Preparation of poly(methacrylic acid-g-poly(ethylene glycol)) nanospheres from methacrylic monomers for pharmaceutical applications

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Abstract

Nanospheres of poly(methacrylic acid-grafted-poly(ethylene glycol)) were prepared by solution/precipitation polymerization. As colloidal drug delivery carriers, they present unique properties that render them promising candidates for oral protein delivery. The polymerization was carried out in water and the resulting suspension was freeze-dried. As with many colloidal systems, the freeze-dried suspension showed strong agglomeration after drying. The effects of preparation conditions on the particle size and redispersion were investigated using photon correlation spectroscopy. Furthermore, the ability of different types and concentrations of stabilizers (cryoprotectants and steric stabilizers) in preventing this phenomenon was addressed. Pluronics®, block copolymers widely used as nonionic surfactants, were the most effective in stabilizing the particles during the freeze-drying process. Pluronic® P123, however, increased significantly the particle size of the nanospheres. On the other hand, lyophilizates obtained in the presence of Pluronic® F68 had good redispersion properties and no change in particle size was observed.

Introduction

The ever-increasing evolution of the pharmaceutical field, discovery of disease mechanisms and improved understanding of the human body physiology have rendered the need of ‘smart’ delivery systems more compelling over the last decade. Biosensors, responsive polymeric networks (Lowman and Peppas, 1999c, Peppas et al., 2000a, Kost and Langer, 2001) and controlled drug delivery systems possess great potential for filling the need for better control of drug administration. The common feature of these systems is the attempt to mimic the physiological needs of the body. Pulsatile delivery, controlled release and site-specific delivery are among the strategies endeavored (Wise et al., 2000, Siepmann and Peppas, 2001).

The ultimate goal in developing a new drug delivery system is improvement of the efficacy of the active compound administered, attenuation of undesired side effects, and ultimately increase of the patient compliance. Colloidal drug delivery systems are among the carriers used to achieve this objective (Kreuter, 1994, Torres-Lugo and Peppas, 2002, Torres-Lugo et al., 2002a, Torres-Lugo et al., 2002b). It has been shown that drug properties such as solubility, absorption through biological membranes, bioavailability, as well as carrier properties like residence time in a certain site and site specificity can be improved by decreasing the drug or carrier particle size (Müller et al., 2001). Micronization and lately nanosizing have been investigated as potentially good techniques (Robinson and Peppas, 2002) for targeting the drug directly or close to the site of action. Tarr et al. (1987) demonstrated that microemulsions possess better intestinal absorption characteristics compared to the conventional emulsions. This result was explained in terms of greater surface area of the dosage form, and therefore, increase in the release of the drug and more intimate contact with the intestinal wall. Yet, nanoparticulate systems have attracted more attention in the field. Compared to the micron range systems, they possess a higher surface area that can lead to higher loading efficiency of active ingredients and a more intimate contact with biological tissues.

Colloidal systems that have been investigated over the years range from liposomes and niosomes to microemulsions and nanospheres (De Jaeghere et al., 1999a). Nevertheless, one of the shortcomings is the stability of these carriers. Both chemical and physical stability are challenges that sometimes hamper the development of colloidal drug carriers. A nanoparticulate system, as well as any other carrier designed for drug delivery, should preserve its original physical and chemical properties during the formulation and storage, maintain the content of drug achieved at the end of the loading, and guarantee an effective release of the drug in the body (Schwarz and Mehnert, 1997). However, in the case of nanoparticulate drug delivery systems in the form of either emulsions or solid formulations problems have been encountered such as leaking, flocculation, agglomeration after redispersion. Therefore, preparation conditions as well as storage represent critical stages (Morishita et al., 2002, Sipahigil et al., 2002).

In this contribution, we address the optimization of complexation-based, pH-sensitive nanoparticulate formulations as possible delivery carriers for proteins and peptides. In particular, we have focused on grafted hydrogels composed of poly(ethylene glycol) (PEG) grafted on poly(methacrylic acid) (PMAA), henceforth designated as P(MAA-g-EG) hydrogels.

