3. literature review - inflibnetshodhganga.inflibnet.ac.in/bitstream/10603/37531/9/09...3....

3. Literature Review


Akshay R. Koli 60

Contents

3.1 Review of work done on microemulsion and self- microemulsifying drug

delivery system.......................................................................................... 62

3.1.1 Review of work done on Oral microemulsion ..................................... 62

3.1.2 Review of work done on Self Microemulsifying drug delivery systems 68

3.1.2.1 Review of work done on Solid Self Microemulsifying Drug Delivery

System………………………………………………………………………………………….…………….73

3.2 Review of work done on drugs used in the study....................................... 76

3.2.1 Felodipine ........................................................................................... 76

3.2.2 Valsartan ............................................................................................ 79

3.3 Review of work done on excipients used in the study ............................... 84

3.3.1 Capmul MCM...................................................................................... 84

3.3.2 Polysorbate 20 and Polysorbate 80 .................................................... 87

3.3.3 Polyethylene Glycol 400 ..................................................................... 90

3.4 References................................................................................................. 93


Akshay R. Koli 61

List of Tables

Table 3.1: Bioavailability enhancement of some drugs using microemulsion /

SMEDDS technique ............................................................................. 67

Table 3.2: Marketed Lipid- based and Surfactant-based Drug Formulation ......... 92


Akshay R. Koli 62

3.1 Review of work done on microemulsion and self-

microemulsifying drug delivery system

3.1.1 Review of work done on Oral microemulsion

Solanki SS et al. (2012) enhanced the dissolution rate and bioavailability of Ampelopsin,

one of the most common flavonoids by developing microemulsion. Capmul MCM-based

ME formulation with Cremophor EL as surfactant and Transcutol as cosurfactant was

developed for oral delivery of ampelopsin. The optimised microemulsion formulation

containing ampelopsin, Capmul MCM (5.5%), Cremophor EL (25%), Transcutol P

(8.5%), and distilled water showed higher in vitro drug release, as compared to plain drug

suspension and the suspension of commercially available tablet. These results

demonstrate the potential use of ME for improving the bioavailability of poor water

soluble compounds, such as ampelopsin[1]

.

Gundogdu E et al. (2012) formulated imatinib (IM) loaded to oral water-in-oil (w/o)

microemulsions as an alternative formulation for cancer therapy and evaluated the

cytotoxic effect of microemulsions Caco-2 and MCF-7. Moreover, permeability studies

were also performed with Caco-2 cells. According to cytotoxicity studies, all

formulations did not exert a cytotoxic effect on Caco-2 cells. The permeability studies of

IM across Caco-2 cells showed that permeability value from apical to basolateral was

higher than permeability value of other formulations. In conclusion, the microemulsion

formulations as a drug carrier, especially M3IM formulation, may be used as an effective

alternative breast cancer therapy for oral delivery of IM[2]

.

Du H et al. (2012) reform the dosage forms of andrographolide to improve its aqueous

solubility and oral bioavailability. An formulation of O/W microemulsion consisting of

an oil phase of isopropyl myristate, a surfactant phase of Tween 80, a co-surfactant of

alcohol, and water was found to be ideal, with mean droplet size of 15.9 nm, a high

capacity of solubilisation for andrographolide. Such an andrographolide-loaded

microemulsion was stable by monitoring the time, temperature and gravity-dependent

change, and had a much better anti-inflammatory effect and a higher biological

availability than andrographolide tablets[3]

.


Akshay R. Koli 63

Park JH et al. (2011) investigated the effects of silymarin, on oral bioavailability of

paclitaxel in rats, and to compare pharmacokinetic parameters of paclitaxel between a

commercial formulation of paclitaxel and a paclitaxel microemulsion. Oral bioavailability

of paclitaxel in a Taxol® formulation was enhanced in the combination with silymarin. In

particular, the mean maximum plasma concentration and the mean area under the plasma

concentration-time curve of paclitaxel in the formulation were significantly increased 3-

fold and 5-fold compared with control, respectively, following oral co-administration

with 10mg/kg of silymarin (p<0.01). When the paclitaxel microemulsion was co-

administered with silymarin orally, it caused a maximum increase in the absolute

bioavailability of paclitaxel [4]

.

Thakkar H et al. (2011) developed microemulsion and Self-Microemulsifying Drug

Delivery System (SMEDDS) formulations of Raloxifene. The results indicated that high

drug loading, optimum size and desired zeta potential and transparency could be achieved

with both SMEDDS and microemulsion. The in vitro intestinal permeability results

showed that the permeation of the drug from the microemulsion and SMEDDs was

significantly higher than that obtained from the drug dispersion and marketed

formulation[5]

.

Nagariya K et al. (2010) prepared oral microemulsion of Isotretinoin for improvement

of bioavailability. A captex-355-based microemulsion formulation with cremophor EL as

surfactant and ethanol as co-surfactant was developed for oral delivery of isotretinoin.

The in vitro diffusion study revealed an increase of bioavailability (38.56 times) after in

vitro drug diffusion analysis of the microemulsion formulation as compared with the

commercially available soft gelatin capsules[6, 7]

Patel V et al. (2010) developed microemulsion for solubility enhancement of

Clopidogrel. Solubility of Clopidogrel was successfully enhanced by 80.66 times, via

capmul microemulsion, compared with distilled water[8]

.

Mandal S et al. (2010) formulated Carbamazepine mucoadhesive microemulsion.

Carbamazepine microemulsion (CME) was prepared using labrafil M 1944 CS as oil,

accenon CC as surfactant and transcutol P as co-surfactant by water titration method.


Akshay R. Koli 64

Mucoadhesive microemulsion containing Carbamazepine (CMME) was prepared using

carbopol 934. Results from 8 hrs ex-vivo release study revealed that CME and CMME

showed 29% and 17.6% higher drug release than that of plain drug solution of

Carbamazepine (PDSC)[9]

.

Piao HM et al. (2010) developed a microemulsion of Fexofenadine for intranasal

delivery. Nasal absorption of Fexofenadine from these microemulsions was found to be

fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg

dose, and the absolute bioavailability (0–4 h) was about 68% compared to the intravenous

administration in rats[10]

.

Chaudhari SP et al. (2010) formulated and evaluated thermoreversible mucoadhesive

microemulsion based in-situ gel (TMMIG) of an anti-osteoporotic agent, Raloxifene

(RLX). On the basis of results obtained TMMIG lead to increased in bioavailability of

RLX when tested in suitable in vivo model[11]

.

Yin YM et al (2009) prepared a microemulsion system of docetaxel and evaluated for its

solubilization capacity and oral bioavailability improvement. Based on a solubility study

and pseudo ternary phase diagrams, microemulsions of about 30 nm in mean diameter

were formulated with improved solubilization capacity towards the hydrophobic drug,

docetaxel. Both the ultrafiltration and dialysis studies revealed that the release of 80% of

docetaxel from the microemulsions within 12 h in vitro. Compared to the commercial

product Taxotere, the apical to basolateral transport of docetaxel across the Caco-2 cell

monolayer from the Microemulsion formulation was significantly improved. Moreover,

the oral bioavailability of the M-3 formulation in rats (34.42%) rose dramatically

compared to that of the orally administered Taxotere (6.63%)[12]

.

Mandal S et al. (2009) prepared microemulsion of Saquinavir for oral bioavailability

enhancement. In vivo oral absorption of Saquinavir from the microemulsion containing

labrafac CM10 (4.0%), tween 80 (36.0%), polyethylene glycol 400 (9.0%) and distilled

water (51%) was investigated in rats. The in vitro intraduodenal diffusion and in vivo

study revealed an increase of bioavailability (10.68 times) after oral administration of the

microemulsion formulation as compared with the commercially available tablets[13]

.


Akshay R. Koli 65

Nornoo AO et al. (2009) developed cremophor-free oral microemulsions of paclitaxel

(PAC) to enhance its permeability and oral absorption. Oral microemulsions of PAC

were developed that increased both the permeability and AUC of PAC as compared to

Control[14]

.

