According the rate-limiting step in cholesterol synthesis. In addition,

According to Stokes–Einstein equation, increase in temperature will
lead to decrease in dynamic viscosity and then the diffusion constant will be
high which lead to increase the nanosuspension diffusion which affect electrostatic
repulsion result to nanosuspension aggregation ,In addition, the more labile
APIs may be affected by higher nanonization temperature (Milewski
et al., 2010).

For example quercetin nanosuspension when stored at 40 °C was unstable
when compared to its stability at 25 °C and 4 °C (Kakran
et al., 2012)

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1.     
Simvastatin (SIM)

2.1.  
Chemical
structure, category 1

Simvastatin (SIM), is (1S,3R,7S,8S,8aR)-8-2-(2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-ylethyl-3,7-dimethyl-1,2,3,7,8,8ahexahydronaphthalen-1-yl
2,2-dimethylbutanoate, Fig 2

 

                                              

 

 

 

 

 

Figure 2. SIM chemical structure of simvastatin

 

Characters of simvastatin

SIM is a white or almost white, crystalline powder. SIM is solubility
Practically insoluble in water, very soluble in methylene chloride and freely
soluble in ethanol (96 per cent) (Ph. Eur. 9.2).

 

Indication of simvastatin

Simvastatin belongs to anticholesteremic agents.It is used as
cholesterol-lowering agent in human by inhibitor of 3-hydroxy-3-methylglutaryl
coenzyme A reductase (hydroxymethylglutaryl CoA reductases), which is the
rate-limiting enzyme in cholesterol biosynthesis.It also has been widely used
in the treatment of, dyslipidemia and coronary heart disease.(Nirogi
et al., 2007)

 

 

Mechanism of action of simvastatin

Simvastatin consider as a prodrug which hydrolyzed to its active
?-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a
specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme HMG-CoA reductase
that catalyses the conversion of HMG-CoA to mevalonate, the rate-limiting step
in cholesterol synthesis. In addition, simvastatin reduces very low density
lipoprotein (VLDL) and TG and increases HDL-cholesterol.(Robinson
et al., 2005).

  (Figure 3) represents Mechanism
of action of simvastatin

Pharmacokinetics of simvastatin

SIM is absorbed rapidly following oral administration, with time to
reaches the peak plasma concentration (Tmax) of 4 hours and its elimination is
only 2 hours. It has high permeability with a
problem with an aqueous solubility, which is only 30 ?g/ml, so it is known as
class II in the BCS. The low aqueous solubility of SIM limits its
bioavailability, however, enhancing its solubility can greatly increase its
bioavailability (Schachter,
2005; Margulis-Goshen and Magdassi, 2009; Jiang
et al., 2012).

SIM bioavailability is very low (less than 5%) after oral
administration due to its poor aqueous solubility and extensive metabolism by
cytochrome-3A (CYP3A) system in intestinal guts and liver (Corsini
et al., 1999).

Simvastatin which consider as prodrug is lipophilic and absorbed
rapidly after oral administration 60% to 85% then
rapidly hydrolysis to form many active metabolites. Both simvastatin and the
active metabolite are strongly bound to plasma proteins (95%). It taken up by
cells other than hepatocytes and penetrates the CNS. Simvastatin undergoes extensive first-pass metabolism in the liver
after absorption in humans which is the primary site of action

 About 60% of an absorbed
simvastatin dose excreted in the feces and about 13% in the urine which lead
half-life is 1.9 hours  (Todd
and Goa, 1990).

The bioavailability of the simvastatin is low: the absolute
bioavailability of ?-hydroxyacid-simvastatin less than 5% due to its poor aqueous solubility and extensive metabolism by
cytochrome-3A (CYP3A) system in intestinal guts and liver. for the total
HMG-CoA reductase inhibitors the area under the plasma concentration-time curve
(AUC) in the circulation is clearly related to dose over the range
from 5 to 120mg in humans after the administration of single oral doses of
simvastatin

It has high permeability with a problem with an aqueous solubility,
which is only 30 ?g/ml, so it is known as class II in the BCS. The low aqueous
solubility of SIM limits its bioavailability, however, enhancing its solubility
can greatly increase its bioavailability  (Schachter 2005; Margulis-Goshen and Magdassi
2009; Jiang, Han et al. 2012).

 

 

 

 

 

 

 

Figure 3: Mechanism of action of simvastatin by inhibition of HMG-CoA
reductase.

Adverse effects of simvastatin

The most common adverse reactions of SIM (incidence ?5.0%) are upper
respiratory infection, headache, abdominal pain, constipation, and nausea.

