Olmesartan medoxomil (OLM) is an angiotensin II receptor blocker (ARB) antihypertensive agent administered orally that has absolute bioavailability of only 26% due to the poor aqueous solubility (7.75
Approximately, 40% of the new drug candidates in development today are water insoluble and associated with poor bioavailability. There were various formulation approaches reported to overcome these problems; these include the use of drug nanoparticles, solid dispersions, micronization, lipids, surfactants, complexation with cyclodextrin, and permeation enhancers [
Olmesartan medoxomil is a novel selective angiotensin II receptor blocker that is approved for the treatment of hypertension. It is a prodrug that is rapidly deesterified during absorption from the gastrointestinal tract to produce an active metabolite, olmesartan. However, the oral BA of olmesartan medoxomil was only 26% in healthy humans due to low solubility in water and unfavorable breakage of the ester drug to a poorly permeable parent molecule in the gastrointestinal fluids [
SMEDDSs are isotropic and thermodynamically stable solutions consisting of an oil, surfactant, cosurfactant (CoS; or solubilizer), and drug mixtures that spontaneously form oil-in-water (o/w) microemulsions when mixed with water under gentle stirring. The motility of stomach and intestine provides the agitation required for self-emulsification
Thus, improving solubility and dissolution rate of olmesartan medoxomil can increase clinical efficacy or reduce the oral dosage required to achieve the same effect. Therefore, we use SMEDDS formulation with Acrysol EL135 as oil, Tween 80 as a surfactant, and Transcutol P as a co-surfactant to enhance the solubility and dissolution velocity of olmesartan medoxomil. The formulation was characterized for its ability to form microemulsions based on droplet size, zeta potential, and dissolution characteristics.
Olmesartan medoxomil was obtained as a gift sample from Alembic Pharma Ltd., Baroda, India. The following materials were gifted by Abitec Corp., USA, and were used as received: Capmul MCM (Glycerol monodicaprylate), Acconon C-80 (Polyoxyethylene 80 Coconut Glycerides), Captex 200 (Propylene Glycol Dicaprylocaprate), and Captex 355 (Glyceryl Tricaprylate). Transcutol P (highly purified diethylene glycol monoethyl ether), Plurol Oleique (polyglyceryl-3 dioleate), labrafil M 2125CS (linoleoyl macrogol-6 glycerides), Lauroglycol 90 (propylene glycol monolaurate) were received as gift sample from Gattefosse, France. Acrysol K 140 (polyoxyl 40 hydrogenated castor oil) and Acrysol El 135 (Polyoxyl 35 castor oil) were also gifted from Corel Pharma Chem., Ahmedabad, India. Tween 80 (polyoxyethylene sorbitan monooleate), Tween 60 (polyoxyethylene sorbitan monostearate), and propylene glycol were bought from Finar Chemical Limited, Ahmedabad, India. Polyethylene glycol 200 (PEG 200) and polyethylene glycol 400 (PEG 400) were bought from S. D. Fine Chemical Limited, Mumbai, India. Sunflower oil and castor oil were purchased from Gujarat Glycol Private Limited, Ankaleshwar, India, and Kush Proteins Private Limited, Anand, India. Double distilled water was used throughout the study. All other chemicals were of reagent grade.
FTIR spectra of olmesartan medoxomil and formulation.
In a similar manner, calculations for the other ratios of oil and Smix were also done. For each Smix ratio, a separate phase diagram was constructed, and for each phase diagram visual observations were recorded. The pseudoternary phase diagram (Figure
Selected formulations at a different % vol./vol. of oil, surfactant, and co-surfactant.
Formulation Code | Composition (% vol./vol.) | ||
---|---|---|---|
Acrysol El 135 | Tween 80 | Transcutol P | |
S1 | 30 | 35 | 35 |
S2 | 34 | 33 | 33 |
S3 | 36 | 32 | 32 |
S4 | 40 | 30 | 30 |
All experiments and protocols described in this study were approved by the Institutional Animal Ethics Committee (IAEC), and all experiments were conducted as per the norms of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Social Justice and Empowerment, Government of India. Male Wister rats (250–300 g) were sacrificed by CO2 inhalation method. Intestine was isolated and cleaned properly. One milliliter of the OLM SMEDDS and plain drug suspension sample (5 mg/mL) was filled into the intestine which was tied at both ends. The tissue was placed in an organ bath with continuous aeration at 37°C. The receptor compartment (organ tube) was filled with 30 mL of phosphate-buffered saline pH 7.4 with 1% sodium lauryl sulphate. At predetermined time intervals, samples were withdrawn from the receptor compartment [
Solubility studies were aimed at identifying a suitable oily phase for the development of the OLM SMEDDS. Identifying the suitable oil having the maximal solubilizing potential for the drug under investigation is very important to achieve optimum drug loading [
Solubility of olmesartan medoxomil in few oils, surfactants, and cosurfactants.
Vehicle | Function in SMEDDS | Avg. solubility* |
---|---|---|
(mg/mL) | ||
Capmul MCM | Oil |
|
Sunflower oil | Oil |
|
Castor oil | Oil |
|
Plurol Olieque | Oil |
|
Labraphil | Oil |
|
Lauroglycol | Surfactant |
|
Transcutol | Cosurfactant |
|
Captax200 | Surfactant |
|
Captax355 | Surfactant |
|
Propylene glycol | Cosurfactant |
|
Tween 80 | Surfactant |
|
Tween 60 | Surfactant |
|
Acconon C80 | Cosurfactant |
|
Acrysol EL135 | Oil |
|
PEG 200 | Co-surfactant |
|
PEG 400 | Co-surfactant |
|
*Values are expressed as mean ± SD (
Nonionic surfactants are generally considered less toxic than ionic surfactants. They are usually accepted for oral ingestion [
Emulsification efficiency of various surfactants, and cosurfactants.