Karamustafa et al. (2008) prepared oral microemulsion formulation for Alendronate.

The release of Alendronate from the microemulsion formulation was examined by

dialysis method and found to be 97.2% at the end of 7 h. None of the parameters except

refractive index changed significantly during the determined periods. This study

succeeded in preparing a stable microemulsion formulation of Alendronate[15]

.

Date A et al. (2008) has investigated and evaluated the potential of the microemulsions

to improve the parenteral delivery of propofol. The propofol microemulsions were

evaluated for globule size, Physical and chemical stability, osmolarity, in vitro hemolytic,

pain caused by injection using rat paw-lick test and in vivo anesthetic activity. The

microemulsions exhibited globule size less than 25 nm and demonstrated good physical

and chemical stability. Rat paw-lick test indicated that propofol microemulsions were

significantly less painful as compared to the marketed propofol formulation[16]

.

Kantarci G et al. (2007) prepared and compared different W/O microemulsions

containing Diclofenac sodium. The in vitro release rate of diclofenac sodium (DS) from

microemulsion (M) vehicles containing soybean oil, nonionic surfactants (Brij 58 and

Span 80), and different alcohols (ethanol [E], isopropyl alcohol [I], and propanol [P]) as

co-surfactant. According to the release rate of DS, M prepared with P showed the

significantly highest flux value (0.059±0.018 mg/cm2/h) among all formulations (P< 0

.05). A skin irritation study was performed with microemulsions on human volunteers,

and no visible reaction was observed with any of the formulations. In conclusion, M

prepared with P may be a more appropriate formulation than the other 2 formulations

studied as drug carrier for topical application[17]

.

Ghosh PK et al. (2006) developed microemulsion system of Acyclovir for improvement

of oral bioavailability. A labrafac-based microemulsion formulation with labrasol as

surfactant and plurol oleique as co-surfactant was developed for oral delivery of


Akshay R. Koli 66

Acyclovir. With the increase of labrasol concentration, the microemulsion region area

and the amount of water and labrafac solubilized into the microemulsion system

increased; however, the increase of plurol oleique percentage produced opposite effects.

Acyclovir, a poorly soluble drug, displayed high solubility in a microemulsion

formulation using labrafac (10%), labrasol (32%), plurol oleique (8%), and water (50%).

The in vitro intraduodenal diffusion and in vivo study revealed an increase of

bioavailability (12.78 times) after oral administration of the microemulsion formulation

as compared with the commercially available tablets[18]

.

Zhang Q et al. (2004) developed Nimodipine-loaded microemulsion for intranasal

delivery. The optimal microemulsion formulation consisted of 8% labrafil M 1944CS,

30% cremophor RH 40/ethanol (3:1) and water, with a maximum solubility of NM up to

6.4 mg/ml, droplet size of 30.3 ± 5.3 nm, and no ciliotoxicity. After a single intranasal

administration of this preparation at a dose of 2 mg/kg, the plasma concentration peaked

at 1 h and the absolute bioavailability was about 32%. The uptake of NM in the olfactory

bulb from the nasal route was three folds, compared with intravenous (i.v.) injection. The

ratios of AUC in brain tissues and cerebrospinal fluid to that in plasma obtained after

nasal administration were significantly higher than those after i.v. administration[19]

.

Kang BK et al. (2004) prepared SMEDDS for oral bioavailability enhancement of a

poorly water soluble drug, Simvastatin. The release rate of Simvastatin from SMEDDS

was significantly higher than the conventional tablet. Bioavailability was 1.5-fold higher

compared to that of the conventional tablet[20]

.

Gao ZG et al. (1998) investigated microemulsion system for oral delivery of

Cyclosporin A with improvement of solubility and bioavailability. Microemulsions with

varying weight ratios of surfactant to co-surfactant were prepared using captex 355 as an

oil, cremophor EL as a surfactant, transcutol as a co-surfactant and saline. The solubility

of Cyclosporin A in microemulsion systems reached the maximum with 2:1 mixture of

cremophor EL and trancutol. The maximal blood concentration (Cmax) of Cyclosporin A

and the area under the drug concentration-time curve (AUC) after oral administration of

this Cyclosporin A loaded microemulsion was 3.5 and 3.3 fold increased compared with


Akshay R. Koli 67

Sandimmun. The absolute bioavailability of Cyclosporin A loaded in this microemulsion

system was increased about 3.3 and 1.25 fold compared with Sandimmun and

Sandimmun Neoral. The enhanced bioavailability of Cyclosporin A loaded in this

microemulsion system might be due to the reduced droplet size of microemulsion

systems[21]

.

Table 3.1: Bioavailability enhancement of some drugs using microemulsion /

SMEDDS technique[22]

Sr.

No

Drug Category System

1 Paclitaxel Anticancer Microemulsion

SMEDDS

2 Fenofibrate

Antihyperlipidemic

SMEDDS

3 Cholesterol ester transfer protein

inhibitor

SMEDDS

4 Atorvastatin, Fluvastatin SMEDDS

5 Rapamycin Immunosuppresive SMEDDS

6 Cyclosporine SMEDDS

7 Nifedipine Antihypertensive Microemulsion

8 Indomethacin Analgesic SMEDDS

9 Ibuprofen SMEDDS

10 Tipranavir Anti HIV Microemulsion

11 Progesterone, testosterone Hormones SMEDDS

12 Vit A, D, E, K Nutrition

supplement

Microemulsion

13 Acyclovir Antiviral Microemulsion

14 Melatonin Immunomodulator Microemulsion


Akshay R. Koli 68

3.1.2 Review of work done on Self Microemulsifying drug

delivery systems

Mezghrani O et al. (2011) designed an optimized self micro-emulsifying drug delivery

system (SMEDDS) to enhance the bioavailability of the poor water soluble drug, astilbin.

Pseudoternary phase diagrams were used to select the components and their ranges by

evaluating the micro-emulsification area. In vitro drug release profile study was

performed using the reverse dialysis method where 95% of the drug was released after 4

h. The developed astilbin SMEDDS was subjected to bioavailability studies in beagle

dogs by LC-MS and showed a significant enhancement of bioavailability, indicating the

possibility of using SMEDDS as possible drug carrier for astilbin[23]

.

Cui J et al. (2009) prepared a self-microemulsifying drug delivery system to improve the

solubility and oral absorption of curcumin. Suitable compositions of SMEDDS

formulation were screened via solubility studies of curcumin and compatibility tests. The

optimal formulation of SMEDDS was comprised of 57.5% surfactant, 30.0% co-

surfactant and 12.5% oil (ethyl oleate). The solubility of curcumin (21 mg/g) significantly

increased in SMEDDS. The average particle size of SMEDDS-containing curcumin was

about 21 nm when diluted in water. No significant variations in particle size and

curcumin content in SMEDDS were observed over a period of 3 months at 4 degrees C.

The results of oral absorption experiment in mice showed that SMEDDS could

significantly increase the oral absorption of curcumin compared with its suspension[24]

.

Lee et al. (2009) Daewoong pharmaceuticals CO., Ltd. disclosed in WO Patent

WO/2009/022 the SMEDDS composition containing coenzyme Q 10 and method for

preparing the same. They claimed improvement in solubility and bioavalability using

polyglucerine fatty acid ester as surfactants and polyethylene-sorbitan fatty acid ester as

cosurfactant[25]

.

Ofokansi KC et al. (2009) used Peanut oil and Tween 80 blends devoid of any

cosurfactant and employed in the formulation of different batches of liquid SMEDDS and

their suitability as vehicles for the delivery of a typical lipophilic drug griseofulvin was

investigated. The release profile of griseofulvin from the optimized SMEDDS was


Akshay R. Koli 69

evaluated in citrate/phosphate buffer solutions of pH 2.0, pH 6.5, and pH 7.4. The release

of griseofulvin from the SMEDDS into aqueous media of pH 6.5 and pH 7.4 showed

enhanced and controlled dissolution of the drug from the formulation. Incorporation of

griseofulvin into this proposed formulation is suggested as a strategy to overcome the

irregular dissolution and absorption behaviors often associated with conventional

griseofulvin tablets[26]

.