 

Administration and dosage

Simvastatin Administrate in form tablets with dose 5 mg; 10 mg; 20
mg; 40 mg; 80 mg. The recommended usual starting dose is 10 or 20 mg once a day
in the evening.  US FDA licensed product allows
a maximum of 80 mg once daily in patients who have been taking simvastatin 80
mg chronically. A daily dose of 10 mg simvastatin decreases low-density
lipoprotein (LDL) cholesterol by about 25-30% in individuals with mild hypercholesterolemia.
Absorption is not significantly reduced if taken before a low-fat meal and no accumulation
appears to occur with repeated administration of normal therapeutic doses.(Neuvonen
et al., 2008)

 

1.4.   Rationale for enhanced SIM
dissolution from oral dosage form

Simvastatin has high permeability with a problem with an aqueous
solubility, which is only 30 ?g/ml, so it is known as class II in the BCS. The
low aqueous solubility of SIM limits its bioavailability. However, enhancing SIM
solubility can greatly increase its bioavailability (Schachter,
2005; Margulis-Goshen and Magdassi, 2009; Jiang
et al., 2012). To
enhance the simvastatin oral bioavailability, solubility and dissolution are
key element to improve its therapeutic efficacy. It
is  well known that the enhancement of
drug solubility of poorly water soluble drugs still one of the most difficult step
of drug development (Pandya
et al., 2011).

There were many approaches have been used previously to enhance SIM
solubility, including solid dispersion, salt formation, micronization, chemical
modification, and use of surfactant (Vargas
et al., 2013).  Silva et al. tried to
enhance the SIM solubility using solid dispersion (SD) with PEG or PVP. They
find the drug release was significantly improved (greater than 80% in 60
minutes.) when compared to their corresponding physical mixture or SIM alone. They
conclude that the preparation of SIM SD with PEG or PVP is a promising strategy
to improve the bioavailability of the drug. (Silva
et al., 2010). Also, Meng and Zheng used self-microemulsification technique to
get better bioavailability of SIM by enhancing their apparent solubility
through solubilization. The result how simvastatin apparent solubility between

0.0024 ? 29.0 mg/mL. Moreover, this technique showed that simvastatin
apparent solubility was mainly influenced by microemulsion concentration (Meng
and Zheng, 2007).  

Vargas et al. compared all study published from January over 12
years (2000 to April 2012) that try to enhance the aqueous solubility of simvastatin using solid dispersions, microencapsulation, supercritical fluid and the
cyclodextrin inclusion system .They concluded that the better results were achieved
with process involving the formation of microemulsions and nanoparticles but
it’s not absolutely the most proper methods and it need to connect the in
vitro to in vivo study. (Vargas
et al., 2013).

 

1.5.  
Nanonization of simvastatin

One of the most successful approaches that are adopted to enhance
SIM solubility and dissolution rate are the  nanonization techniques, which despond on
decreasing drug particle size to nanometer range, which lead to increase the
surface area resulting in increasing the drug dissolution rate and changing the
drug crystalline forms (Junghanns
and Muller, 2008; Marcato and Duran,
2008).
Several investigations studied the effect of preparing of SIM nanoparticles using
nanonization techniques by either top-down techniques or bottom-up techniques to
enhance its dissolution properties. Pandya et al. prepared SIM nanosuspension
using a ball mill by applying ball made of zirconium and they used ball size of
(0.4–0.7 mm) as a milling medium and Pluronic F-127 as a stabilizer (Pandya
et al., 2011). The results showed that nanosuspensions prepared with the highest
concentrations of Pluronic F127 and the higher quantities of ZrO2 (up to 8 g)
reduced the particle size and enhanced the dissolution rate of the formulation.

Chavhan et al prepared and optimized SIM nanosuspensions using
media milling in presence of two stabilizers (tween 80 and Pluronic F-127). SIM
nanosuspension showed a significant increase in saturation solubility and
decrease in crystallinity of the drug as compared to the plain drug suspension (Chavhan
et al., 2013). Fattahi, Karimi-Sabet et al Prepare simvastatin nanoparticles using rapid expansion of supercritical
solution (RESS) with trifluoromethane as the
supercritical fluid. SIM nanoparticles showed more than a 4-fold increase in
dissolution rate .(Fattahi
et al., 2016). Moreover Jun, Kim et al prepared of
simvastatin/hydroxypropyl-b-cyclodextrin inclusion complex nanoparticles using
supercritical antisolvent (SAS) process to improve the aqueous solubility and
the dissolution rate of drug. The aqueous solubility and dissolution studies
indicated that the dissolution rates were remarkably increased in SAS processed
SV/HP-b-CD complex with approximately 6.6- and 34-fold increases
in terms of both DE60 and RDR , compared with the physical mixture and drug alone
(Jun
et al., 2007).
Furthermore Pandya, Patel et al study effect of different stabilizer like
sodium lauryl sulphate, tween-80, polyvinyl alcohol, poloxamer-188, PVP-30,
etc. on the formulations of simvastatin nanosuspension prepared by
nanoprecipitation technique. The result show that using  PVP-30 as stabilizer with simvastatin give
significantly enhanced the drug dissolution rate compared to the pure simvastatin
,and also compared with all other stabilizers (Pandya
et al., 2010).

 

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