Surfactants/co-surfactants | Transparency*(%) | No. of inversions* |
---|---|---|
Tween 80 | 99.8 | 5 |
Tween 20 | 98 | 15 |
Span 80 | 50.5 | 40 |
Transcutol P | 100 | 5 |
Plurol Oleique | 88.6 | 25 |
PEG 200 | 98.1 | 35 |
PEG 400 | 99.3 | 30 |
Propylene glycol | 99.4 | 10 |
Capmul MCM C-8 | 80 | 40 |
*Values are expressed as mean (
Addition of a co-surfactant to the surfactant-containing formulation was reported to improve dispersibility and drug absorption from the formulation [
Pseudoternary phase diagrams were constructed in the absence of OLM to identify the self-emulsifying regions and to optimize the concentration of oil, surfactant, and co-surfactant in the SMEDDS formulations. A series of the SMEDDSs were prepared, and their self-emulsifying properties were observed visually. The phase diagrams were constructed at surfactant/co-surfactant ratios of 1 : 1, 1.5 : 1, and 2 : 1 (v/v). Phase diagram of different surfactant and co-surfactant ratio is shown in Figure
(a) Surfactant/co-surfactant 1 : 1, (b) surfactant/co-surfactant 1.5 : 1, and (c) surfactant/co-surfactant 2 : 1. Pseudoternary phase diagram of the system, Acrysol EL 135, Tween 80: Transcutol P, and water.
Particle size distribution of batches S1 to S4.
Particle Size Distribution of Batch S1
Particle Size Distribution of Batch S2
Particle Size Distribution of Batch S3
Particle Size Distribution of Batch S4
Based on above results, a three-component SMEDDS formulation was established containing 34% Acrysol EL 135 as oil (on the basis of the solubility study and required target amount of OLM, 20 mg), 33% Tween 80 as the surfactant, and 33% Transcutol P as the co-surfactant (on the basis of phase diagrams). Four SMEDDS formulations were prepared, and their self-emulsifying performance was compared.
In the self-emulsifying systems, the free energy required to form an emulsion was very low, thereby allowing a spontaneous formation of an interface between the oil droplets and water. Moreover, since the drug released will be in nanosize, it will increase the effective surface area for dissolution.
The efficiency of self-emulsification could be estimated primarily by determining the rate of emulsification which is an important index for the assessment of the efficiency of emulsification, that is, the SMEDDS should disperse completely and quickly when subjected to aqueous dilution under mild agitation. The emulsification time of these formulations was in the range of 15 to 35 sec (Table
Evaluation parameters of formulations (S1 to S4).
Formulation code | Emulsification time (sec)* | Particle size in water (nm)* | Zeta potential (mV)* | Drug content*(%) |
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S1 |
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S2 |
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S3 |
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S4 |
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*Values are expressed as mean ± SD (
The droplet size of the emulsion is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as absorption [
Zeta potential can be defined as the difference in potential between surface of the tightly bound layer (shear plane) and the electroneutral region of an emulsion. It has got practical application in the stability of emulsion since
Dissolution studies were performed for the SMEDDS formulations in phosphate buffer pH 6.8, and the results were compared with the pure drug (Figure
Dissolution profile of SMEDDS formulations and plain drug.
Irrespective of difference in composition, the drug content of formulations S1 to S7 was found in range of 99.35–101.79% (Table
Optical clarity measured by directly taking the absorbance of the diluted SMEDDS is a measure of droplet stability. The result indicates that formulation S2, and S3 were well stable till 24 hrs as their absorbance values did not change at the end of 24 hrs. Moderate changes in absorbance values were observed for formulation S1 at the end of 24 hrs. For formulation S4, a drastic change in absorbance values was observed indicating instability of droplets with time (Table
Variation in optical clarity with time in water.
Formulation code | Absorbance at 400 nm* | ||
---|---|---|---|
0 hrs | 6 hrs | 24 hrs | |
S1 | 3.2290 ± 0.0012 | 3.2000 ± 0.0026 | 3.0897 ± 0.0024 |
S2 | 0.0467 ± 0.0021 | 0.0472 ± 0.001 | 0.0479 ± 0.0001 |
S3 | 0.0570 ± 0.0011 | 0.0650 ± 0.0003 | 0.0671 ± 0.0022 |
S4 | 0.2990 ± 0.0013 | 0.3200 ± 0.0036 | 0.3506 ± 0.0026 |
*Values are expressed as mean ± SD,
The results of the
It was concluded that SMEDDS formulations containing olmesartan medoxomil significantly increase in the dissolution rate and
The authors are very thankful to Alembic Pharma Ltd. (India), Abitec Corp. (USA), Gettefosse (France), BASF (India), and Corel Pharma (India) for providing gift samples. All the authors agree that the contents of the paper are confidential and will not be copyrighted, submitted, or published elsewhere (including the Internet), in any language, while acceptance by the journal is under consideration. There is no any financial conflict of interests.