The presence of ionic moieties in the polymeric network renders these systems responsive to pH changes in the surrounding environment (Lowman et al., 1998a, Lowman et al., 1998b, Peppas and Lowman, 1998, Lowman and Peppas, 1999a, Lowman et al., 1999). The unique behavior of this system is the hydrogen bonding between the hydrogen on the carboxylic acid group of the PMAA and the oxygen in the grafted PEG chain. In acidic conditions, at pH lower than the pKa of the methacrylic acid, the carboxylic acid groups of the PMAA are nonionized and the system is able to form hydrogen bonds within the network. Therefore, complexes form and the crosslinked network is collapsed (Torres-Lugo and Peppas, 1999, Lowman and Peppas, 1999b, Ichikawa and Peppas, 1999, Lowman and Peppas, 2000, Peppas et al., 2000a). When the pH rises and reaches values in the alkaline region, the complexation reverses and the system swells (Fig. 1). This type of complex formulation is reversible in nature (Lowman et al., 2000). This behavior has been extensively studied in our laboratories. (Drummond et al., 1989, Brannon-Peppas and Peppas, 1989, Klier and Peppas, 1991, Bell and Peppas, 1996, Peppas and Bures, 1999). Furthermore, this system has been shown to be able not only to respond to pH change in the surrounding environment, but has also been proven to inhibit the proteolytic enzymes of the gastrointestinal tract and open the tight junctions present in the intestinal wall and responsible for the poor absorption. Therefore, it is a promising candidate for the delivery of environmentally-susceptible bioactive agents characterized by a poor permeation through the intestinal wall (Kim and Peppas, 2002, Huang et al., 2002a, Huang et al., 2002c, Peppas et al., 2000b, Peppas et al., 2000c, Kim and Peppas, 2001).

Recently, we have been able to produce P(MAA-g-EG) hydrogels as a monodisperse nanospheres suspension using a solution/precipitation polymerization method in water (Robinson and Peppas, 2002, Foss and Peppas, 2001). Yet, as stated before, it is important to ensure stability of the system both in the form of dispersion and after drying. In the latter case, the solid product obtained has to be able to reconstitute into the original system.

Therefore, the main goal of this research was to investigate the critical parameters in the formulation process in order to have a successful production of pH sensitive nanospheres. In particular, we addressed the redispersion and size preservation of the particles after the drying step.

Section snippets

Nanospheres preparation and purification

The monomers used were methacrylic acid (MAA, Polysciences, Warrington, PA) and poly(ethylene glycol) monomethylether monomethacrylate (PEGMA, Polysciences, Warrington, PA) with PEG molecular weights of 200, 400, and 1000. Tetraethylene glycol dimethacrylate (TEGDMA, Polysciences, Warrington, PA) was used as a crosslinking agent and 1-hydroxy-cyclohexyl phenyl ketone (Irgacure® 184, CIBA-GEIGY, Hawthorne, NY) was selected as the photoinitiator. MAA was vacuum distilled at 54 °C/25 mmHg in order

Polymerization and nanospheres purification

Nanospheres of P(MAA-g-EG) were synthesized by a UV initiated free radical solution/precipitation polymerization in water. The kinetics of this reaction has been reported in the literature before (Scott and Peppas, 1999, Ward and Peppas, 2000, Scott et al., 2000, Ward and Peppas, 2001, Ward et al., 2002). After exposure to UV light, the reaction mixture, initially in the form of a clear solution, turned into a milky suspension of nanospheres. The effect of the washing process on the particle

Conclusions

P(MAA-g-EG) nanospheres present very promising characteristics for oral delivery of proteins. However, the small size range, and the sensitivity to pH changes in the surrounding environment render the drying step and the resuspension challenging tasks. Preparation conditions and the drying method have to be tailored in order to maintain a narrow particle size distribution and guarantee a good redispersability. This study has showed that optimizing the conditions during the preparation leads to

Acknowledgements

This work was supported in part by grant No. EB 00246-11 of the (U.S.) National Institutes of Health. C.D. would like to thank the Italian CNR for partial financial support.

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