1. INTRODUCTION:

Till the date for majority of the therapeutically active agents, oral route is the major route of drug administration. Intrinsic solubility and rate of dissolution of drug are very critical and important critical parameters for the drug oral absorption especially for poorly soluble or insoluble drugs. Similarly permeability of drug across the gastro intestinal tract is also crucial especially for highly hydrophilic drugs. Hence, dissolution is the rate limiting step for highly lipophilic drugs and permeation is the rate limiting steps for highly hydrophilic drugs in the process of their absorption from the gastro intestinal tract when they have administered through oral route.

Due to poor solubility/limited dissolution rate and poor/limited permeability, class II and or class IV drugs suffer less bioavailability thereby decreased therapeutic effect. Several techniques have been reported to improve the solubility and dissolution properties of poorly soluble drugs which intern can improve absorption and bioavailability [1-2].

Among the various techniques established, solid dispersion approach is one by which the bioavailability of BCS class II drug shall be significantly increased. This technique is most promising approach and has been proved to improve the bioavailability of poorly soluble drugs by several research scientists [3–5]. It was also reported that lipid based solid dispersion shall be prepared with using lipid based hydrophilic carriers by which the bioavailability of class II drugs have been increased by improving the drug dissolution rate and bioavailability of class IV drugs have been increased by improving both the dissolution and permeability [6-10].

Olmesartan Medoxomil, novel prodrug, is a selective angiotensin II receptor blocker that is approved in the treatment of hypertension. As it is a prodrug, it undergoes rapid de-esterification in the GIT before its absorption and produces its active form olmesartan. Though it is administered as prodrug, still the drug is having very less oral bioavailability of about 26% in healthy humans as the drug belongs to BCS class II and due to unfavorable breakage of the ester drug to a poorly permeable parent molecule in the gastrointestinal fluids [11-15].

Hence, the objective of the present work was to enhance the solubility, dissolution rate and permeability and hence the oral bioavailability of poorly soluble BCS Class II drug, olmesartan medoxomil using lipid based solid dispersion approach.

2. MATERIALS AND METHODS:

2.1 Materials:

Olmesartan medoxomil was received as a gift sample from Alembic Pharma Ltd., Baroda, India. The following materials were gifted by Abitec Corp., USA and were used as received: Gelucire 44/14 and Gelucire 50/13 were received as gift samples from Gattefosse. Pearlitol SD 200, were received from Signet, India.

2.2 Saturation Solubility Studies:

Saturation solubility studies of Olmesartan medoxomil was done in various buffers and non volatile liquid vehicles. Excess amount of drug was added to two mL of each solvent in a screw capped vial and were kept on isothermal mechanical shaker at 25°C for 72 hours. After equilibrium/saturation, each solution was centrifuged at 5000 rpm for 30 minutes. Supernatant was collected and filtered through membrane filter using 0.45 μm filter disk. Filtered solution was appropriately diluted with methanol, and UV absorbances were measured at 249 nm wavelength. Concentration of dissolved drug was determined using standard equation.

2.3 Phase solubility studies:

Phase solubility studies were done by taking different concentrations of Gelucire 44/14 and Gelucire 50/13 (1%, 3%, 5%, and 7%) in distilled water. To each of these concentrations excess amount of drug was added. Then these solutions were kept for shaking on shaker for 48 hours. After 48 hours samples were filtered through the Whatman filter paper then the solution diluted and estimated for olmesartan concentration using UV-spectroscopy at 249 nm. Three determinations were carried out for each sample to calculate the solubility.

2.4. Preparation of Lipid Based Solid Dispersions.:

Lipid based solid dispersions of olmesartan were prepared by using different hydrophilic lipid based carriers such as gelucire 44/14 and gelucire 50/13 in different ratios such as 1:1,1:2 and 1:3. These ratios were decided based on the results obtained in phase solubility studies. Pearlitol SD 200 was used as inert carrier in all the formulations. Compositions of various formulations are given in the Table 1. LBSD of olmesartan were prepared by solvent evaporation method. Olmearatn 40 mg was taken and dissolved in 10 ml solvent mixture of ethanol and dichloromethane. To the drug required quantity of lipid based carrier and porous inert carrier were added. This solution was taken into round bottom flask, attached to the rotary flash evaporator and evaporated at 37°C, rpm was 60 for 15 min. Solid dispersions were obtained, collected and dried in the dessicator till it was completely dried.

