Development of 5-fluorouracil loaded poly(acrylamide-co-methylmethacrylate) novel core-shell microspheres: In vitro release studies

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Abstract

Novel poly(acrylamide-methylmethacrylate) copolymeric core-shell microspheres crosslinked with N,N′-methylene bisacrylamide have been prepared by free radical emulsion polymerization using varying amounts of acrylamide (AAm), methylmethacrylate (MMA) and N,N′-methylene bisacrylamide (NNMBA). 5-Fluorouracil was loaded into these microspheres during in situ polymerization (method-I) as well as by the absorption and adsorption technique (method-II). The core-shell microspheres have been characterized by differential scanning calorimetry (DSC) and X-ray diffractometry (X-RD) to understand about the drug dispersion in microspheres. Scanning electron microscopy (SEM) was used to assess the surface morphology of particles prepared. In vitro release of 5-fluorouracil has been studied in terms of core-shell composition, amount of crosslinking agent and amount of 5-fluorouracil in the microspheres. Core-shell microspheres with different copolymer compositions have been prepared in yields ranging 80–85%. DSC and X-RD techniques indicated a uniform distribution of 5-fluorouracil particles in core-shell microspheres, whereas SEM suggested the formation of well-defined core-shell structures. The in vitro drug release indicated that particle size and release kinetics depend upon copolymer composition, amount of crosslinking agent used and amount of 5-fluorouracil present in the microspheres. Prolonged and controlled release of 5-fluorouracil was achieved when drug was loaded by method-I instead of method-II.

Introduction

Evolution of pharmaceutical technology has lead to the development of newer methods of drug administration as well as the design and application of controlled release (CR) formulations for the effective targeting of certain drugs to the site of action. In particular, the use of polymeric systems provides a clear optimization to develop the CR dosage formulations to achieve desired therapeutic results to the target site as well as optimization of CR of the drug to obtain maximum dose regimen with minimum side effects (Garcia et al., 2000). The release of a drug from a polymeric matrix occurs due to transport of solute molecules (drug) to the medium that surrounds the system by molecular diffusion through the polymeric walls of the microspheres. This makes the solubility of the solute in the polymer matrix an important factor in controlling the delivery. Drug diffusion from monolithic systems have been analyzed by Fick's second law of diffusion (Peppas et al., 1980), based on the principle of permeability of polymeric matrix after when it swells in the hydration media. Swelling kinetics and release rates depend strongly upon the degree of matrix swelling. However, the majority of polymeric drug-loaded formulations used in CR studies are often prepared from hydrophilic polymers that are crosslinked with acrylic monomers (Lorenzo et al., 2005) that are biocompatible. Alternatively, copolymers of hydrophilic and hydrophobic monomers with appropriate compositions have also been employed in CR studies of bioactive molecules (Kim et al., 2000).

One important step in the development of CR drug delivery systems is the loading of the drug into the polymeric matrix. In the previous literature, two methods have been mainly used (Kim et al., 1992). One is the polymerization in the presence of a drug (Hennick et al., 1996, Franssen et al., 1997, Ward and Peppas, 2001) or by imbibitions (Bromberg et al., 2002, Lorenzo and Concheiro, 2002). In the former case, drug is added to the polymerization media together with monomers, crosslinker and initiator. In the latter case, particles are soaked in the drug solution. The second method could offer some advantages over the first method, since polymerization may affect drug release characteristics because of the secondary reactions taking place between the drug and the active monomers. On the other hand, the first method presents some inconveniences such as those including the use of organic solvents that could be hazardous to the biological environment. In any case, drug loading within the polymer matrix depends upon the release, which involves factors such as rate and swelling degree of the microparticles (Kim et al., 2003), drug/polymer interactions (Lee et al., 1991; Fu et al., 2004), drug solubility and its concentration (Siepmann et al., 2002) in the swelling medium as well as diffusion of the drug throughout the swollen polymeric matrix. Langer et al. (1996) and Kim et al. (1992) reviewed the compositional/structural effects of polymers on drug loading and their CR characteristics. Lee and Kim (1991) investigated the effect of drug loading on drug release characteristics from the microparticles. They concluded that drug loading has a definite effect on drug release mechanism from such matrices.