Mandawgadea SD et al. (2008) has investigated SMEDDS of β-Artemether (BAM)

using a novel, indigenous natural lipophile (N-LCT) as an oily phase. SMEDDS based on

N-LCT and commercially available modified oil (capryol90) was formulated.

Comparative in vivo anti-malarial performance of the developed SMEDDS was evaluated

against the (Larither) in Swiss male mice infected with lethal ANKA strain of

Plasmodium berghei. Both the BAM–SMEDDS showed excellent self-

microemulsification efficiency and released >98% of the drug in just 15 min whereas

Larither showed only 46% drug release at the end of 1h. The anti-malarial studies

revealed that BAM–SMEDDS resulted in significant improvement in the anti-malarial

activity (P <0.05) as compared to that of (Larither) and BAM solubilized in the oily

phases and surfactant[27]

.

Zang Yao et al. (2008) has prepared nobiletin SMEDDS and investigate its intestinal

transport behavior using the single-pass intestinal perfusion (SPIP) method in rat. SPIP

was performed in each isolated region of the small intestine over three concentrations of

nobiletin and the effective permeability coefficients in rats were calculated. The intestinal

permeability of nobiletin in SMEDDS, sub-microemulsions and micelles was compared.

The Peff in jejunum at 15 µg/ml was significantly higher than that at 60 µg/mL (p< 0.01).

The estimated human absorption of nobiletin for the SMEDDS dilutions was higher than

that for sub-microemulsions (p<0.01) and similar to that of the micelles (p>0.05)[28]

.

Zhang P et al. (2008) developed SMEDDS of ordonin to enhance its oral bioavailability.

The influence of the oil, surfactant and co-surfactant types on the drug solubility and their

ratios on forming efficient and stable SMEDDS were investigated in detail. The

SMEDDS were characterized by morphological observation, droplet size and zeta-


Akshay R. Koli 70

potential determination, cloud point measurement and in vitro release study. In vitro

release test showed a complete release of Oridonin from SMEDDS in an approximately

12h. The absorption of Oridonin from SMEDDS showed a 2.2-fold increase in relative

bioavailability compared with that of the suspension[29]

.

Patel AR et al. (2007) formulated a SMEDDS of Fenofibrate and evaluated in-vitro and

in- vivo potential. SMEDDS formulations were tested for microemulsifying properties,

and the resultant microemulsions were evaluated for clarity, precipitation, and particle

size distribution. The optimized SMEDDS formulation showed complete release in 15

minutes as compared with the plain drug, which showed a limited dissolution rate. The

SMEDDS formulation significantly reduced serum lipid levels in phases I and II of the

triton test, as compared with plain Fenofibrate[30]

.

Liu L et al. (2007) formulated SMEDDS in order to enhance the solubility, release rate,

and oral absorption of the poorly soluble drug, Silymarine. In vitro release was

investigated using a bulk-equilibrium reverse dialysis bag method. Differences in the

release medium significantly influenced the drug release from SMEDDS and the release

profiles of Silymarine from SMEDDS was higher than that for commercial capsules, and

significantly higher than that for commercial tablets. The optimal formulation of

SMEDDS is an alternative oral dosage form for improving the oral absorption of

Silymarine[31]

.

Lanlan Wei et al. (2005) developed a new self-emulsifying drug delivery system and

SMEDDS of carvedilol to increase the solubility, dissolution rate, and ultimately, oral

bioavailability. The in vitro dissolution rate of carvedilol from SEDDS and SMEDDS

was more than two-fold faster compared with that from tablets. The developed SEDDS

formulations significantly improved the oral bioavailability of carvedilol significantly,

and the relative oral bioavailability of SEDDS compared with commercially available

tablets was 413%[32]

.

Lin J (2005) in US20060275358 demonstrated increase in solubility and dissolution of

poorly soluble active compounds like co-enzyme Q10 by SMEDDS comprising a


Akshay R. Koli 71

combination of a pair of hydrophilic and lipophilic surfactant. The formulations exhibited

excellent storage stability[33]

.

Peracchia M et al. (2005) in EP1498143 prepared Self microemulsifying formulation for

oral administration of taxoids using cremophor EL as surfactant, and at least one oil and

co-surfactant[34]

.

Benameur et al.(2004) in US20036652865 have found that the incorporation of an

active agent, particularly statins, into a self-microemulsifying system made it possible to

reduce the first intestinal passage effect, and thus improve the systemic bioavailability of

the active molecule[35]

.

Ghosal SK et al. (2004) developed SMEDDS to improve the solubility and

bioavailability and to get faster onset of action of celecoxib. Composition of SMEDDS

was optimized using simplex lattice mixture design. Dissolution efficiency, t85%,

absorbance of diluted SMEDDS formulation and solubility of celecoxib in diluted

formulation were chosen as response variables. The SMEDDS formulation optimized via

mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of

Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which

showed significantly higher rate and extent of absorption than conventional capsule. The

relative bioavailability of the SMEDDS formulation to the conventional capsule was

132%[36]

.

Kanga BK et al. (2004) prepared SMEDDS for oral bioavailability enhancement of a

poorly water soluble drug, Simvastatin. The release rate of Simvastatin from SMEDDS

was significantly higher than the conventional tablet. Bioavailability was 1.5-fold higher

compared to that of the conventional tablet[20]

.

Kocheriakota C et al. (2004) prepared a novel capsule SMEDDS formulations of

etoposide for oral use (US 0220866). Self microemulsifying pharmaceutical compositions

comprising Etoposide that are encapsulated comprising a a solvent; a co-solvent and an

emulsifying base[37]

.


Akshay R. Koli 72

Annette M et al. (2003) has formulated SMEDDS to improve the lymphatic transport

and the portal absorption of a poorly water-soluble drug, halofantrine. Two different

structured triglycerides were incorporated in SMEDDS; (MLM) and (LML). A

previously optimized SMEDDS formulation for halofantrine, comprising of triglyceride,

Cremophor EL, Maisine 35-1 and ethanol was selected for bioavailability assessment.

The extent of lymphatic transport via the thoracic duct was 17.9% of the dose for the

animals dosed with the MLM SMEDDS and 27.4% for LML. The data indicate that the

structure of the lipid can affect the relative contribution of the two absorption pathways.

The MLM formulation produced a total bioavailability of 74.9%, which is higher than

that of total absorption previously observed after post-prandial administration[38]

.

Farah et al. (2000) in US Patent 6054136 provided a SMEDDS capable of forming a

microemulsion in situ with the physiological fluid of the stomach and intestine for the

enhancement of drug bioavailability[39]

Crison et al (1999) in US5993858 taught a self-microemulsifying formulation for

increasing the bioavailability of a drug which included oil/ lipid material, a surfactant,

and a hydrophilic co-surfactant. HLB of hydrophilic co-surfactant was greater than 8. The

self-microemulsifying formulation could also include the addition of an aqueous solvent

such as triacetin. They had found that a more hydrophilic co-surfactant not only increased

the dissolution of poorly water-soluble drugs but, that it also increased their in vivo

bioavailability[40]

.


Akshay R. Koli 73

3.1.2.1 Review of work done on Solid Self Microemulsifying Drug

Delivery System

Hu X et al. (2012) prepared self-microemulsifying pellets to enhance the dissolution and

oral absorption of water insoluble drug sirolimus. The selected liquid SMEDDS

formulations were prepared into pellets by extrusion-spheronization method and the

optimal formulation of 1mg SMEDDS pellets capsule was finally determinated by the

feasibility of the preparing process and redispersibility. The optimal SMEDDS pellets

showed a significant quicker redispersion rate than the dissolution rate of commercial

SRL tablets Rapamune in water. The droplet size and polydispersity index of the

reconstituted microemulsion was almost unchanged after solidification, and pellet size

and friability were all qualified. DSC, XRPD, and IR analysis confirmed that there was

no crystalline sirolimus in the pellets. Pharmacokinetic study in beagle dogs showed the

greater oral relative bioavailability of SMEDDS pellets to the commercial tablets[41]

.

