Dissolution behavior of Olmesartan Medoxomil drug in Polymeric Micelles of Soluplus and Pluronic F127

 

 Suchetana Dutta, P. K. Kulkarni, Shailesh T.*

Department of Pharmaceutics, JSS College of Pharmacy, Sri Shivarathreeshwara Nagara, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru – 570015, Karnataka, India.

*Corresponding Author E-mail: shailesht@jssuni.edu.in

 

ABSTRACT:

The aim of the present work was to study the dissolution behaviour of a poorly water-soluble Olmesartan Medoxomil (class II drug), by forming polymeric micelles (PMs) of SoluPlus and Pluronic F127. Polymeric Micelles of SoluPlus and Pluronic F127 were prepared by the co-solvent evaporation method. Drug and excipient compatibility study were carried out by Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry. The formulations were evaluated for particle size, Zeta Potential, Solubility studies, drug loading and encapsulation efficiency. Scanning Electron Microscopy (SEM) analysis was performed to study the surface morphology of the PMs. The SEM images showed spherical surface of the micelles. The drug loading efficiency was more for SoluPlus micelles compared to Pluronic F127 micelles. The Polymeric micelles showed negative zeta potential value indicating that they are stable and resist aggregation. The particle size was around 100nm and polydispersity index was less than 1 indicating uniform size distribution. The drug release from the SoluPlus micelles was higher than the Pluronic micelles. These results suggest that the polymeric micelles can be used to increase the solubility of poorly water-soluble drugs.

 

KEYWORDS: Polymeric micelles, SoluPlus, Pluronic F127, hypertension, Olmesartan Medoxomil, Angiotensin II Receptor, Co-solvent evaporation.

 

 


1. INTRODUCTION:

Oral Formulations are the most extensively used route of administration of drugs around the world. This corresponds to the ease of administration and hence patient compliance nature of this form of drug delivery. Solid dosage forms provide superior stability compared to most other formulations. So, quite a number of New Chemical Entities (NCEs) are intended for delivery as solid dosage forms. The challenge of converting these NCEs into solid dosage forms to be administered through the oral route persists. Almost 40% of the NCEs being discovered these days have issues of water solubility. Hence for the drugs with poor water solubility, dissolution is the rate limiting step and the therapeutic efficacy of the drug depends on its concentration at the site of action.

 

After the oral administration there are a number of factors which can be used to check the bioavailability and since the dissolved drug alone can pass through the gastrointestinal membrane hence dissolution is one of those factors. In general, it is stated that the rate of absorption and in turn the onset along with the extent of the clinical effect can be determined by the dissolution of the drug and its oral bioavailability. Drugs with low solubility and high permeability are referred to as Class II drugs. One of the widely used methods to improve the bioavailability of this class of drug includes the preparation of Polymeric micelles and incorporating the drug in them.1

 

Polymeric Micelles (PMs) are a class of nano-particles that has received considerable attention in the recent past and is supposed to be a multifunctional nanotechnology-based drug delivery system for the poorly water-soluble drugs. These polymeric micelles are said to have a core/shell structure. They are said to be formed by the self-assembly of amphiphilic block copolymers in an aqueous media above the Critical Micellar Concentration (CMC). The core consists of a hydrophilic domain and acts as a reservoir.

 

In the present work an attempt have been made to study and record the dissolution behaviour of the PMs by incorporating Olmesartan Medoxomil, an anti-hypertensive drug into them. In the study PMs were prepared using two polymers, SoluPlus and Pluronic F127 and their dissolution data were compared.2,3

 

MATERIALS AND METHODS:

Olmesartan Medoxomil was received as a gift sample from Verdant Life Sciences Pvt. Ltd. SoluPlus obtained from BASF, Pluronic F12 procured from Sigma Aldrich, Bangalore, Sodium Hydroxide was procured from Merck Specialties Pvt. Ltd., Mumbai, Potassium Dihydrogen Phosphate was procured from Loba Chemicals Pvt. Ltd., Mumbai and Acetone was procured from Finar Ltd. Ahmedabad.

 

Methods:

Preparation of Olmesartan Loaded Polymer Micelles of SoluPlus:

Co-Solvent evaporation method was used to prepare Olmesartan Medoxomil loaded polymeric micelles. Soluplus (10mg) of Polymer and Olmesartan Medoxomil (7mg) of were dissolved in organic solvent acetone followed by evaporation of the solvent under pressure in rotary evaporator at 35°C. Then deionized water was added to it and self-assembly was allowed to form polymer micelles at 650rpm. Finally, the whole solution was lyophilized and made into a powder form to carry out the further characterization.4

 

Preparation of Olmesartan Loaded Polymer Micelles of Pluronic F127:

Co-solvent evaporation method was used to prepare Olmesartan Medoxomil loaded polymeric micelles. Pluronic F127 (250mg) was dissolved in 10ml acetone and a solution of 20mg Olmesartan Medoxomil in 4ml acetone was added. The mixture was stirred for 6 hours at room temperature. To this solution, 50ml of deionized water was added slowly under stirring at 150 to 200rpm until a clear solution was obtained. The solution was filtered through filter paper of 0.45µm pore size. The solution was lyophilized and stored for 2 days.5