Table 1: Composition of Lipid Based Solid Dispersions

Name of the Ingredient	OSD1	OSD2	OSD3	OSD4	OSD5	OSD6
Olmesartan Medoxomil API	40	40	40	40	40	40
Gelucire 44/13	40	80	120	--	--	--
Gelucire 50/13	--	--	--	40	80	120
Pearlitol SD 200	120	80	40	120	80	40
Total Unit Weight (mg)	200	200	200	200	200	200

2.5. Evaluation of Formulations:

Flowability of admixture is important in formulation of tablet dosage form on industrial scale. Therefore, it was essential to study the flowability of these solid dispersion powder admixtures. Flowability can be evaluated using parameters such as Carr’s index, angle of repose, and Hausner’s ratio.

2.5.1. Angle of Repose:

The angle of repose of powder blend was determined by fixed height funnel method. Angle of repose (θ) was calculated using the following equation:

θ = Tan^‑1 (h/r)

Where ‘h’ and ‘r’ are the height and radius of powder cone.

2.5.2. Compressibility Index:

The compressibility index of the powder blend was determined by Carr’s compressibility index. The formula for Carr’s index is as below:

2.5.3. Hausner’s Ratio:

Hausner’s ratio was calculated from the equation:

Hausner’s Ratio = Tapped Density/Bulk Desnity

2.5.4. Content Uniformity:

Weight equivalent (200mg) to one unit dose of olmesartn medoxomil (40mg) of each formulation was accurately weighed and transferred into a 100 mL volumetric flask. Initially, 10 mL of methanol was added and shaken for 10 min. Then, the volume was made up to 100 mL with phosphate buffer pH 6.8. The solution in the volumetric flask was filtered, diluted suitably, and analyzed spectrophotometrically at 249 nm using UV-visible double-beam spectrophotometer (UV1800, Shimadzu, Japan).

2.5.5. Saturation Solubility Studies:

Saturation solubility studies of all the prepared formulations were done in water using the same method as mentioned above

2.5.6. In-Vitro Drug Release Study:

The in vitro drug release study of the prepared formulations, marketed formulation and pure drug were performed using USP type II apparatus paddle (EDT-08L, Shimadzu, Japan) at 37°C ± 0.5°C using phosphate buffer pH 6.8 (900 mL) as a dissolution medium and 50 rpm. At the predetermined time intervals, 10 mL samples were withdrawn and replaced with fresh dissolution media. Withdrawn samples were filtered through a 0.45 μm membrane filter, diluted, and assayed at 249 nm using a Shimadzu UV-1800 double-beam spectrophotometer. Cumulative percentage drug release was calculated using an equation obtained from a calibration curve.

2.5.7. Ex vivo permeability studies:

The ex vivo permeability studies were conducted by using goat intestinal membrane after approval from Institutional Animal Ethics Committee (IAEC Number: 517/01/A/CPCSEA). Intestinal membranes of goats were collected from local animal slaughter house. Male goats were used to obtain freshly excised fully thickness intestinal membrane. Care was taken while collecting the intestinal membrane to prevent the damage of epidermal layer. An open ended glass tube was taken; goat intestinal membrane (0.025cm) was stretched over the one end of the glass tube. Tube was immersed in 250 ml beaker containing 100 ml of 7.4pH phosphate buffer and kept in vertical position so that the membrane touches the (1-2mm deep) surface of the buffer solution. The surface area available for the drug diffusion was 1.76 cm². The glass tube (donor) and beaker (acceptor) both were maintained at 37^ºC±0.5ºC by keeping the entire set up on hot plate magnetic stirrer. Beaker was maintained at 100 rpm throughout the experiment. Weight equivalent to 40 mg of optimized formulation (OSD3), pure drug and marketed formulation (Olmezest; powdered) was added in 5ml of 7.4 pH phosphate buffer and placed in donor compartment. At predetermined time intervals 5mL samples were collected from acceptor compartment and replaced with fresh buffer. Samples were analyzed spectrophotometrically after suitable dilution with buffer at 249nm. The study was conducted for a period of 6 hrs and amount of drug diffused was calculated from standard graph at each time interval.