In continuation of the above mentioned studies and as a part of our on going program of research on the development of novel CR systems (Agnihotri and Aminabhavi, 2004, Agnihotri et al., 2005), we now present new experimental data on the development of novel core-shell microspheres involving monomers, viz., methylmethacrylate (MMA) and acrylamide (AAm) for the slow delivery of 5-fluorouracil (5-FU), an anticancer drug, used widely in pharmaceutical research. MMA has wide-spread biomedical applications, due to its biocompatibility and it can be easily copolymerized with other monomers like sulfopropylmethacrylate (Saraydin et al., 1994) and alkylmethacrylate with various acrylic acid derivatives including acrylamide, acrylic acid, butyl ester as well as with styrene (Rolland et al., 1986, Kreuter et al., 1988) to increase the hydrophilicity of the nanoparticles formed. However, poly(acrylamide) has limited applicability because of its poor mechanical properties due to its high degree of hydration. The copolymers of acrylamide as hydrogels are important in biomedical applications (Karadag et al., 1996, Sommadossi et al., 1982). 5-Fluorouracil is an antimetabolic drug, used extensively in cancer chemotherapy (Einmahl et al., 1999, Fournier et al., 2004) and is an antimetabolite, which is used to prevent the subsequent scarring following trabeculectomy and to improve the prognosis for long-term retinal reattachment. 5-Fluorouracil is an acidic, water soluble (Ermis and Yuksel, 1999), hydrophilic drug and is an antineoplastic agent of extensive use in clinical chemotherapy for the treatment of solid tumours. It has been widely used in drug administration due to its large number of secondary effects that accompany its conventional administration.

Traditionally, the core-shell particles can be lightly crosslinked by using difunctional monomers. In order to the prepare core-shell particles, it is important to maintain the precise spatial arrangement of the functional groups in the binding site and to preserve the overall shape of the template, all of which requisites for efficient imprinting. Core-shell microparticles usually refer to spheres formed by making the core units through a normal preparative method, followed by the addition of an outer layer by a dipping, mixing emulsifying or in situ polymerization (Jones and Lyon, 2000, Lee et al., 2002, Sparnacci et al., 2002, Zhou et al., 2002, Gref et al., 1994). Employment of a shell usually helps to enhance and possibly reduce the effect of the initial burst effect. Microparticles and nanoparticles based on core-shell structures or polymeric micelles are advantageous in terms of their long circulation in the body in addition to drug solubility, stability and high level of drug encapsulation (Kwon et al., 1995). Moreover, the main advantage of core-shell type microspheres is that both hydrophilic and hydrophobic drugs can be incorporated. In this research, novel 5-fluorouracil-loaded poly(acrylamide-co-methylmethacrylate) core-shell microspheres have been prepared. The particles formed have been characterized by particle size analyzer, differential scanning calorimetry, X-ray diffractometer and scanning electron microscopy. The in vitro release studies have been performed in 7.4 pH buffer solution at 37 °C.

Section snippets

Materials

Acrylamide (AAm), methylmethacrylate (MMA), N,N′-methylene bisacrylamide (NNMBA), sodium laurylsulfate, sodium hydrogen phosphate, potassium persulfate and calcium chloride were all purchased from s.d. fine chemicals, Mumbai, India. 5-Fluorouracil was purchased from MP Biochemicals, Eschwege, Germany.

Synthesis of poly(acrylamide-co-methylmethacrylate)

Sodium laurylsulfate (1 g) and sodium hydrogen phosphate (100 mg) were dissolved in 80 mL of water taken in a three-necked round bottom flask equipped with a mechanical stirrer, a condenser and a gas

Differential scanning calorimetry (DSC)

DSC tracings of pure 5-fluorouracil, drug-loaded core-shell microspheres and plain microspheres are displayed in Fig. 1. The onset-melting peak of 5-FU was observed at 285.16 °C. However, no characteristic peak of 5-FU was observed in DSC curves of the drug-loaded microspheres, suggesting that drug is molecularly dispersed in the polymer matrix. Fig. 1c shows a small sharp peak at 286 °C in which drug was loaded by solvent evaporation technique (method-II), confirming that drug was absorbed into

Conclusions

A common way to prepare new materials is to combine two or more polymers. Grafting, block polymerization or copolymerization are most often used for this purpose. Poly(acrylamide) and poly(methylmethacrylate) are among the most popular polymers; consequently, their combination is of great interest to develop the core-shell microspheres. In this research, core-shell microparticles have been prepared by copolymerizing hydrophilic and hydrophobic monomers by free radical emulsion polymerization.

Acknowledgement

The authors thank the University Grants Commission (UGC), New Delhi, India for a major funding (Grant No: F1-41/2001/CPP-II) to establish Center of Excellence in Polymer Science at Karnatak University, Dharwad.

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