FORMULATION DEVLOPMENT AND EVALUATION OF MUCOADHESIVE MICROSPHERE OF LOSARTAN POTASSIUM BY USING NATURAL POLYMER

FORMULATION DEVLOPMENT AND EVALUATION OF MUCOADHESIVE MICROSPHERE OF LOSARTAN POTASSIUM BY USING NATURAL POLYMER

Sonali M. Khobragade* and Kanchan P. Upadhye

J.L. Chaturvedi College of Pharmacy, Electronic Building, Hingna Road, Nagpur- 440 016, Maharashtra, India

ABSTRACT: The present work is regarding formulation, development and evaluation of losartan potassium microspheres using natural polymer. The mucoadhesive microspheres of losartan potassium were successfully developed by W/O emulsion solvent evaporation technique using two different natural polymers katira gum and babul gum. Total 12 batches were formulated. Six formulations were prepared by using each natural polymer i.e. LKM1 to LKM6 using katira gum (KG) and LBM1 to LBM6 using babul Gum (BG). All the formulations were evaluated for micromeritic properties, physical evaluation, which includes particle size analysis, percentage yield, drug content, drug entrapment efficacy, percent moisture loss and swelling index, in vitro dissolution studies, in vitro mucoadhesion, scanning electron microscopy, in vitro mucoadhesion and drug polymer interaction studies. The Optimized batch LKM5 was found to release the drug for 12 h (99.78%) and follows Higuchi Matrix model in dissolution studies, indicating the matrix-forming potential of natural polymer and diffusion controlled release mechanism.

Losartan potassium, Katira Gum, Babul Gum, in vitro dissolution

INTRODUCTION:A drug delivery system is defined as a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs in the body. The efficiency of any drug therapy can be described by providing a therapeutic amount of drug to the proper site of action to achieve the desired concentration of the drug in blood or tissues, for the desired therapeutic response which is therapeutically effective and non-toxic for a prolonged period of time.

Recently the novel dosage forms which can control the release rate and target the active drug molecule to a particular site have attained a great formulation interest. Microspheres are one of the novel drug delivery system which possess several applications and are made up of assorted polymers ².

Microspheres can be defined as solid, approximately spherical particles ranging in size from 1 to 1000 μm range in diameter having a core of drug and entirely outer layers of polymers as coating material. They are made up of polymeric, waxy or other protective materials i.e. biodegradable synthetic polymer and modified natural products such as starches, gums, proteins, fats and waxes.

However, the success of these microspheres is limited due to their short residence time at site of absorption.

It would, therefore be advantageous to have means for providing an intimate contact of the drug delivery system with the absorbing membrane. This can be achieved by coupling bioadhesion characteristics to Microspheres ³. Microspheres constitute an important part of such particulate drug delivery systems by virtue of their small size and efficient carrier capacity ⁴. They have varied applications and are prepared by using various polymers. Mucoadhesive drug delivery system are delivery system which utilizes the property of bioadhesion of certain polymers which become adhesive on hydration and can be used for targeting a drug to a particular region of the body for extended periods of time.

Losartan Potassium is an effective antihypertensive drug but it undergoes hepatic first pass metabolism. Its half-life (t_1/2) is 1.5-2 hrs and it should be administered 3-4 times to maintain plasma drug concentration ^{5, 6}. So, it requires control release of a drug. Hence an alternative drug delivery system is needed for increasing therapeutic efficacy, reducing the dosing frequency of drug and improving its half-life and bioavailability ⁷.

Therefore, it is necessary to develop a newer formulation which releases the drug in a sustained release manner. Thus losartan potassium would become promising candidate for mucoadhesive microspheres in the management of hypertension.

Thus, the  present study reports a novel attempt to prepare microspheres of antihypertensive drug Losartan potassium by using natural polymers Katira gum (Cocholospermum religiosum) andBabul gum (Acacia niloctica) as carriers by using W/O emulsion solvent evaporation Technique.

