Preparation of the drug to the systemic circulation

Preparation
of injectable Rosuvastatin in situ gel formulation with minimum initial burst
of the drug

 

Introduction

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In situ gelling
systems administered parenterally have received a huge attention over the
years. These systems have the advantages of releasing the Active pharmaceutical
constituents in a controlled manner from a gelled depot leading to a very
acceptable drug profile over a prolonged period of time, which results in
improving bioavailability of poorly available drugs, improving patient
compliance as a result of reduced numbers of injectable drug administration 1. In regards to poorly available active
pharmaceutical substance, parenteral administration is the most effective and
efficient rout of administration for poorly available drugs as it’s provide
direct access of the drug to the systemic circulation simply 2. But the main disadvantages of this type of
formulation is initial burst which must be controlled in order to provide
successful formulation.

 

Smart polymers
can be incorporated into in situ gelling systems for different reasons. These polymers
are known for being biocompatible and can undergo phase transition process when
administered into the biological environments. This phase transition can be
triggered by small changes in different environmental factors such as temperature
& pH. Different polymers  are used in “in situ” gelling formulation such as: PLGA and
poly-caprolactone, alginic acid, gellan gum, chitosan and pectin . solvents
such as water, dimethylsulphoxide, N-methyl pyrrolidone, triacetin and
2-pyrrolidone are used also based on the drug chemical characteristics 3.

 

Abnormal excessive elevation in the blood level of lipids as
a condition known as hyperlipidemia. This condition can be managed by different
approaches, and one of them in the inhibition of HMG-CoA reductase enzyme, an
enzyme responsible for synthesis of cholesterol in the human body. HMG-CoA
reductase inhibitors (statins) are the most common clinical method of lowering
the blood lipids. But poor bioavailability is known in this class of drugs and
many studies and formulations have been developed to increase the blood
bioavailability of these compound. Care must be taken as increasing extrahepatic
level of these compound will lead also to increased side effects. Rosuvastatin
are reported to be available intrahepaticlly by 90% with low level of toxicity 4.

 

Rosuvastatin is a synthetic HMG-CoA reductase inhibitor and
considered as a newer generation in this class. It has some structural features
that give more lipophilicity and more ionic interaction with HMG-CoA reductase
enzyme 5,6. Rosuvastatin at every prescribed dose compared favorably with
other statins regarding liver dysfunction, myopathy, cataract, oesophageal
cancer and acute renal failure 7. This may be contributed to the high affinity of the drug to
the enzyme, as Rosuvastatin is considered the highest in term of affinity when
compared to other Europe marketed Statins 8. This affinity combined with the strong interaction with the
enzyme will results in lipid lowering effect even after stoppage of the therapy.
Rosuvastatin is mainly  distributed to liver cells with low
peripheral  concentrations 9. The bioavailability of Rosuvastatin is 20% and
is 88% bound to plasma protein with 19 hour half-life. It is primarily
eliminated in feces. Also Rosuvastatin is less lipophilic than other statins resulting
in less extra-hepatic distribution leading to decrease muscular side effect 10 11 12.

 

The aim of the study is to prepare an injectable Rosuvastatin
in situ gel formulation to improve bioavailability and to provide sustained
release formulation with minimum initial burst.

 

Objectives

·       
The aim of the study is to prepare an injectable
Rosuvastatin in situ gel formulation to improve bioavailability and to provide
sustained release formulation with minimum initial burst.

Methodology

 

·       
Preparation technique:

1.     
Determination of maximum UV absorbance and
construction of standard calibration curve.

2.     
Establishing proper HPLC analytical method for
analysis of Rosuvastatin in the formulation.

3.     
Preparation of Rosuvastatin in situ gelling formulation
using different ratio of PLCA polymer.

4.     
Preparation of Rosuvastatin in situ gelling
formulation using proper solvent.

5.     
Characterization of the prepared formulation by
examination of the morphological properties using scanning electro microscopy as
well as the viscosity studies.

6.     
In vitro release studies and kinetic analysis.