Milovic M et al. (2012) investigated solid SMEDDS (S-SMEDDS), as potential delivery

system for poorly water soluble drug carbamazepine. SMEDDS was formulated using the

surfactant polyoxyethylene 20 sorbitan monooleate [Polysorbate 80] (S), the cosurfactant

Cremophor RH40] (C) and the oil caprylic/capric triglycerides [Mygliol 812] (O). Four

different adsorbents with high specific surface area were used: Neusilin UFL2, Neusilin

FL2 (magnesium aluminometasilicate), Sylysia 320 and Sylysia 350 (porous silica). It

was found that CBZ has great influence on rheological behaviour of investigated system

upon water dilution. For SSMEDDS with different magnesium aluminometasilicate

adsorbents, release rate of CBZ decreased with increasing specific surface area due to

entrapment of liquid SMEDDS inside the pores and its gradual exposure to dissolution

medium. With porous silica adsorbents no difference in release rate was found in

comparison to physical mixtures. In physical mixtures at 12.5% (w/w) CBZ content,

presence of amorphous CBZ led to high dissolution rate[42]

.

Oh DH et al. (2011) compared the effects of hydrophilic and hydrophobic solid carrier

on the formation of solid SMEDDS. Two solid SMEDDS formulations were prepared by

spray-drying the solutions containing liquid SMEDDS and solid carriers. Colloidal silica


Akshay R. Koli 74

and dextran were used as a hydrophobic and a hydrophilic carrier, respectively. The

liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Trasncutol HP with 2% w/v

flurbiprofen, gave a z-average diameter of about 100 nm. Colloidal silica produced an

excellent conventional solid SMEDDS in which the liquid SMEDDS was absorbed onto

its surfaces. It gave a microemulsion droplet size similar to that of the liquid SMEDDS

(about 100 nm) which was smaller than the other solid SMEDDS formulation. In the

solid SMEDDS prepared with dextran, liquid SMEDDS was not absorbed onto the

surfaces of carrier but formed a kind of nano-sized microcapsule with carrier. However,

the drug was in an amorphous state in two solid SMEDDS formulations. Similarly, they

greatly improved the dissolution rate and oral bioavailability of flurbiprofen in rats. They

showed that except appearance, hydrophilic carrier (dextran) and hydrophobic carrier

(colloidal silica) hardly affected the formation of solid SMEDDS such as crystalline

properties, dissolution and oral bioavailability[43]

.

Kim DW et al. (2011) developed a novel flurbiprofen-loaded S-SMEDDS with improved

oral bioavailability using gelatin as a solid carrier, the solid SMEDDS formulation was

prepared by spray-drying the solutions containing liquid SMEDDS and gelatin. The

liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Transcutol HP

(12.5/80/7.5%) with 2% w/v flurbiprofen, gave a z-average diameter of about 100 nm.

The flurbiprofen-loaded solid SMEDDS formulation gave a larger emulsion droplet size

compared to liquid SMEDDS. It greatly improved the oral bioavailability of flurbiprofen

in rats[44]

.

Huan D et al. (2011) studied the influences of silica on the absorption of S-SMEDDS.

An in vitro lipolysis model was used to evaluate the influence of silica on self-

microemulsifying drug delivery system digestion from intestinal tract. S-SMEDDS

containing silica were prepared by extrusion/spheronization. The results showed that

lipolysis rate and drug concentration in aqueous phase after intestinal lipolysis both

increased by adding silica, which was benefit to drug absorption. And silica was not

benefit to absorption for slowing drug release. Consistently, there was no significant

influence of silica on intestinal absorption[45]

.


Akshay R. Koli 75

Ito Y et al. (2010) formulated Oral gentamicin (GM) SMEDDS with PEG-8

caprylic/capric glycerides (Labrasol), and the mixture was solidified with several kinds of

adsorbents. The used adsorbents were microporous calcium silicate (Florite RE),

magnesium alminometa silicate (Neusilin US2), and silicon dioxide (Sylysia 320). The in

vivo rat absorption study showed that Florite RE 10 mg preparation had the highest

C(max) and AUC. These results suggested that an adsorbent system is useful as an oral

solid delivery system of poorly absorbable drugs such as GM[46]

.

Legen I et al. (2008) in EP1961412 prepared free flowing and compressible powder

comprising an admixture of drug containing SMEDDS and solid particle adsorbents[47]

.


Akshay R. Koli 76

3.2 Review of work done on drugs used in the study

3.2.1 Felodipine

Bazzo GC et al. (2012) incorporated Felodipine into microparticles prepared with

Eudragit E and it blended with poly(3-hydroxybutyrate) (PHB) using the emulsion-

solvent evaporation technique, with the aim of improving the dissolution rate of the drug.

The formulation prepared with Eudragit E showed irregular and fragmented

microparticles, with a loading efficiency (LE) of 82.6%. When the microparticles were

prepared with a blend of Eudragit E and PHB, they had a spherical form with a LE of

103.9%. X-ray diffraction and differential thermal analysis indicated a reduction in the

crystallinity of felodipine after its incorporation into the microparticles, which caused a

significant increase in the felodipine dissolution rate[48]

.

Basalious EB et al. (2011) applied quality by design (QbD) for pharmaceutical

development of felodipine solid mixture (FSM) containing hydrophilic carriers and/or

polymeric surfactants, for easier development of controlled-release tablets of felodipine.

Not only did the ternary mixture of Pluronic, HPMC with Inutec SP1 enhance the

dissolution rate and inhibit crystallization of felodipine, but also they aided Carbopol 974

in controlling felodipine release from the tablet matrix. It could be concluded that a

promising once-daily CR tablets of felodipine was successfully designed using QbD

approach[49]

.

Karavas E et al. (2011) prepared solid dispersion systems of felodipine with polyvinyl

pyrrolidone (PVP) in order to enhance solid state stability and release kinetics. The

dispersion of FEL was found to be in nano-scale particle sizes and dependent on the

FEL/PVP ratio. The above dispersion shown a significant effect on the dissolution

enhancement and the release kinetics of FEL, as it causes the pattern to change from

linear to logarithmic. An impressive optimization of the dissolution profile is observed

corresponding to a rapid release of FEL in the system containing 10% w/w of FEL,

releasing 100% in approximately 20 min[50]

.


Akshay R. Koli 77

Alonzo DE et al. (2011) prepared amorphous solid dispersions of Felodipine for

bioavailability enhancement. The purpose of this research was twofold. First, the degree

of supersaturation generated upon dissolution as a function of drug-polymer composition

was investigated. Second, an investigation was conducted to correlate physical behavior

upon dissolution with polymer loading. Hydroxypropylmethylcellulose (HPMC) and

polyvinylpyrrolidone (PVP) were used to form the dispersions. The supersaturation

generated upon dissolution may enhance the bioavailability of the drug.

Sahu et al. (2011) developed and evaluated mucoadhesive nasal gel of Felodipine. The

aim of the present study was to prepare mucoadhesive nasal gels containing Felodipine

from mucoadhesive substance isolated from fruits of Dillenia indica L to enhance

absorption of the drug. The gels prepared from fruits of Dillenia indica L exhibited

favourable mucoadhesive properties that caused them to adhere to the nasal mucosa for a

long time and hence enhance the absorption of drugs administered intranasally[51]

.