 

Characterization:

Fourier transform infrared (FT-IR) studies of Olmesartan Medoxomil and Polymer:

To determine the compatibility of the drug and polymer, FT-IR spectroscopy was used. Results were recorded using FT-IR (8400S, Shimadzu Corporation, Japan). Olmesartan medoxomil was mixed with potassium bromide in a mortar, the blend is triturated into a fine powder with the using compression gauge, and the triturated powder blend was compressed in a holder by applying a pressure of 5 ton for 5 min, the pellet was placed in a light path, and the results were recorded.6

 

Differential Scanning Calorimetry (DSC):

All DSC studies of pure drug and prepared formulations were carried out on Shimadzu Thermal Analyzer (TA-60WS). A few milligrams of the sample were entirely sealed into aluminum pans and heated under a nitrogen atmosphere with the heating rate of 10°C/min.7

 

Particle size and PDI determination and Zeta potential determination:

The particle size and polydispersity index (PDI) and zeta potential of prepared micelles were determined by using a Zetasizer 3000 (Malvern Instruments Ltd., Japan). The analysis of the samples was done at a temperature of 25°C using a disposable folded capillary cell. Scattered light was detected at 90° angle with laser attenuation and measurement position was adjusted automatically by the instrument’s software. The particle size was calculated based on photon correlation spectroscopy (PCS).8

 

Solubility studies:

Drug solubility was determined by adding excess amount of pure Olmesartan Medoxomil, SoluPlus and Pluronic F127 in distilled water and phosphate buffers pH 7.4 respectively. Each of the mixture was incubated at 37 ± 0.5°C and rotated at 100rpm until equilibrium was reached (24 h). The solution was filtered and the filtrate was analyzed for drug content by UV spectroscopy (1800, Shimadzu, Japan) at 257nm, and all experiments were performed in triplicate.9

 

Drug loading and encapsulation efficiency:

The Olmesartan Medoxomil loaded SoluPlus micelles and Olmesartan Medoxomil loaded Pluronic F127 micelles were dissolved in ethanol. The solution was sonicated for 30 minutes and solution was filtered through 0.22µm filter and the absorbance of the solution was measured by UV spectroscopy (1800, Shimadzu, Japan) at 257nm. Results were based on triplicate determination, was calculated using following formula.10

 

Scanning electron microscopy (SEM):

SEM photographs were taken with a Scanning electron microscopy at the desired magnification. The photographs were observed for morphological features and to confirm spherical nature of the micelles. SEM was performed using Hitachi and SEM at 5 kV having different magnifications using Hitachi Noran System 7 manufactured by Thermo Fisher Scientific.11

 

In vitro drug release studies:

The release behavior of Olmesartan Medoxomil from the formulations was carried out by dialysis method. Polymeric micelles were taken into an end sealed dialysis bag (MWCO = 1200-1400D), which was submerged in 50ml of phosphate buffer solution 7.4 at 37 ±0.5ºC with constant stirring at 100rpm under sink conditions. At appropriate time intervals, 1 ml sample was withdrawn and replaced with an equal volume of fresh medium. The withdrawn sample was filtered and analyzed for the OLM using UV spectrophotometer (1800, Shimadzu, Japan) at 257nm.12

 

RESULTS AND DISCUSSION:

Pure drug and the drug with the different polymers were subjected to FT-IR analysis for compatibility studies in order to ascertain compatibility between the drug and the polymer used. The FT-IR spectra obtained for OLM pure drug and the physical mixture of OLM with SoluPlus and Pluronic F127 are shown in Figure 4 and Figure 5 respectively. Both the drug and drug with polymer showed characteristic peaks of C-H Stretching, C=O Stretching, N-H stretching vibration, Aromatic C-H plane deformation, Aromatic -O-CH3. It was evident that there was no appearance of new peaks or any absence of existing peaks in the spectra of formulation, which suggests that the drug and polymer used for the formulation are compatible.

 

Figure 1: FTIR spectrum of Olmesartan Medoxomil pure drug, Olmesartan Medoxomil with SoluPlus and Olmesartan Medoxomil with Pluronic F127

 

Differential Scanning Calorimetric Studies:

DSC studies were carried out for pure drug and formulations. The thermograms obtained are shown in Figure 2. From the phase transition study, it was observed that DSC thermogram of pure drug showed a sharp endothermic peak at, which corresponds to its melting point. DSC thermogram of formulations containing Olmesartan Medoxomil and SoluPlus showed two endothermic peaks at corresponding to their melting point respectively. DSC thermogram of formulation containing Olmesartan Medoxomil and Pluronic F127 showed two endothermic peaks at and. The thermograms revealed no interaction between the drug and the polymer.