MATERIALS AND METHODS: Losartan Potassium was obtained as a gift sample from Vasudha Pharma and Chem Limited, Hyderabad, AP. Katira Gum and Babul Gum was purchase from local market, Nagpur. Liquid paraffin, Tween 80 was purchased from Loba chemicals, Mumbai and iso propyl alcohol was purchased from SD Fine Chemicals Ltd., Mumbai. All other reagents used were of analytical grade.

Preparation of Losartan potassium Microspheres: Mucoadhesive microspheres containing Losartan potassium were prepared by the water-in-oil (W/O) emulsification solvent evaporation technique. The drug was dissolved in each polymeric aqueous solution. The solution was poured in 200ml liquid paraffin contains 0.5 % tween 80 as an emulsifying agent. The aqueous phase was emulsified into oily phase by stirring the system in a 1000 ml beaker (table 1).

Constant stirring at 1000 rpm was carried out using mechanical stirrer and its content was heated by a heating mantle at 20^oC. Stirring and heating were maintained for 2 hours until the aqueous phase was completely removed by evaporation. The light oil was decanted and collected microspheres were washed three times with 100 ml aliquots of isopropyl alcohol, filtered through Whatman filter paper, dried in oven at 50^oC for 2 hours and stored in desiccators at room temperature ⁸ (fig. 1).

FIG. 1: SCHEMATIC REPRESENTATION OF PREPARATION OF MUCOADHESIVE MICROSPHERES OF LOSARTAN POTASSIUM BY W/O EMULSION SOLVENT EVAPORATION TECHNIQUE

TABLE 1: FORMULATION DESIGN OF MUCOADHESIVE MICROSPHERES OF LOSARTAN POTASSIUM USING DIFFERENT NATURAL POLYMERS.

Evaluation of Drug loaded Mucoadhesive Microspheres:

1. Micromeritic Properties: The flow properties of drug loaded microspheres were studied by determining various parameters like the Bulk density, Tapped density, Angle of repose, Carr’s consolidation Index, Hausner’s Ratio^{9, 10, 11}.
2. Physical characterization of prepared Microspheres:
   1. Particle size analysis ¹²:
   2. Percentage yield ¹²: The percentage yield of each batch was calculated on weight basis with respect to the weight of starting material. All experiments were carried out in triplicate. The percent yield of prepared microsphere was calculated by following formula;

• All the microspheres were evaluated with respect to their size and shape using MOTIC PLUS – 2.0 (ml) instruments. The average sizes of the microspheres were calculated.
• Scanning electron microscopy (SEM): The shape and surface morphology of the microspheres was studies by using scanning electron microscopy.

Percentage Yield=

Weight of Microspheres            x 100

Weight of Drug + Weight of Polymer

1. Drug content estimation ¹²: The drug content of the prepared microspheres was determined by the method of extraction of drug present in microspheres. Drug loaded microspheres (100mg) were powdered and extracted in 100 ml Phosphate buffer 6.8 P^H for 24 hrs. Then the resultant dispersion of microspheres was sonicated for 30 minutes for complete mixing and filtered through a Whatman filter paper. The concentration of drug present in filtrate was determined spectrophotometrically at 206.3 nm using 6.8 P^H phosphate buffer as blank. Each determination was made in triplicate. The drug content of prepared microsphere was calculated by following formula;

Drug Content=

Calculated Drug Content        x 100

Total amount of Microspheres

1. Drug Entrapment efficiency ¹²: The drug entrapment efficacy of the prepared microspheres was determined by the method of extraction of drug present in microspheres. Drug loaded microspheres (100mg) were powdered and extracted in 100 ml Phosphate buffer 6.8 P^H for 24 hrs.

Then the resultant dispersion of microspheres was sonicated for 30 minutes for complete mixing and filtered through a Whatman filter paper. The concentration of drug present in filtrate determined spectrophotometrically at 206.3 nm using 6.8 pH phosphate buffer as blank. Each determination was made in triplicate.