Kulkarni et al. (2010) formulated fast dispersible tablets of Felodipine by using super

disintegrant croscarmellose sodium and solid dispersion with polyvinyl alcohol (PVA) as

a carrier. Tablets prepared by solid dispersion having drug to carrier ratio of 1:4 (A3)

yielded the best drug release in terms of dissolution rate. The formulation did not show

any change in disintegration time, wetting time and drug content after stability period[52]

.

Patil PR et al. (2009) developed a extended release Felodipine self-nanoemulsifying

system (SNES) in which miglycol 840 as a oil, cremophore EL as surfactant and capmul

MCM as a co-surfactant were used for nanoemulsion. The SNES showed good

emulsification, median droplet size of 421 nm, and rapid FLD release (>90% release in

15 min). Gelling was induced in the SNES by addition of aerosil 200 (A 200). The

hydrophobic gelucire 43/01 (GEL) coat to extend the release of FLD and caprol PGE-860

(CAP) was added to this coat as a release enhancer. 89.7% of the drug content were

found to be released within 20 h in the in-vitro study[53]

.

Aboul-Einien et al. (2009) formulated and evaluated of Felodipine in softgels with a

solubilized core. In this study, softgels with a solubilized-drug core were used to improve

the solubility and consequently the bioavailability of felodipine. Dissolution tests (under


Akshay R. Koli 78

sink or non-sink conditions) revealed a correlation between the composition of the softgel

core fill liquid and drug dissolution parameters. The incorporation of water in the fill

formula as well as the use of ingredients with low hygroscopicity was found to be

essential to minimize water migration to the fill liquid during storage. In vivo studies

showed rapid and enhanced absorption of Felodipine from solubilized core softgels

compared with control drug powder filled in hard gelatin capsules. The total amount of

drug absorbed over a 24-h period was markedly enhanced (1.6-fold) for softgels

compared with control capsules[54]

.

Narkhede et al. (2007) investigated the effect of the presence of the water soluble

polymers viz HPMC, PVP and PEG 6000 on aqueous solubility and complexation

abilities of Felodipine with or without presence of β-cyclodextrin and HP βCD by phase

solubility studies. All the polymers under study showed synergistic effect on Felodipine

cyclodextrin solublization by increasing complexation efficiency. The highest solubility

improvement up to 81.8% was obtained for βCD ternary system when 0.25% w/v of PVP

was used[55]

.

Karavas E et al. (2006) investigated Solid dispersion systems for the dissolution

enhancement of Felodipine by polyvinylpyrrolidone (PVP). The intensity of interactions

promoted the dissolution enhancement. Investigation of the solubility and the particle size

distribution of felodipine in the binary system appeared to have similar behaviour

indicating that the interactions affect the release profile through these two factors. The

hydrophilicity of PVP does not significantly affect this enhancement as the contact angle

was found to be linear to PVP concentration. Microscopic observation of the dissolution

behaviour showed that felodipine remains in fine dispersion in aqueous solution,

verifying the release mechanism[56]

.


Akshay R. Koli 79

3.2.2 Valsartan

Yan YD et al (2012) developed a novel valsartan-loaded solid dispersion with enhanced

bioavailability and no crystalline changes, various valsartan-loaded solid dispersions

were prepared with water, hydroxypropyl methylcellulose (HPMC) and sodium lauryl

sulphate (SLS). The drug-loaded solid dispersion improved the drug solubility by about

43-fold. It gave a higher AUC, C(max) and shorter T(max) compared to valsartan powder

and the commercial product. The solid dispersion improved the bioavailability of the

drug in rats by about 2.2 and 1.7-fold in comparison with valsartan powder and the

commercial product, respectively[57]

.

Cao QR et al (2012) formulated novel mucoadhesive pellets containing valsartan with

enhanced oral bioavailability. The coated pellets displayed distinct mucoadhesive

property in vitro and delayed gastrointestinal transit in vivo. Furthermore, the coated

pellets exhibit significantly higher AUC (0-12h) and C(max), as compared to the core

pellets and drug suspension. It was concluded that the mucoadhesive pellets could render

poorly water soluble drugs like valsartan with a rapid drug release, delayed GI transit and

enhanced oral bioavailability[58]

.

Ibrahim HK et al. (2011) improved the pH-independent solubility and dissolution

characteristics of valsartan via the preparation of solid dispersions (SD) with poloxamer

407. The improved dissolution of valsartan via SD formulation appeared to be well

correlated with the enhanced oral exposure of valsartan in rats. SDs increased C(max)

and AUC(0-24) of valsartan by 2-7 folds in rats, implying that SDs should be effective to

improve the bioavailability of valsartan [59]

.

Sung J et al (2011) developed a novel valsartan-loaded solid dispersion with enhanced

bioavailability and no crystalline changes; various valsartan-loaded solid

dispersions were prepared with water, hydroxypropyl methylcellulose (HPMC) and

sodium lauryl sulphate (SLS). The bioavailability of the solid dispersions in

rats was evaluated compared to valsartan powder and a commercial product


Akshay R. Koli 80

(Diovan). The drug-loaded solid dispersion composed of improved the drug solubility by

about 43-fold. It gave a higher AUC, Cmax and shorter Tmax compared to valsartan powder

and the commercial product. The solid dispersion improved the bioavailability of the drug in

rats by about 2.2 and 1.7-fold in comparison with valsartan powder and the commercial

product, respectively[57]

.

Chowdary H et al. (2011) prepared solid inclusion complexes of valsartan-

βCD with and without Poloxamer 407 by kneading method as per 22-factorial design

and were evaluated for dissolution rate and efficiency. Poloxamer 407 alone gave

higher enhancement in the dissolution rate of Valsartan (1.96 fold) than βCD alone

and combination of βCD and Poloxamer 407. Drug- βCD- Poloxamer 407 inclusion

complexes and their tablets also gave markedly enhanced dissolution rate when

compared to those formulated employing βCD alone. As such

Poloxamer 407 alone and in combination with βCD is recommended to enhance the

dissolution rate of valsartan tablets[60]

.

Darira P et al. (2011) prepared solid dispersion of a poorly soluble drug valsartan by

using Soluplus as carrier material to enhance the solubility as well as dissolution rate.

Five different formulations were prepared using hot melt extrusion technique in

different ratios i.e., 1:1, 1:3, 1:5, 1:7, and 1:9. All the formulations showed a marked

increase in the solubility behavior and improved drug release when tested for their In

vitro studies. Formulation containing drug: polymer of 1:9 showed the best release with

a cumulative release of 100%. Hence, it was concluded that soluplus as a carrier can be

very well utilized to improve the solubility of poorly soluble drugs [61]

.

Mahapatra A et al. (2011) have prepared solid dispersions (SDs) and physical mixtures of

valsartan in β-cyclodextrin, HP β-CD, and polyvinyl pyrolidone (PVP K-30) to

increase its solubility characteristics. The phase solubility behavior of valsartan in

various concentrations of β-CD, HP β-CD, and PVP K-30 (0.25-1.0% w/v) in distilled

water was obtained at 37 ± 2 °C. The dissolution of valsartan is increased with increasing

amounts of the hydrophilic carriers. Compared with β-CD, HP β-CD showed better

enhancement of dissolution rate; compared with HP β-CD, PVP K-30 showed better


Akshay R. Koli 81

solubility and dissolution enhancement [62]

.

Youn SY et al. (2011) did the recrystallization of valsartan by ASES (Aerosol Solvent

Extraction System), a supercritical micronization process, using compressed CO2 to

improve the bioavailability of valsartan through preparation of micro sized particles

without excessive agglomeration. Fine valsartan particles from an ethyl acetate (EA)

solution were precipitated using compressed CO2 as an antisolvent at low temperature.

