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Chapter 2
Review of Literature
CHAPTER-II
REVIEW OF LITERATURE
2.1.
REVIEW
OF
PATENTS
AND
RESEARCH
LITERATURE
RELATED TO SMEDDS / SNEDDS IN GENERAL
Literature survey carried out for the present work includes reports on all
previous work done by other workers in the field of SMEDDS. The level of
interest in SMEDDS was increased substantially as is evident by the number of
research activities done on this subject. The foregoing literature SMEDDS
formulation and in vivo evaluation for the Isotretinoin drug reveals that the
delivery of the drug in a solubilised SMEDDS form has not been investigated in
detail. This lacuna is noticed and the present work is attempted to address these
issues in order to further enhance the solubility of the molecule and hence the
bioavailability.
In order to overcome the problems associated with Isotretinoin and other
poorly soluble compounds, and to develop a stable and robust oral dosage form
for such active ingredients, several approaches have been adapted in patent
publications and research literature as listed below; however, some of them may
bare the issue of invalidity or impracticality in terms of commercialization.
Holm et al. (2003) examines oral absorption and lymphatic transport of
halofantrine in a triple-cannulated canine model after administration in selfmicroemulsifying drug delivery system (SMEDDS) containing structured
triglycerides.
O’Driscoll CM. (2002) reveals that the recent monitoring halofantrine
(Hf), in a fed versus fasted dog study, have shown that a higher degree of
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
54
Chapter 2
Review of Literature
lymphatic transport is possible (>50% dose) in the postprandial state, this study
should result in stimulating renewed interest in the potential of achieving
significant levels of lymphatic targeting. This review analyses the success and
limitations of a formulation approach using lipid-based vehicles and highlights
potential areas for further research.
Hauss et al. (1998) reveals that Ontazolast is practically insoluble in water
(0.14 microgram/mL) and previous studies in animals have demonstrated
extensive presystemic drug clearance through hepatic first-pass metabolism.
Bioavailability of a suspension formulation in rats was less than 1%, but increased
to approximately 9% when administered as a 20% soybean oil-in-water emulsion.
The bioavailability of ontazolast was significantly and substantially enhanced by
all of the lipid-based formulations.
Abu.T.M.Serajuddin et al. (2008) investigated the solution of a poorly
water-soluble drug in a liquid lipid–surfactant mixture, which served as a
microemulsion preconcentrate, was converted into a solid form by incorporating it
in a solid polyethylene glycol (PEG) matrix. The solid microemulsion
preconcentrates thus formed consisted of Capmul PG8 (propylene glycol
monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and
hydrophilic polymer PEG 3350 as solid matrix. It was confirmed that a solid
microemulsion preconcentrate is a two-phase system, where clusters of crystalline
PEG 3350 formed the solid structure (m.p. 55–60°C) and the liquid
microemulsion preconcentrate dispersed in between PEG 3350 crystals as a
separate phase. The drug remained dissolved in the liquid phase. In vitro release
testing showed that the preconcentrate dispersed readily in water forming a
microemulsion with the drug dissolved in the oil particles (<150 nm) and the
presence of PEG 3350 did not interfere with the process of selfmicroemulsification.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
55
Chapter 2
Review of Literature
Uno et al. (1999) investigated an oleic acid oil-in-water (o/w)-type
emulsion of a new tacrolimus formulation that presented an improvement in the
delivery of the drug for oral absorption. This investigation was undertaken to
assess a sustained release drug delivery system and selective drug transfer into the
lymphatic system. The whole blood
concentration profiles
after oral
administration at a dose of 2 mg/kg and bone marrow, spleen, liver, lung, small
intestine, kidney, brain, and whole blood distribution after oral administration at a
dose of 1 mg/kg of o/w emulsion formulation of tacrolimus (O/W group) were
compared with those of commercially available formulation (T group) in the rat.
The area under the whole blood concentration-time curve (AUC) in the O/W
group was significantly higher (P<0.01) than that in the T group. In contrast, the
values of constant elimination rate and total clearance in the O/W group were
significantly lower (P<0.01) than those in the T group, with a comparative
bioavailability of 115.9%.