The drug entrapment efficiency (DEE) was calculated by the following formula;

Drug Entrapment Efficiency=

Calculated Drug Content x 100

Theoretical Drug Content

1. Theoretical Drug Content was determined by calculation assuming that the entire LP present in polymer solution used get entrapped in LP microspheres, and no loss occurs at any stage of preparation of LP microspheres.
2. Practical drug Content was analyzed by using following procedure;

Weighed amount of LP microspheres equivalent to 100 mg microspheres was dissolved in 100 ml of phosphate buffer P^H 6.8. This solution was kept for 2 hours for the complete dissolution of the LP in Phosphate buffer pH 6.8. This solution was filtered and further diluted to make the concentration of 10ug/ml solution. The absorbance of the solution was measured at 206.3 nm using double beam UV -Visible Spectrophotometer against Phosphate buffer pH 6.8 as a blank and calculated for the percentage of drug present in sample.

1. Swelling Index¹³: Swelling index illustrate the ability of the mucoadhesive microspheres swell at the absorbing surface by absorbing fluids available at the site of absorption, which is a primary requirement for initiation of mucoadhesion.

A weighed amount of microspheres (100mg) was placed in 100 ml of 6.8 P^H phosphate buffer and swelling was allowed at 37^oC and change in weight variation between initial weight of microspheres and weight due to swelling is measured by taking weight periodically and socking with filter paper. The percent swelling value can be determined using following equation.

Swelling Index=

Mass of Swollen Microspheres – Mass of Dry Microspheres x 100

Mass of Dried Microspheres

1. Percent of Moisture loss ¹⁴: The LP loaded microspheres of different polymers were evaluated for percentage moisture loss which gives idea about its hydrophilic nature. The microspheres were weighed initially and kept in desiccators containing calcium chloride at 37^oc for 24 hrs. The final weight was noted when there was no further change in the weight of sample.

3. In vitro drug release studies: Prepared Microspheres equivalent to 100 mg were accurately weighed and filled into tight in the Muslin cloth. In vitro drug release study was carried out in USP paddle type dissolution test apparatus using phosphate buffer pH 6.8 as dissolution medium, Volume of dissolution medium was 900 ml and bath temperature was maintained at 37±1°C throughout study. Paddle speed was adjusted to 50 rpm. An interval of 1 hour, five ml of sample was withdrawn with replacement of five ml fresh medium and analyzed for losartan potassium content by UV-Visible spectrophotometer at 206.3 nm.
4. In vitro drug release kinetics: Analysis of drug release from microspheres was performed with a flexible model that can identify the contribution to overall kinetics, mechanism of drug release and the dissolution data obtained for optimized formulation was treated with the different release kinetic equations ¹⁴. In order to study the exact mechanism of the drug release from microspheres, drug release data was analyzed according to Zero Order, First Order, Higuchi square root, Hixon Crowell, Koresmeyer model. The criterion for selecting the most appropriate model was chosen on the basis of goodness to fit test ^{15, 16}.
5. In-vitro mucoadhesion study^{17, 18}:A piece of intestinal mucosa (2x2 cm) was mounted on to glass slide of (3x1 inch) using elastic bands. Weighed microspheres were spread onto wet rinsed tissue specimen and immediately thereafter the slide was hung onto the arm of a USP tablet disintegrating test apparatus. The disintegration machine containing tissue specimen was adjusted for up and down movement in 6.8 pH Phosphate buffer at 37^oC in a beaker. Numbers of microspheres still adhering on to the tissue were weighed at hourly intervals upto 8-10 hrs. The weight of microspheres leached out at different intervals is measured. The % mucoadhesion is calculated by the following equation

Where, Wa is the weight of microspheres applied W1 is the weight of microspheres leached out

6. Compatibility Studies¹⁹:
   1. FTIR Studies: In the preparation of microspheres, the drug and polymer may interact as they are in close contact with each other, which could lead to the instability of preformulation studies. FTIR spectra of pure drug (LP), pure polymers and formulations (Drug loaded microspheres) containing both drug and polymers were performed to study the drug polymer interaction. FTIR study was performed by using Fourier transformed infrared spectrophotometer (Bruker, Vertex 70)
7. Accelerated stability studies for the optimised formulation ^{20, 21}: The purpose of stability testing is to provide evidence on how the quality of drug substance or drug product varies with time under the influence of a variety of environmental factor such as temperature, humidity and light and enables recommended storage condition. Accelerated stability studies ofthe optimized drug loaded mucoadhesive microspheres were carried out as per ICH guidelines, at 40 ± 2⁰C /75 ± 5% RH or 25^°C ± 2^°C /60 % RH ±5 for 60 days. The samples were investigated for particle size analysis, particle size, drug content, drug release, and appearance at regular intervals (0 days, 15 days, 30 days, 45 days, and 60 days).