The EA was considered a proper organic solvent to prevent agglomeration of the

prepared valsartan associating to the solubility parameters of the solvents. Processed

valsartan with compressed CO2 at a low temperature improved its dissolution rate due to

the small size of the particles attributing to low level of particle agglomeration[63]

Parmar B et.al. (2011) developed solid lipid nanoparticles of valsartan for improvement

of bioavailability with poloxamer 188 by solvent evaporation technique. The

nanoparticles were characterized by DSC, XRD and TEM analysis. The optimized

formulation was found to have particle size 142.5nm, zeta potential of -14.3 mV and 84%

drug entrapment. The optimized formulation showed better in-vitro and ex-vivo release

profile than valsartan suspension. The Solid lipid nanoparticles of valsartan shown

promise to improve bioavailability[64]

.

Sharma A et al., (2010) investigated the influence of Poloxamer 188 to increase

the solubility and dissolution rate of Valsartan for enhancement of oral

bioavailability. In this investigation solid dispersions with Poloxamer 188 were

prepared by melting method and evaluated for physicochemical parameters and

dissolution and reported that the solubility of drug increased with increasing polymer

concentration. The dissolution rate was substantially improved for Valsartan from its solid

dispersion compared with pure drug and physical mixtures[65]

.

Kshirsagar S et al. (2010) formulated solid dispersion of Valsartan using HPMC

E5 LV as water soluble carrier. But film formation took place during solid dispersion

formulation and was creating difficulty in releasing the drug from formulation; and

those solid dispersions, were not free flowing. Thus such preparations are not useful


Akshay R. Koli 82

from the formulation development point of view. So to improve the flow properties,

some inert materials were tried like microcrystalline cellulose (MCC) and Lactose and

the incorporation of inert carriers improved the flow property of solid dispersion [66]

.

Dixit AR et al. (2010) prepared SMEDDS of valsartan with captex and tween 80.

Diffusion of valsartan SMEDDS showed maximum drug release when compared to pure

drug solution and marketed formulation. The area under curve and time showed

significant improvement as the values obtained were 607 ng h/mL and 1 h for SMEDDS

in comparison to 445.36 and 1.36 h for market formulation suggesting significant

increase (p < 0.01) in oral bioavailability of valsartan SMEDDS[67]

.

Kumar KV et al. (2009) made another attempt to improve the solubility and dissolution

rate of a poorly soluble drug, Valsartan by solid dispersion method using skimmed milk

powder (SMP) as carrier. SMP is hydrophilic compound which combines with parent

drug and change their physical properties. This hydrophilicity of carrier molecule

markedly improved solubility of valsartan[68]

.

Agnivesh R et al. (2009) prepared dispersion granules using a hot melt

granulation technique which involved preparation of a homogenous dispersion of

valsartan in gelucire-50/13 melt, followed by its adsorption on to the surface of

aeroperl-300pharma, an inert adsorbent. DSC and XRD data indicated the retention of

amorphous form of valsartan. The in-vitro dissolution rate of these tablets was

significantly better in comparison with marketed formulation. In conclusion the statistical

model enabled us to understand the effects of formulation variables on the dispersion

granules of Valsartan [69]

.

Kumar KV et al. (2009) prepared solid dispersion method using skimmed milk

powder as carrier. Four different formulations were prepared with varying drug: carrier

ratios viz.1:1, 1:3, 1:5 and 1:9 and the corresponding physical mixtures were also

prepared. All the formulations showed marked improvement in the solubility behavior

and improved drug release. Formulation containing drug: polymer ratio of 1:9 showed the

best release with a cumulative release of 81.60% as compared to 34.91 % for the pure


Akshay R. Koli 83

drug. The interaction studies showed no interaction between

the drug and the carrier. It was concluded that skimmed milk powder as a carrier can be

very well utilized to improve the solubility of poorly soluble drugs [68]

.

Cifter U et al. (2008) in WO 9524901 A1 directed to the use valsartan for the treatment

of diabetic nephropathy. WO 9749394 A2, discloses compressed solid oral dosage forms,

e.g., by compaction of valsartan optionally combined with HCTZ. In patent no having

WO 0038676 A1, it has been found surprisingly that it is possible to improve the

bioavailability characteristics of known solid formulation of valsartan by increasing the

proportion of microcrystalline cellulose [70]

Cappello B et al. (2006) developed co-formulation of drug with cyclodextrins (CD).

Hydroxypropyl-b-cyclodextrin (HP-b-CD) was used due to its higher solubility to

improve the solubility in water and dissolution of Valsartan. This work also reveals the

potential of HP-b-CD from the stability point of view, since the inclusion complex

VAL/HP-b-CD exhibits a greater thermal stability than the neat drug [71]

Vrbinc M et al. (2005) tried to overcome the problem of poor dissolution of valsartan by

formulation of tablet containing valsartan particles having size (D50) 150 µm or below[72]

.


Akshay R. Koli 84

3.3 Review of work done on excipients used in the

study

3.3.1 Capmul MCM

Solanki SS et al. (2012), enhanced the dissolution rate and bioavailability of

Ampelopsin, one of the most common flavonoids by developing microemulsion. Capmul

MCM-based ME formulation with Cremophor EL as surfactant and Transcutol as

cosurfactant was developed for oral delivery of ampelopsin. The optimised

microemulsion formulation containing ampelopsin, Capmul MCM (5.5%), Cremophor

EL (25%), Transcutol P (8.5%), and distilled water showed higher in vitro drug release,

as compared to plain drug suspension and the suspension of commercially available

tablet. These results demonstrate the potential use of ME for improving the

bioavailability of poor water soluble compounds, such as ampelopsin[1]

.

Bajaj A et al. (2012) developed self nanoemulsifying drug delivery to the solubility,

permeability and oral bioavailability of cefpodoxime proxetil, β-lactam antibiotic. It is

BCS Class IV drug having solubility 400 µg/ml. Various surfactant and co-surfactants

such as tween 80, tocopheryl polyethylene glycol succinate (TPGS), propylene glycol

and Capmul MCM as oil phase were used and ternary phase diagrams were constructed

to identify stable microemulsion region. Capmul MCM as oil phase were found to

produce stable nanoemulsions[73]

.

Cho HJ et al. (2012) achieved rapid onset of action and improved bioavailability of

udenafil, by microemulsion system for its intranasal delivery. A single isotropic region

was found in pseudo-ternary phase diagrams developed at various ratios with Capmul

MCM as an oil, Labrasol as a surfactant, and Transcutol or its mixture with ethanol

(1:0.25, v/v) as a co-surfactant. Optimized microemulsion formulations with a mean

diameter of 120-154 nm achieved enhanced solubility of udenafil (>10mg/ml) compared

with its aqueous solubility (0.02 mg/ml)[74]

.

Prajapati HN et al. (2012) compared physiochemical properties of mono-, di- and

triglycerides of medium chain fatty acids for development of oral pharmaceutical dosage


Akshay R. Koli 85

forms of poorly water-soluble drugs using phase diagrams, drug solubility, and drug

dispersion experiments. The monoglyceride gave microemulsion (clear or translucent

liquid) and emulsion phases, whereas di- and triglycerides exhibited an additional gel

phase. Among individual mono-, di- and triglycerides, the oil-in-water microemulsion

region was the largest for the diglyceride. Dispersion of drug in aqueous media from

mixtures of mono- and diglyceride or mono- and triglyceride was superior to individual

lipids[75]

.

Du H et al. (2012) reform the dosage forms of andrographolide to improve its aqueous

solubility and oral bioavailability. The formulation, characterisation, stability, anti-

inflammatory effect, pharmacokinetics and oral toxicity of andrographolide-loaded

microemulsion, were studied. An formulation of O/W microemulsion consisting of an oil

phase of capmul, a surfactant phase of Tween 80, a co-surfactant of alcohol, and water

was found to be ideal, with mean droplet size of 15.9 nm, a high capacity of solubilisation

for andrographolide[3]

.

Kadu PJ et al. (2011) formulated a self-emulsifying drug delivery system of atorvastatin

calcium. The solubility of atorvastatin calcium was determined in various vehicles such

as Captex 355, Captex 355 EP/NF, Ethyl oleate, Capmul MCM, Capmul PG-8, Gelucire

44/14, Tween 80, Tween 20, and PEG 400. Pseudoternary phase diagrams were plotted

on the basis of solubility data of drug in various components to evaluate the

microemulsification region. In vivo performance of the optimized formulation was

evaluated using a Triton-induced hypercholesterolemia model in male Albino Wistar rats.

