Performance evaluation of PAMAM dendrimer based simvastatin formulations

Abstract

The purpose of this investigation was to evaluate the performance of poly (amidoamine) (PAMAM) dendrimers, with three different surface groups, to be used as drug carriers. Drug–dendrimers complexes were investigated for solubility studies, dissolution studies, in vitro drug release studies, and for stability studies. The solubility enhancement was found maximum with PEGylated dendrimers (33 times) followed by amine (23 times) and hydroxyl (17.5 times) dendrimers. The solubility profile of simvastatin–dendrimer complex showed a linear correlation (Higuchi A_L-type diagram) between solubility and dendrimers concentration. The formation of the complexes between drug molecules and dendrimers were characterized by the FTIR spectra of these complexes, showing the appearance of the bond formed between the functional groups of the drug (OH and COOH) and dendrimers (NH₂ and OH). The drug–dendrimer complexes displayed the controlled release action during in vitro release studies. Pure simvastatin (SMV) was released in 5 h whereas the PEGylated dendrimers–SMV complexes released the drug up to 5 days. The non-PEGylated formulations released the drug up to 24 h. Formulations with amine and PEGylated dendrimers were subjected to accelerated stability studies. Formulations with amine dendrimers were found to be most stable in dark, low temperature (0 °C) whereas the dark, RT was most suitable storage conditions for formulation with PEGylated dendrimers.

Introduction

Currently available all novel drug delivery systems basically involve the use of lipids or polymers. Each type of system has its limitations: lipid based drug delivery systems (i.e., liposomes, solid lipid nanoparticles, nanostructured nanocarriers) have poor physical stability, drug leakage, difficulty in drug targeting (Arulsudar et al., 2004, Tabatt et al., 2004) and low drug loading capacity due to the formation of a perfect lipid crystal matrix (Mehnert and Mader, 2001) whereas polymer based systems use linear polymers which are polydisperse in nature, in addition to regulatory issues and scaling up problems.

Dendrimers are a unique class of synthetic macromolecules having a highly branched, three dimensional, nanoscale architecture with very low polydispersity (1.00002–1.005) and high functionality. The unique structure makes dendrimers an excellent building block to create an ideal polymeric drug-delivery system with multiple functionalities, which is otherwise difficult to achieve with linear polymers. The basic advantage of dendrimers is to deliver drugs efficiently and effectively, at the same time they also improve the biopharmaceutical and pharmacokinetic properties of drugs (Svenson and Tomalia, 2005). Various studies have been carried out to use dendrimers as drug delivery via various routes of administration: oral (Tripathi et al., 2002, D’Emanuele et al., 2004, Man et al., 2006), intravenous (Malik et al., 1999, Padilla et al., 2002, Kukowska-Latallo et al., 2005, Bhadra et al., 2003, Bhadra et al., 2005, Chauhan et al., 2004, Asthana et al., 2005), transdermal (Chauhan et al., 2003, Wang et al., 2003a, Wang et al., 2003b, Cheng et al., 2006), and ocular (Shaunak et al., 2004, Vandamme and Brobeck, 2005).

Among the three basic family of dendrimers: poly (amidoamine) (PAMAM), diaminobutane (DAB) and polypropyleneimine (PPI), PAMAM dendrimers have been extensively used in drug delivery because they allow the precise control of size, shape and placement of functional group (dimensional stability), controlled method of synthesis, minimum toxicity and wide availability.

In this investigation, performance of PAMAM dendrimers with different surface groups was evaluated for their application as drug delivery system using simvastatin as model drug. Simvastatin is a hypolipidemic drug and is used to control hyper-cholesterolemia and to prevent cardiovascular diseases. Simvastatin inhibits the rate determining step in cholesterol biosynthesis; catalyzed by 3-hydroxy-3-methylgluteryl coenzyme A (HMG-Co-A) reductase (Alberts et al., 1980, Goodman et al., 2001). This inhibition leads to up-regulation of low-density lipoprotein (LDL) receptors and increase in catabolism of LDL cholesterol (Brown and Goldstein, 1986). Simvastatin is practically insoluble in water and hence poorly absorbed from the gastro-intestinal tract; oral bioavailability is less (<5%) (Martindale, 2005).

Attempts have been made to deliver simvastatin by the use of lipids (as self-emulsifying drug delivery system) (Patil et al., 2007, Kang et al., 2004) and cyclodextrins (Patel and Patel, 2007, Yoshinari et al., 2007). But all the formulations suffer with some and other disadvantages. The major problem associated with SEDDS is thermodynamically instability. A SEDDS is either diluted just prior to administration or else in the body, the required droplet stability is less than 6 h (i.e., the transit time of materials down the small intestine) (Lawrence and Warisnoicharoen, 2006). Secondly, as per lipid formulation classification system, proposed by Pouton, 2000, Pouton, 2006, self emulsifying drug delivery systems are type-II lipid formulation, which requires 20–60% water-insoluble surfactants (HLB < 12) to make the stable formulations. The use of such a large quantity of surfactants can induce GI irritation (Tang et al., 2008).

Patel et al. increased the solubility of SMV by 7.35 fold and 13.3 fold at 14 mM/L concentration of β-CD and HP-β-CD, respectively. But the use of cyclodextrins in more than 6 mM/L concentration induces very rapid hemolysis (due to extraction of lipids from the erythrocytic membrane) (Arikan, 2003).

So the basic objective of this project was to evaluate the performance of three different G4 poly (amidoamine) (PAMAM) dendrimers to be used as drug carriers and to simultaneously develop the controlled release formulation of lipid lowering drug simvastatin. The reason behind to develop this formulation is that the patient suffered with hypercholesterolemia requires a long-term treatment and secondly statins take 2–3 days to display their effects.