RESULT AND DISSCUSSION:

Evaluation of Mucoadhesive Microspheres:

1. Micromeritic Properties of Prepared Mucoadhesive Microspheres

TABLE 2: MICROMERITIC PROPERTIES OF KATIRA GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

TABLE 3: MICROMERITIC PROPERTIES OF BABUL GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

2. Physical Characterization of Prepared Microspheres

  Particle Size and Shape: 

FIGURE 2: PHOTOGRAPHS SHOWING MICROSPHERES PREPARED FROM KATIRA GUM AND BABUL GUM

TABLE 4: PARTICLE SIZE ANALYSIS OF KATIRA GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

 TABLE 5: PARTICLE SIZE ANALYSIS OF BABUL GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

Percentage yield, Drug Content and Percent Drug Entrapment:

TABLE 6: PERCENTAGE YIELD, DRUG CONTENT AND PERCENT DRUG ENTRAPMENT OF KATIRA GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

TABLE 7: PERCENTAGE YIELD, DRUG CONTENT AND PERCENT DRUG ENTRAPMENT OF BABUL GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

Percent Moisture Loss and Swelling Index:

TABLE 8: PERCENT MOISTURE LOSS AND SWELLING INDEX OF KATIRA GUM LOADED MICROSPHERES (MEAN ± S.D., N=3)

TABLE 9: PERCENT MOISTURE LOSS AND SWELLING INDEX OF BABUL GUM LOADED MUCOADHESIVE MICROSPHERES (MEAN ± S.D., N=3)

In vitro drug release studies:

TABLE 10: IN VITRO DRUG RELEASE DATA OF KATIRA GUM LOADED MUCOADHESIVE MICROSPHERES (MEAN ± S.D., N=3)

Pharmacokinetic Profile:

TABLE 11: PHARMACOKINETIC PROFILE OF KATIRA GUM LOADED MICROSPHERES

 In vitro Mucoadhesion test:

FIG. 4: MUCOADHESION BEHAVIOR OF KATIRA GUM LOADED MUCOADHESIVE MICROSPHERES FORMULATIONS IN pH 6.8

 Drug-polymer interaction studies:

FTIR Studies: The FTIR spectrum of Losartan Potassium and Katira Gum alone and the optimized batches of Katira Gum loaded Microspheres were presented in figures:

FIGURE 5: INFRARED SPECTRUM OF LOSARTAN POTASSIUM

FIGURE 6: INFRARED SPECTRUM OF COCHOLOSPERMUM RELIGIOSUM (KATIRA GUM)

FIGURE 7: INFRARED SPECTRUM OF LKM5 BATCH

FIGURE 8: INFRARED SPECTRUM OF LKM6 BATCH

Scanning Electron Microscopy:

FIGURE 9: SEM PHOTOMICROGRAPH OF LKM5 BATCH

Accelerated Stability Studies:

TABLE 12: PHYSICAL STABILITY CHARACTERISTICS OF OPTIMIZED KATIRA GUM LOADED MUCOADHESIVE MICROSPHERES:  (Mean ± S.D; n = 3) Condition:  room temp: 40^oC, Relative Humidity: 75%

DISCUSSION: The Losartan Potassium (LP) microspheres were prepared by W/O Emulsion solvent evaporation technique by using two different natural polymers i.e. katira gum (KG) and babul gum (BG). Total 12 formulations were prepared.  Six formulations were prepared by using each natural polymer i.e. LKM1 to LKM6 using katira gum and LBM1 to LBM6 using babul gum. These formulations were prepared by using common oil phase i.e. Liquid paraffin.