The formulation significantly reduced serum lipid levels as compared with atorvastatin

calcium[76]

.

Nornoo AO et al. (2009) developed cremophor-free oral microemulsions of paclitaxel

(PAC) to enhance its permeability and oral absorption. The microemulsion region on the

phase diagrams utilizing surfactant-myvacet oil combinations was in decreasing order:

lecithin: butanol: myvacet oil (LBM, 48.5%)>centromix CPS: 1-butanol: myvacet oil

(CPS, 45.15%)>capmul MCM: polysorbate 80: myvacet oil (CPM, 27.6%)>capryol 90:

polysorbate 80: myvacet oil (CP-P80, 23.9%)>capmul: myvacet oil (CM, 20%). The

area-under-the-curve of PAC in CM was significantly larger than LBM, CPM and CE.


Akshay R. Koli 86

Oral microemulsions of PAC were developed that increased both the permeability and

AUC of PAC as compared to CE[14]

.

Kale AA et al (2008) developed lorazepam (LZM) microemulsions as an alternative to

the conventional cosolvent based formulation. Solubility of LZM in various oils and

Tween 80 was determined. Capmul MCM demonstrated highest solubilizing potential for

LZM and was used as an oily phase. LZM microemulsions were compatible with

parenteral dilution fluids and exhibited mean globule size less than 200 nm. The LZM

microemulsions containing amino acids exhibited good physical and chemical stability

when subjected to refrigeration for 6 months[77]

.

Fricker et al.(1999) used a microemulsion preconcentrate carrier medium for their

effective oral delivery. A lipophilic component selected from the group consisting of

fatty acid triglycerides (Miglyol, Captex, Capmul, etc.), mixed mono-, di-,and tri-

glycerides and transesterified ethoxylated vegetable oils (e.g. Maisine), and a surfactant

which was selected from the group consisting of polyethyleneglycol, natural or

hydrogenated castor oils (Cremophor EL®, Cremophor RH40®), polyethylene-sorbitan

fatty acid esters (Tweens), polyoxyethylene fatty acid esters (Myrj), polyoxyethylene-

polyoxypropylene co-polymers, and block co-polymers (Pluronic, Polaxamers). The

composition on dilution with water gave a microemulsion having an average particle size

of <150 nm[78]

.

Constantiides PP et al. (1994) developed self-emulsifying water-in-oil (w/o)

microemulsions incorporating medium-chain glycerides and measured their conductance,

viscosity, refractive index and particle size. Formulation of Calcein (a water-soluble

marker molecule, MW = 623), or SK&F 106760 (a water-soluble RGD peptide, MW =

634) in a w/o microemulsion having a composition of Captex 355/Capmul MCM/Tween

80/Aqueous (65/22/10/3, % w/w), resulted in significant bioavailability enhancement in

rats relative to their aqueous formulations. [79]

.


Akshay R. Koli 87

3.3.2 Polysorbate 20 and Polysorbate 80

Mahdi Es et al. (2012) studied the effect of Nonionic surfactant blends of Tween and

Tween/Span series based on their solubilization capacity with water for palm kernel oil

esters. Tween 80 and five blends of Tween 80/Span 80 and Tween 80/Span85 in the

hydrophilic-lipophilic balance (HLB) value range of 10.7-14.0 were selected to study the

phase diagram behavior of palm kernel oil esters using the water titration method at room

temperature. High solubilization capacity was obtained by Tween 80 compared with

other surfactants of Tween series. High HLB blends of Tween 80/Span 85 and Tween

80/Span 80 at HLB 13.7 and 13.9, respectively, have better solubilization capacity

compared with the lower HLB values of Tween 80/Span 80[80]

.

Edris AE et al. (2012) investigated the solubilization behaviour of a number of essential

oils (EOs) containing volatile phenolic constituents in five different micellar solutions.

These oils include clove bud (Eugenia caryophyllata), thyme (Thymus serpyllum) and

oregano (Thymus capitatus). Ternary and pseudo-ternary phase diagrams were

constructed to assess the ability for microemulsion formation and dilutability of each

system using non-ionic surfactants. Results showed that Tween 20 (T20) was more

suitable to solubilize these oils compared with Tween 80 (T80)[81]

.

Xu Sx et al. (2012) developed a food-grade water-dilutable microemulsion system with

cassia oil as oil, ethanol as cosurfactant, Tween 20 as surfactant and water and its

antifungal activity in vitro and in vivo against Geotrichum citri-aurantii was assessed.The

phase diagram results confirmed the feasibility of forming a water-dilutable

microemulsion based on cassia oil. One microemulsion formulation, cassia

oil/ethanol/Tween 20 = 1:3:6 (w/w/w), was selected with the capability to undergo full

dilution with water[82]

.

Saha R et al. (2012) prepaed an edible microemulsion (ME) composed of Tween

80/butyl lactate/isopropyl myristate (IPM)/water. Pseudoternary phase diagram of the

system contains a large single isotropic region. The study finds strong correlation in the

relaxation dynamics of water with the structure of host assembly and offers an edible ME


Akshay R. Koli 88

system which could act as a potential drug delivery system and nontoxic nanotemplate

for other applications[83]

.

Franzini CM et al (2012) investigated anionic microemulsions containing soya

phosphatidylcholine, Tween-20, sodium oleate as surfactant, and cholesterol as oil phase

were investigated as drug carriers for amphotericin B. They suggested that for both

amphotericim B-loaded and amphotericim B unloaded microemulsions, the increase in

the O/S ratio led to the formation of ordered structures with lamellar arrangements[84]

.

Panapisal V et al (2012) studied the potential of several microemulsion formulations for

dermal delivery of silymarin was evaluated. The pseudo-ternary phase diagrams were

constructed for the various microemulsion formulations which were prepared using

glyceryl monooleate, oleic acid, ethyl oleate, or isopropyl myristate as the oily phase; a

mixture of Tween 20, Labrasol, or Span 20 with HCO-40 (1:1 ratio) as surfactants; and

Transcutol as a cosurfactant. Oil-in-water microemulsions were selected to incorporate

2% w/w silymarin. The silybin remainings depended on the type of surfactant and were

sequenced in the order of: Labrasol > Tween 20 > Span 20. In vitro release studies

showed prolonged release for microemulsions when compared to silymarin solution.

Microemulsions containing Labrasol also were found to enhance silymarin solubility.

Other drug delivery systems with occlusive effect could be further developed for dermal

delivery of silymarin[85]

.

Tian Q et al. (2012) investigated the skin permeation microemulsion with high content

of naproxen for transdermal delivery and its solubilization mechanism was studied.

Naproxen micoremulsions composed of 4% isopropyl myristate, 18% Tween 80, 18%

ethanol and water were prepared and phase inversion temperature (PIT) method was used

to increase drug content. The powerful permeation enhancing ability of microemulsion

induced by the solubilization of PIT method makes it a promising vehicle for the

transdermal delivery of naproxen[86]

.

Ryu JK et al (2012) prepared oral microemulsion to overcome problems associated with

the poor solubility and low oral bioavailability of bicyclol and evaluated in vitro and in


Akshay R. Koli 89

vivo. The optimized premicroemulsion concentrate consisted of transcutol, Tween 20,

Cremophor RH 40, propylene glycol monocaprylate and bicyclol (ratio,

50:150:100:150:3) [87]

.