Preparation and in vitro characterization of self-nanoemulsified drug
delivery system (SNEDDS) of all-trans-retinol acetate by Mansoor A. Khan et.al
(2004) investigated the preparation of SNEDDS with All-trans-retinol acetate
using different concentrations of soybean oil (solvent) Cremophor EL (surfactant)
and Capmul MCM-C8 (co-surfactant). The results showed that that surfactant to
co-surfactant ratio has the main impact on the physical characteristics of the
emulsion formed. The optimum surfactant to co-surfactant ratio was reported to be
2:1 (37.5–50% for Cremophor EL, and 18.75–25% for Capmul MCM-C8). With
this ratio, the resultant nanoemulsions obtained had a particle size range of 0.103–
0.051 μm, turbidity range of 18.12–2.18 NTU and t30 values (cumulative% alltrans-retinol acetate dissolved in 30 min) of 90.42–99.5. The study finally
concluded that the self-nanoemulsified drug delivery system of all-trans-retinol
acetate increased its dissolution rate and reports the potential to enhance its
bioavailability without interaction or incompatibility between the ingredients.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
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Chapter 2
Review of Literature
Development of self-microemulsifying drug delivery systems (SMEDDS)
for oral bioavailability enhancement of simvastatin in beagle dogs by Sun Hang
Cho et al. (2004) investigated the preparation of self-microemulsifying drug
delivery system (SMEDDS) for oral bioavailability enhancement of a poorly
water soluble drug, simvastatin. The prepared SMEDDS was compared with the
conventional tablet (Zocor®) by administering the prefilled hard capsules to
fasted beagle dogs. The absorption of simvastatin acid from SMEDDS form
resulted in about 1.5-fold increase in bioavailability compared with the
conventional tablet. The studies illustrated the potential use of SMEDDS for the
delivery of hydrophobic compounds, such as simvastatin by the oral route.
Design and evaluation of self-nanoemulsifying drug delivery systems
(SNEDDS) for cefpodoxime proxetil by Nagarsenker et al. (2006) investigated
the development of Self-nanoemulsifying drug delivery systems (SNEDDS) with
the objective to overcome problems associated with the delivery of cefpodoxime
proxetil (CFP), a poorly bioavailable high dose antibiotic having pH dependant
solubility. Solubility of CFP in oily phases and surfactants was determined to
identify components of SNEDDS. Various surfactants and co-surfactants were
screened for their ability to emulsify selected oily phases. Ternary phase diagrams
were constructed to identify area of nanoemulsification for the selected systems.
The influence of CFP and the pH of dilution medium on the phase behavior of
selected system were assessed. The globule size of optimized CFP SNEDDS in
various dissolution media was determined to check the effect of pH on its
behavior. The optimized CFP SNEDDS needed surfactant content less than 40%
and yielded nanoemulsion of mean globule size 170 nm, which was not affected
by the pH of dilution medium. The optimized SNEDDS released CFP completely
within 20 min irrespective of the pH of dissolution medium.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
57
Chapter 2
Review of Literature
Ehab I Taha et.al. (2007) investigated to assess and compare the
bioavailability of three different oral dosage forms of vitamin A in rats. The
formulations included vitamin A self-nanoemulsified drug delivery (SNEDD)
optimized formulation-filled capsule (F1), vitamin A SNEDD optimized
formulation compressed tablet (F2) and vitamin A oily solution-filled capsules
without any additives (control, F3). From the pharmacokinetic parameters, both
F1 and F2 showed improved bioavailability compared to F3. The increase in
AUC, Cmax and Tmax was significant (p < 0.05). The bioavailability increased
almost twofold and 1.4 times for F1 and F2, respectively. The study showed that
the newly developed vitamin A SNEDD formulations increased the rate and
extent of drug absorption compared to the oily drug solution. The present
investigation demonstrated that vitamin A SNEDD optimized formulations, either
as filled capsules or as compressed tablets, were superior to its oily solution with
regard to their biopharmaceutical characteristics.
Ehab I Taha et.al. (2009) investigated the preparation Vitamin A selfnanoemulsifying drug delivery system (SNEDDS), which comprises soybean oil,
Cremophor EL, and Capmul MCM-C8, prepared and mixed with different grades
of Avicel to produce homogenized powders. The resultant powders were
compressed into tablets. The prepared tablets were characterized for their
thickness, hardness, friability, disintegration time, and dissolution rate. In
addition, the relative bioavailability of the tablets in comparison to solid-state
Vitamin A oily solution (SSVAOS) tablets was investigated in rats. Vitamin A
dissolution rate was markedly different from one formulation to another. From the
bioavailability data, it was observed that Vitamin A SNEDD tablets have higher
bioavailability (relative bioavailability 143.68%) compared with SSVAOS tablets.