Micromeritic  properties: The flow  properties  of  microspheres  were  evaluated  by  measuring  the  bulk density, tapped density, angle   of  repose, Carr’s index and  Hausner’s  ratio.

• Katira Gum loaded Microspheres  show  excellent  flow  characteristics  with  the  angle  of  repose  <25⁰. The Carr’s index of  the  maximum  batches  was  in  the  range of  10.19±0.04%  to 17.26±0.1, which  indicate  excellent  packability  of  microspheres, whereas the Hausner’s ratio of the maximum batches was less than 1.16, which indicate good flow ( Table 2).
• Babul  Gum loaded Microspheres  show  excellent  flow  characteristics  with  the  angle  of  repose <25⁰ (LBM2, LBM3, LBM5, LBM6) >25⁰ (LBM1, LBM4). The Carr’s index of  the  maximum  batches  was  in  the  range of  12.4±0.14   to 19.16±0.04,  which  indicate  good packability  of  microspheres, whereas the Hausner’s ratio of the maximum batches was less than 1.21  indicate   good  flow (Table 3).

Particle size Analysis: The particle size of katira gum loaded microspheres ranged from 17.07 ± 0.04 µm to 37.21 ± 0.07µm, and babul gum loaded microspheres ranged from 13.45 ± 0.29 µm to 20.80 ± 0.14µm. It was noticed that the microspheres prepared from BG have small particle size and they are irregular in shape as compared to KG. KG has a higher particle size and almost all the batches of katira gum loaded microspheres are spherical in shape. Babul gum loaded microspheres have moderate size range and shows spherical, oval and irregular shape of microspheres at different batches (Table 4, 5).

Percentage  yield: The  percentage yield  of katira gum loaded microspheres ranged from  28.28± 0.49% to  42.04±0.58%, and babul gum loaded microspheres ranged from  45.40±0.007% to  70.67±0.70%. It was noticed  that the  Percentage yield of babul gum loaded microspheres  has  the  maximum  yield  compared  to  katira gum loaded microspheres (Table 6,7).

Drug Content: The  %  drug  content  recovered  from  the katira gum loaded microspheres ranged from 33.03±0.077% to 74.97±0.04% and babul gum loaded microspheres ranged from 12.63±0.28% to 33.24±0.028%. It  was  noticed    that  the  katira gum loaded microspheres  shows maximum  drug  concentration  as  compared  to   microspheres  prepared  from babul gum (Table 6,7).

Drug Entrapment Efficacy:  The drug entrapment efficacy of katira gum loaded microspheres ranged from 63.90±0.16% to 96.26±0.29 and babul gum loaded microspheres ranged from 40.48±0.11% to 80.40±0.14. It was noticed that the percent drug entrapment efficacy of katira gum loaded microspheres showed maximum entrapment of a drug as compared to babul gum loaded microspheres. In case of katira gum loaded microspheres, it is observed that the drug entrapment efficiency is increased as the concentration of katira gum decreased (Table 6, 7).

Percent Moisture loss: The percent moisture loss of katira gum loaded microspheres ranges from 2.15±0.03% to 3.00±0.14% and babul gum loaded microspheres ranges from 2.1±0.02% to 3.97±0.02%. It was noticed that the katira gum loaded microspheres show minimum percent moisture loss as compared to babul gum loaded microspheres. The percent moisture  loss was  determined  for  all  the  formulations   prepared   from  katira gum and babul gum  and  tabulated  in  Table 8 and 9.

Swelling Index: The swelling index of katira gum loaded microspheres ranges from 1.35±0.2 to 1.94±0.02 and babul gum loaded microspheres ranges from 0.79±0.02 to 1.3±0.04. It was noticed that the katira gum loaded microspheres show maximum swelling index as compared to babul gum loaded microspheres.

The swelling index was  determined  for  all  the  formulations   prepared   from  katira gum and babul gum  and  tabulated  in  Table 8 and 9.

Katira gum loaded mucoadhesive microspheres formulations were optimized over babul Gum loaded microspheres, on the basis of the results obtained from the Physical evaluation of prepared mucoadhesive microspheres. For the preparation of drug loaded mucoadhesive microspheres, the concentration of gum required for micro-encapsulation is only 1-2 % in case of katira gum; whereas the concentration of gum required for microencapsulation in case of babul gum is 6-7 %.