Zheng G et al (2011) investigated the solubilization of organochlorine pesticides (DDT

or gamma-HCH) in oil-in-water (Winsor I) microemulsions (microE) composed of non-

ionic surfactant (Tween 80 or Triton X-100), plant oil (linseed oil or soybean oil), and the

cosurfactant (1-pentanol). Results show that the cosurfactant to surfactant ratio (C/S ratio,

w/w) is the major factor influencing the microemulsion formation, and C/S ratios of 1:3

and 1:6 are superior to 1:1 for microemulsion formation. The solubilization of gamma-

HCH also increased by 40.6-57.5% in microemulsion formed with Tween 80[88]

.

Zeng Z. et al. (2010) developed an elemene oil/water (o/w) microemulsion and evaluated

its characteristics and oral relative bioavailability in rats. Elemene was used as the oil

phase and drug, polysorbate 80 as a surfactant along with ethanol, propylene glycol, and

glycerol as the cosurfactants. The study demonstrated the elemene microemulsion as a

new formulation with ease of preparation, high entrapment efficiency, excellent clarity,

good stability, and improved bioavailability[89]

.

Mehta SK et al (2010) studied the microemulsion composed of oleic acid, phosphate

buffer, ethanol, and Tween (20, 40, 60, and 80) in the presence of antitubercular drugs of

extremely different solubilities, viz. isoniazid (INH), pyrazinamide (PZA), and rifampicin

(RIF). The phase behavior showing the realm of existence of microemulsion has been

delineated at constant surfactant/co-surfactant ratio (K (m) = 0.55) with maximum

isotropic region resulting in the case of Tween 80. To compare the release of RIF, PZA,

and INH from Tween 80 formulation, the dissolution studies have been carried out. It

shows that the release of drugs follow the order INH>PZA>RIF. The results have given a

fair success to predict that the release of PZA and INH from Tween 80 microemulsion is

non-Fickian, whereas RIF is found to follow a Fickian mechanism[90]

.

Kale AA et al (2008) developed lorazepam (LZM) microemulsions as an alternative to

the conventional cosolvent based formulation. Solubility of LZM in various oils and


Akshay R. Koli 90

Tween 80 was determined. The ternary diagram was plotted to identify area of

microemulsion existence and a suitable composition was identified to achieve desired

LZM concentration. Capmul MCM demonstrated highest solubilizing potential for LZM

and was used as an oily phase alongwith tween 80 as surfactant. LZM microemulsions

were compatible with parenteral dilution fluids and exhibited mean globule size less than

200 nm. The LZM microemulsions containing amino acids exhibited good physical and

chemical stability when subjected to refrigeration for 6 months[77]

.

Pather SI et al (2001) in US2008077823 showed enhancement in the solubility of

pharmaceutical ingredients comprising a polyoxyethylene sorbitan fatty acid ester

emulsifier, a fatty acid ester co-emulsifier and an oil[91]

.

3.3.3 Polyethylene Glycol 400

Dora CL et al (2012) developed oil-in-water nanosized emulsions by the hot solvent

diffusion method, using castor oil as oily phase and poly(ethylene glycol) (400)-12-

hydroxystearate (PEG 660-stearate) and lecithin as surfactants. The effect of the PEG

concentration on the droplet size of the nanosized emulsions and on the ability of these

systems to load quercetin was investigated. They demonstrated that a critical

concentration of PEG 400-stearate (2.5 wt%) was needed to obtain colloidal dispersions

displaying microemulsion characteristics[92]

.

Senhao L et al. (2011) prepared microemulsion gel formulation by a self-

microemulsifying system for transdermal topical delivery of ilomastat. Ilomastat

microemulsion gel was prepared by drawing a ternary phase diagram with PEG 400 and

Pluronic F127 was added as gel matrix for the formulation. The optimal formulations had

wide microemulsion existent field and good self-microemulsifying efficiency. The

droplet size was within 100 nm[93]

.

Li G et al (2012) developed an oil-free o/w microemulsion, composed of pluronic F68,

propylene glycol 400 and saline, which solubilized poorly soluble anesthetic drug

propofol for intravenous administration. The ternary diagram was constructed to identify

the regions of microemulsions, and the optimal composition of microemulsion was


Akshay R. Koli 91

determined by in vitro evaluation such as globule size upon dilution and rheology. The

droplet size of the diluent emulsion corresponding to oil-in-water type ranged from 200

to 300nm in diameter. Stability analysis of the microemulsions indicated that they were

stable upon storage for at least 6 months[94]

.

Ngawhirunpat T et al. (2011) prepared novel microemulsion for transdermal drug

delivery of ketoprofen (KP). The microemulsion composed of ketoprofen as model drug,

isopropyl myristate (IPM) as oil phase, surfactant mixture consisting of polyoxyl 40

hydrogenated castor oil (Cremophor RH40) as surfactant and polyethylene glycol 400

(PEG400) as co-surfactant at the ratio 1:1, and water were prepared. The viscosity,

droplet size, pH, conductivity of microemulsions, and skin permeation of KP through

shed snake skin were evaluated. The particle size, pH, viscosity and conductivity of

microemulsions were in the range of 114-210 nm, 6.3-6.8, 124-799 cPs and 1-45 µS/cm,

respectively. The ratio of IPM, and surfactant:PEG 400 mixture played the important role

in the skin permeation of KP microemulsions.[95]

.

Cui J et al. (2009) prepared a new self-microemulsifying drug delivery system to

improve the solubility and oral absorption of curcumin. Suitable compositions of

SMEDDS formulation were screened via solubility studies of curcumin and compatibility

tests. The optimal formulation of SMEDDS was comprised of 57.5% surfactant

(emulsifier OP:Cremorphor EL = 1:1), 30.0% co-surfactant (PEG 400) and 12.5% oil

(ethyl oleate). The solubility of curcumin (21 mg/g) significantly increased in SMEDDS.

The average particle size of SMEDDS-containing curcumin was about 21 nm when

diluted in water. No significant variations in particle size and curcumin content in

SMEDDS were observed over a period of 3 months at 4 degrees C. The results of oral

absorption experiment in mice showed that SMEDDS could significantly increase the

oral absorption of curcumin compared with its suspension[24]

.

Following is a list of microemulsion based drug formulations available in market. But

very few of them are available in India.


Akshay R. Koli 92

Table 3.2: Marketed Lipid- based and Surfactant-based Drug Formulation[96]

Drug Product Components

Amprenavir Agenerase TPGS, PEG 400, propylene glycol

Ritonavir Norvir Ethanol, oleic acid, cremphor EL, BHT

Ritonavir/

lopinavir Kaletra Oleic acid, Cremophor EL, prorylene glicol

Saquinavir Fortovase Medium chain mono-digllycerides, povidone,

α-tocopherol

Tipranavir Aptivus Ethanol, polyoxyl 35 castor oil, propylene glycol, mono-

diglycerides of caprylic/capric acids

Cyclosporine Neoral Corn oil mono-di glycerides, cremophor RH40, ethanol,

propylene glycol, α-tocopherol

Cyclosporine Sandimmune Corn oil, labrafil, ethanol, glycerol

Cyclosporine Gengraf Ethanol, PEG, Cremophor EL, polysorbate 80, sorbitan

monooleate

Sirolimus Rapimmune Phosal 50 PG, polysorbate 80

Doxecalciferol Hectoral Medium chain triglycerides, ethanol, BHA

Progesterone Prometrium Peanut oil, glycerin, lecithin

The exhaustive literature has revealed few important points which made us to understand

and investigate our research work systematically. We have analyzed critically a segment

of a published body of knowledge through summary, classification, and comparison of

prior research studies, reviews of literature, and theoretical articles to solve the problems

associated with poorly water soluble drugs through concept of microemulsion based drug

delivery systems. It helped us to build a solid background for selection of drugs and

excipients to be used for formulating microemulsion and SMEDDS systems. We came to

know that there has been no study till reported for formulating Solid SMEDDS of

Valsartan using adsorption on solid hydrophilic and hydrophobic carrier approach. Also

no efforts were reported for stable Felodipine Microemulsion formulation. We could also

not found any information about effect of dynamic surface tension on stability of

microemulsion system.


Akshay R. Koli 93

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