The AUC and Cmax of Vitamin A SNEDD tablets were found to be significantly
different from that of SSVAOS tablets.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
58
Chapter 2
Review of Literature
U.S. Patent no. 5,965,160, Benita S, et al. described a Self-emulsifiable
formulation producing an oil-in-water emulsion.The invention claims and
discloses a pharmaceutical composition suitable for oral administration, in form of
an emulsion pre-concentrate, comprising (i) one or more NO-releasing NSAID(s);
(ii) one or more surfactants, of which at least one is phospholipid; said
composition forming an in-situ oil-in-water emulsion upon contact with
gastrointestinal fluids. The composition may optionally also comprise an
additional oil or semi-solid fat. Further, one or more short-chain alcohols can
optionally be included in the composition. Also within the scope of the invention
is a combination with a proton pump inhibitor. The pharmaceutical composition is
useful in the treatment of pain and inflammation.
The U.S. Patent no. 5,716,928 describes a method for increasing
bioavailability and for reducing inter and intra individual variability of an orally
administered hydrophobic pharmaceutical compound, which comprises orally
administering the pharmaceutical compound with an essential oil or essential oil
component in an amount sufficient to provide greater bioavailability of the active
ingredient.
The U.S. Patent no. 6,028,054 relates to a method for increasing
bioavailability of an orally administered hydrophobic pharmaceutical compound
to human, which comprises orally administering the pharmaceutical compound
concurrently with a bioenhancer comprising an inhibitor of e-cytochrome P450
3A enzyme or an inhibitor of P-glycoprotein mediated membrane transport.
The U.S. Patent no. 5,993,858 describes a self microemulsifying excipient
formulation for increasing the bioavailability of a drug Nifedipine, which includes
an emulsion including oil or other lipid material, a surfactant and an hydrophilic
co-surfactant.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
59
Chapter 2
Review of Literature
The U.S. Patent no.
7,867,517B2 describes a prompt-release oral
pharmaceutical composition containing one or more active principle solubilised,
suspended or embedded in a suitably formulated amphilic matrix for improving in
vitro and in vivo bioavailability of medicaments sparingly absorbed through the
oral route with problems of high variability of absorption in gastrointestinal tract.
The said matrix system containing an amphiphilic compound which melts at
below 60°C or forms a eutectic mixture melts at 35 -37°C. In this the active
substance kept in the form of dispersion or partially solubilised or embedded,
granulated with amphiphilic compound previously solubilised or suspended in
solvent (preferably water). This system also contains a surfactant which is
compatible with the amphiphilic matrix in a solubilised form to enhance the bio
availability of the poorly soluble active substances.
2.2.
REVIEW
OF
PATENTS
AND
RESEARCH
LITERATURE
RELATED TO ISOTRETINOIN
Very few publications and/or patents about the pharmaceutical formulation
of Isotretinoin are available. The drug is available on most markets under the form
of a soft gelatine capsule containing a fatty liquid formulation of Isotretinoin.
Vanderbrist et al., 2007, Application number: 11/892,363, Publication
number: US 2008/0171084 A1Filing date: Aug 22, 2007 details about the method
of enhancing the bioavailability of Isotretinoin through the usage of two lipidic
agents in which one of them being hydrophilic and the other is lipophilic in
nature. The SEDDS system containing soya bean oil to Gelucire 50/13 in various
ratios from 3.2 to 0.54 were prepared. The prepared SEDDS system was subjected
for in-vitro dissolution studies and in-vitro Caco-2 diffusion studies.
The
composition contains the lower oil to Gelucire 50/13 ratio, resulted in
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
60
Chapter 2
Review of Literature
nanoemulsion during the dissolution studies. Based on the dissolution and
diffusion studies, the two formulations were prepared and subjected for pilot study
pharmacokinetic study in healthy human volunteers. The formulation which
contains 16 mg of Isotretinoin in 192 mg of Gelucire50/13, soya bean oil 104 mg
and 16 mg of span 80 the exhibited pharmacokinetic response equivalent to that of
commercially available Isotretinoin 20 mg composition (Roacuttane 20 mg). The
author concluded that the developed SEDDS system could improve the
bioavailability by 20%.