Thus from the above parameters we optimized the Katira Gum loaded Microspheres for further evaluation. So further evaluation parameters were carried out with the Katira Gum loaded Mucoadhesive microspheres.

In vitro release studies:  The in-vitro drug release studies of katira gum loaded microspheres ranged from 47.25% to 99.78%. The maximum in vitro drug release was found to be 99.78% for the formulation LKM5 at 12 hrs. Formulation LKM1, LKM2, LKM3, LKM4 LKM6 showed maximum release of 47.25%, 72.00%, 81.08%, 70.35% and 97.03% respectively at 12^th hrs (Table 10).

The mechanism of Losartan Potassium release from katira gum loaded microspheres was studied by fitting the data obtained from in vitro release studies into zero order, first order, Higuchi’s Matrix, and Korsemeyer Peppas and Hixson-Crowell’s kinetic models.

The katira gum loaded microspheres formulation LKM1, LKM3, LKM4; LKM5 was good fitted to Higuchi matrix model, indicating the matrix-forming potential of natural polymer and diffusion controlled release mechanism. LKM2 was good fitted to 1^st order model and LKM6 was good fitted to Korsemeyer Peppas model. The value of ‘n’ was found to be between 0.3289 to 0.6768. For LKM5, the release exponent of ‘n’ was found to be 0.5676 means it follows anomalous (non-Fickian) diffusion, indicating the involvement of more than one drug release mechanism from the formulation and possibly the combination of both diffusion and erosion.

In vitro mucoadhesion test: The number of microspheres adhering to the tissue was calculated after 2hr, 4hr, 6hrs and 8hr. After  determination  it  was  found  that  batch  LKM5  showed  highest  percent  78%  mucoadhesion  than  other  batches (Fig. 4).

FTIR Studies: FTIR Spectral analysis was performed to study the drug polymer interaction. The FTIR spectra of pure drug (LP), pure polymers, Cocholospermum religiosum (Katira Gum) and formulations (LKM5, LKM6) containing both drug and polymers. FTIR studies show no specific interaction between drug and polymer and thus they are compatible with each other (Fig. 5-8).

Scanning electron microscopy: SEM is used to study the shape and surface morphology of prepared microspheres. SEM of Katira gum loaded microspheres were discrete, uniform and spherical with a smooth surface (Fig. 9).

Accelerated stability studies: Accelerated stability study data of the optimized batches of katira gum loaded microspheres is shown in Table 12. At the initial level and at the final level of  the  accelerated  stability study, the tested  microspheres  showed almost similar particle size, drug content and  drug  release  as observed  at  the  beginning  of  the  study. No color changes or unexpected change were observed. All the  optimized  batches  were  found  stable  after  2  months  without  much  variation  in  particle  size,  drug  content,  drug  release.

CONCLUSION:

• Katira Gum possesses all requisite qualities required for sustained drug delivery system in the form of mucoadhesive microspheres.
• Mucoadhesive microspheres of Losartan potassium were successfully formulated by w/o emulsion solvent evaporation technique using Katira gum and Babul gum.
• Katira Gum loaded Mucoadhesive micro-spheres show excellent result as compare to Babul gum loaded microspheres.
• LKM5 Batch, an optimized batch among Katira gum loaded microspheres formulation shows excellent release rate at 99.78% at 12^th hours which shows its ability to sustain the drug for prolonged period of time, which leads to-
• Improve patient’s compliance and convenience due to less frequent dosing of drug.
• Maximum utilization of drug enabling reduction in total amount of dose administered.
• Increased safety margin of potent drug.
• Reductions in health care cost through improve therapy, shorter treatment period and less frequency of dosing.

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    How to cite this article:

    Khobragade SM and Upadhye KP: formulation development and evaluation of Mucoadhesive Microsphere of Losartan potassium by using natural polymer. Int J Pharm Sci Res 2013; 4(11): 4290-02. doi: 10.13040/IJPSR. 0975-8232.4(11).4290-02

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