 

Figure 2: DSC thermograms of Olmesartan Medoxomil, Olmesartan Medoxomil and Soluplus micelles, Olmesartan Medoxomil and Pluronic F127 micelles.

 

Evaluation of Olmesartan Medoxomil Polymeric Micelles:

Particle size determination:

Particle size of SoluPlus and Pluronic F 127 micelles was 106.04 and 105.11nm, indicate a small and favourable particle size and distribution (Table 1 and Figure 3). The overall size of the micelles is primarily depending on the ratio of hydrophilic to hydrophobic block in the copolymer. Since hydrophobic block length is significantly greater than hydrophilic block length, SoluPlus micelles showed large particle size than Pluronic micelles.

 

Zeta potential:

Zeta potential is a measure of electrostatic attraction/repulsion between adjacent, similarly charged particles. The significance of zeta potential is that, it is an aid in predicting the stability of the colloidal dispersion. Particles with large positive or negative zeta potential tend to have better resistance against aggregation stability. PMs Zeta potential mainly depends on the chemical nature of the polymer and size of the particles. It was shown that formulations of Olmesartan Medoxomil loaded PMs prepared using SoluPlus and Pluronic F127, have negative surface charges (Table 1 and Figure 3). For particles with small size, a high zeta potential was observed which confers the stability.

 

Polydispersity index (PDI):

Polydispersity index is a parameter used to define the particle size distribution of PMs. It is the ratio of standard deviation to mean particle size, therefore indicates the uniformity of particle size within the formulation (Table 1 and Figure 3). PDI is a dimensionless number and varies from a value of 0.01 for mono dispersed particles up to values around 0.5-0.7. Higher the polydispersity, lower is the uniformity of the particle size in the formulation. The polydispersity value was less than 1.

 

Table 1: Particle Size, Zeta Potential and Polydispersity index of OLM Polymeric Micelles

Formulation

Particle Size (nm)

Zeta Potential (mV)

Polydispersity Index (PDI)

OLM loaded SoluPlus micelles

106.04

-25.2

0.212

OLM loaded Pluronic F127 micelles

105.11

-23.1

0.219


Figure 3: Particle Size, Zeta Potential and Polydispersity index of OLM Polymeric Micelles

 


 

Determination of drug loading and encapsulation efficiency:

The encapsulation efficiency of drug in the micelles was 84.13% and 72.32%, which implies that most of the drug was encapsulated in the micelles (Table 2). The hydrophilic- lipophilic balance (HLB) of block polymer is a parameter that governs the drug-loading capacity of polymer micelles. SoluPlus micelles showed more drug loading, than pluronic micelles.

 

Table 2: Drug loading and encapsulation efficiency of PMs.

Formulation

Drug loading (%) ± SD*

Encapsulation Efficiency (%) ± SD*

OLM SoluPlus micelles

5.6± 0.179

84.13±0.471

OLM Pluronic micelles

4.2±0.069

72.32±0.117

*Mean± S.D: n=3

 

Scanning Electron Microscopy (SEM):

The shape and surface morphology of the OLM PMs was observed by SEM. The SEM images (Figure 4) showed that polymeric micelles formed were roughly spherical without any deformations. The smooth surface of PMs indicates that the polymeric micelles are around 100nm.

 

Figure 4: SEM image for OLM loaded SoluPlus Micelles and OLM loaded Pluronic F127 Micelles

 

In vitro drug release studies:

In vitro drug release results showed that the micellar carrier enhanced the drug release due to increased dissolution rate. Small particle size of micelles improved drug release and provided larger interfacial area across, from which drug can diffuse and hence improves dissolution rate. The drug release of OLM loaded micelles in SoluPlus and Pluronic F127 micelles in pH 7.4 buffer is shown in Figure 5. Both soluplus and pluronic micelles showed improved dissolution than pure drug. Among soluplus and pluronic, soluplus shows better dissolution than pluronic micelles. This may be attributed to low CMC value of soluplus which formed more micellie than pluronic.

 

Figure 5: In-vitro drug release profile of polymeric micelles in 7.4 PBS

 

CONCLUSION:

The present work was carried out to improve the dissolution behaviour of a poorly water-soluble Olmesartan Medoxomil (class II drug), by forming polymeric micelles (PMs) of SoluPlus and Pluronic F127. The compatibility was confirmed by FT-IR and DSC studies. The formulations w for particle size was found to be 105.11 and 106.04 nm for soluplus and pluronic micellies respectively., Zeta Potential was found to be -25.2 and -23.1 respectively, Hence stable. Scanning Electron Microscopy (SEM) analysis studies revealed that the micelles are spherical in shape. The drug loading efficiency was more for SoluPlus micelles compared to Pluronic F127 micelles. The drug release from the SoluPlus micelles was higher than the Pluronic micelles. These results suggest that the polymeric micelles can be used to increase the solubility of poorly water-soluble drugs.

 

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Received on 26.04.2020            Modified on 23.05.2020

Accepted on 04.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):2200-2204.

DOI: 10.52711/0974-360X.2021.00390