The U.S. Patent no.4,464,394 describes for the first time the therapeutical
use of Isotretinoin, also describes briefly some possibilities of compositions
including it. It involves the use of one antioxidant agent and of one carrier like
lactose, starches or polyethylene glycols.
The U.S. Patent no. 4,545,977 relates to improved compositions of
Isotretinoin wherein taurine is associated with Isotretinoin to reduce the side
effects thereof.
The EP Patent no. 0184942 describes more specific compositions of
Isotretinoin involving the use of one antioxidant, one chelating agent, one
pharmaceutical carrier and one suspending agent. The composition obtained is
stable during time.
WIPO Patent Application WO/2004/084883 describes the use of lowsolubility complexes of natural cyclodextrins (CDs) in order to improve the
bioavailability of Isotretinoin after oral administration. The complexation of
Isotretinoin with natural CDs increases the aqueous solubility and dissolution rate
of Isotretinoin, which results in improved absorption of Isotretinoin. The present
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
61
Chapter 2
Review of Literature
innovation can be used in various oral dosage forms (tablet, capsule, etc.) and it
includes a novel method to prepare solid formulations (e. g. tablet) from
Isotretinoin.
Hai-Shu Lin et al. (2007) demonstrated Biopharmaceutics of 13-cisretinoic acid (Isotretinoin) formulated with modified β-cyclodextrins. Watersoluble formulations of 13-cis-RA have been attempted with 2-hydroxypropyl-βcyclodextrin (HP-β-CD) and randomly methylated-β-cyclodextrin (RM-β-CD). In
this study, the pharmacokinetic profiles of these two formulations were assessed
in Sprague–Dawley rats after single intravenous or oral administration. It was
found that 13-cis-RA was eliminated from the body through a dose-independent
process after intravenous injection of either sodium salt or the HP-β-CD
formulation within the tested dosage range (2.0–7.5 mg/kg). Furthermore, HP-βCD did not alter the kinetic profile of 13-cis-RA after intravenous administration
in comparison with 13-cis-RA sodium salt. It was also found that RM-β-CD
dramatically enhanced the oral absorption of 13-cis-RA. At 10.0 mg/kg, the
bioavailability of 13-cis-RA formulated with RM-β-CD was about three-fold
higher
than
that
of
the
control
(13-cis-RA
suspended
in
0.5%
carboxymethylcellulose (CMC)). Similarly, the oral absorption of 13-cis-RA was
not saturated within tested range (2.5–10.0 mg/kg) and the bioavailability
remained unchanged. These results demonstrated that HP-β-CD and RM-β-CD
were suitable excipients for the delivery of 13-cis-RA.
Yap KL et al. (2005) investigated the effects of the complexation of 13cis-RA with alpha-cyclodextrin (alpha-CD) and hydroxypropyl-beta-cyclodextrin
(HP-beta-CD) on its phase solubility. HP-beta-CD was found to be more effective
in increasing the aqueous solubility of 13-cis-RA compared to alpha-CD. Phase
solubility studies indicated that the solubility of 13-cis-RA was increased
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
62
Chapter 2
Review of Literature
dramatically by the formation of inclusion complex with HP-beta-CD. The
solubility was further enhanced by pH adjustment. The photostability of the
selected inclusion complex of 13-cis-RA:HP-beta-CD was then evaluated.
Complexation with HP-beta-CD was found to delay the photo-degradation of 13cis-RA in aqueous solution. The physicochemical properties of the solid inclusion
complex were characterized by Fourier transform infrared spectroscopy (FTIR),
differential scanning calorimetry (DSC), and X-ray diffractometry (XRD).
Molecular modeling with MMFF94s force field (SYBYL V6.6) was utilized to
predict the preferred orientation of 13-cis-RA in the CD cavity and the main
structural features responsible for the enhancement of its solubility and
photostability. The energy scores estimated from the computational analysis were
found capable of reflecting the stability constants of the cyclodextrin complexes
obtained in the phase solubility studies. The results showed that HP-beta-CD was
a proper excipient for increasing solubility and stability of 13-cis-RA.
Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for
Isotretinoin with enhanced Oral Bioavailability and Improved Stability
63