210-264 mm as shown in Table 3. DEX microsphere was dispersed in 0.1 HCl as simulate gastric fluid.  Floating ability of different formulation was found to be differed according to EC and HPMC ratio.  F₁-F₄ formulations showed best floating ability (91.47-72.97%) in 6 hours.  F₅-F₇ formulation showed less floating ability (66.12-45.09%) as showed in Table 4.  The floating ability of microsphere is decreased by increasing the HPMC ratio. Shape and surface characteristic of Dexrabeprazole sodium microspheres examine by Scanning Electronic Microscopy analysis (Fig. 3). Surface morphology of formulation examines at different magnification, which illustrate the smooth surface of floating microspheres. The drug release from floating microspheres was found to be 82.857% at the end of 8 h for F1 Table 5 & Fig. 4. The In-vitro drug release data of the optimized formulation was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetic equation, Higuchi’s and Korsmeyer’s models in order to determine the mechanism of drug release. When the regression coefficient values of were compared, it was observed that ‘r’ values of Korsmeyer’s was maximum i.e 0.928 hence indicating drug release from formulations was found to follow Korsmeyer’s models kinetics Table 6, 7 & Fig. 5-8. 

Table 2 Percentage yield and % drug entrapment for different formulation

Table 3 Mean particle size of different formulations

Table 4 Percentage buoyancy for different formulation

Table 5 Release study data of formulation F1-F7

Table 6 Release kinetics of optimized formulation F-1

Table 7 Comparative study of regression coefficient for selection of optimize formulation F-1

Figure 1 λmax of dexrabeprazole sodium

Figure 2 FT-IR Spectrum of pure drug DEX

Figure 3 Scanning electronic microscopy image of optimized formulation F-1

Figure 4 Graph of release study of formulation F1-F7

Figure 5 Graph of Zero order release kinetics of F-1

Figure 6 Graph of First order release kinetics of F-1

Figure 7 Graph of Higuchi order release kinetics of F-1

Figure 8 Graph of Korsmeyer- pappas release kinetics of F-1

CONCLUSION 

Floating microspheres of DEX as a gastro retentive drug delivery system specifically control the release rate of drugs to a particular site and facilitate an enormous effect on health care. Microspheres of different size and drug content could be obtained by varying the formulation variables. On the basis of drug release, percentage yield, drug entrapment, percentage buoyancy and floating lag time F1 could be considered as promising formulations. Thus, the prepared floating microspheres may prove to be potential candidates for multiple-unit delivery devices adaptable to any intragastric condition.

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