3. RESULTS AND DISCUSSION:

3.1. Saturation Solubility Studies:

Solubility data of drug olmesartan medoxomil in various liquid vehicles is shown in Figure 1. Olmesartan appears to be more soluble in alkaline pH than acidic pH.

Figure 1: Solubility of Olmesartan in different solvents

3.2. Phase Solubility Studies:

Phase solubility studies were performed in different concentrations of gelucire 44/14 and 50/13 and the values obtained were represented in bar chart which is shown in Figures 2. It was observed that the phase solubility of drug is increased with the increased concentration of carrier.

Figure 2: Phase Solubility Study Results of Olmesartan

Table 3: Results of Formulations

Parameters	Formulations
Parameters	Pure Drug	OSD1	OSD2	OSD3	OSD4	OSD5	OSD6
Bulk Density	0.36	0.56	0.62	0.72	0.59	0.61	0.77
Tapped Density	0.65	0.63	0.73	0.78	0.68	0.71	0.86
Angle of Repose (º)	45.5	21.5	16.4	16.4	17.8	19.2	19.5
Carr's Index	44.6	11.1	15.1	7.7	13.2	14.1	10.5
Hausner's Ratio	1.8	1.1	1.2	1.1	1.2	1.2	1.1
Content Uniformity (%)	100.2	98.8	99.8	99.2	99.2	99.3	99.2

3.3. Evaluation of Formulations

3.3.1. Micromeritics Parameters:

Good flow is required and is crucial for content uniformity. The results of various flow parameters are shown in Table 3. All the formulations have shown good and improved flow compared to pure drug. This could be probably due to the presence of pearlitol.

3.3.2. Content Uniformity:

All the prepared formulations were found to uniform in their drug content.

3.3.3. Saturation Solubility studies:

Results of saturation solubility studies are shown in figure 3. It was observed that all the prepared formulations has shown improved solubility in water and the formulation prepared with gelucire 44/13 carrier at 1:3 ratio (OSD3) has comparatively higher solubility than other formulations.

Figure 3: Saturation Solubility results of Lipid based solid dispersions in water

3.3.4. In Vitro Dissolution Studies:

The dissolution profiles of the pure drug, marketed formulation and lipid based solid dispersions formulations are shown in Figures 4. It was observed that the dissolution rate has been increased significantly compared to the pure drug formulation and marketed formulation. Formulation OSD3 has shown highest drug release in 30 minutes. Improved drug dissolution might be due to the high intrinsic solubility of drug in presence of gelucire 44/14 and hydrophilic coat formation of Pearlitol SD200 surrounding the drug.

Figure 4: Dissolution Profile of Lipid Based Solid Dispersions

3.3.5. Ex vivo Permeability Study:

Ex vivo permeation studies were conducted for 6 hrs using goat intestinal membrane for the optimized formulation, pure drug and marketed formulations. Amount of drug diffused at various time intervals was calculated. Graph was plotted by taking amount of drug permeated on Y-Axis and time on X-axis and shown in Fig. 5. From the results it was noticed that optimized formulation have shown greater amount of drug permeation through membrane than the marketed and pure drug at each time interval.

Figure 5: Ex vivo permeability of Lipid Based Solid Dispersions

4. CONCLUSION:

In the present study, the potential of lipid based solid dispersions to improve the bioavailability of water-insoluble drug Olmesartn Medoxomil was investigated. The results showed that saturation solubility, dissolution and ex vivo permeability has been increased to greater extent. Thus lipid based solid dispersion technology shall be used to improve the bioavailability of poorly water soluble drugs that will make the dosage form will be cost effective.

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Received on 25.10.2019 Modified on 26.12.2019

Research J. Pharm. and Tech 2020; 13(5):2096-2100.

DOI: 10.5958/0974-360X.2020.00377.7