Preparation of polymeric nanoparticles containing corticosteroid by a novel aerosol flow reactor method

Abstract

Polymeric drug-containing nanoparticles were prepared using a novel aerosol flow reactor method. The polymeric drug-containing nanoparticles prepared consist of a poorly water soluble corticosteroid, beclomethasone dipropionate, and polymeric materials Eudragit E 100 or Eudragit L 100. The novel method used in this study allows synthesis of nanoparticles directly as dry powders. The nanoparticles can contain various ratios of drug and polymer, and the use of any additional stabilisation materials is avoided. In this study, nanoparticles with different drug-to-polymer ratios were prepared. Particle size and morphology, crystallinity, and thermal behaviour were determined as a function of particle composition. It was found that all the nanoparticles produced, regardless of particle composition, had geometric number mean diameters of approximately 90 nm, and were spherical showing smooth surfaces. The drug was molecularly dispersed in the amorphous polymeric matrix of the nanoparticles, and drug crystallisation was not observed when the ambient temperature was below the glass transition temperature of the polymer.

Introduction

It has been predicted that in the future a growing number of new, potential drugs will have bioavailability problems related to poor water solubility of the drug molecules. Several methods have been used in efforts to increase solubility and thus, bioavailability of poorly water soluble drugs. Examples of the methods used include solubilisation of drug into micelles or liposomes (Humberstone and Charman, 1997), complexation or coating with hydrophilic substances such as poly(ethylene glycols) or cyclodextrins (Hirayama and Uekama, 1999, Yang and Alexandritis, 2000), solid dispersions (Pignatello et al., 1997), using an amorphous modification of the drug (De Jaeghere et al., 2001, Sarkari et al., 2002), and reduction in particle size (De Jaeghere et al., 2001, Muller et al., 2001, Chen et al., 2002).

Nanosized drug particles, i.e. particles having diameters less than 1 μm, have been used to improve solubility and dissolution rates of poorly water soluble drugs. The solubility and dissolution rate of a drug depend on the drug particle surface area, and reducing the particle size results in larger surface area, which thus promotes dissolution (Adamson, 1990, Buckton, 1995, Muller et al., 2001). Various techniques have been used to manufacture nanosized drug particles with size down to hundreds and even tens of nanometres. Dry and wet milling techniques have been widely used to reduce the particle size (Liversidge and Conzentino, 1995, Muller and Peters, 1998, Muller et al., 2001). Unfortunately, the nanosized particles cause cake formation in the grinding materials and milling chambers, thus significantly reducing the size reduction efficiency and resulting in broad particle size distribution and non-uniformity in particle size. Furthermore, the milling process can introduce changes in particle morphology, uncontrollable changes in particle crystalline structure (Malcolmson and Embleton, 1998), and possibly contamination, which is absolutely unacceptable in pharmaceutical material processing. To reach the desired nanoscale particle size by wet milling processes, surfactants have to be added into the mixture to prevent the agglomeration of nanosized particles. In addition, long processing times ranging over periods of days are often required to achieve particle sizes of nanometre scale. Solvent-based processes, such as emulsification-solvent evaporation (Bodmeier and Chen, 1990), emulsification-solvent diffusion (Leroux et al., 1995, De Jaeghere et al., 2001) and precipitation method (Couvreur et al., 1995) have also been used to manufacture drug nanoparticles. Generally, these methods require the addition of considerable amounts of surfactants to prevent coalescence during particle formation and hardening in an aqueous suspension. Harsh or pharmaceutically unacceptable solvents are commonly used, which might be considered as a risk regarding scale-up or regulatory issues (Allémann et al., 1993). Furthermore, these commonly used methods for production of nanoparticles result in a suspension of nanoparticles in an aqueous solution stabilised by surfactants. Reported problems of nanosuspensions are drug leakage from the particles into water phase, drug degradation, and physical changes in the suspension during the course of time. These stability problems might be avoided by storing the nanoparticles as dry powder (Bodmeier et al., 1989, Bodmeier et al., 1991, Freitas and Muller, 1998, Schmidt and Bodmeier, 1999). However, to acquire dry powder from a suspension, a separate drying step by, e.g. lyophilisation or spray-drying is necessary.

Further increase in bioavailability and dissolution can be achieved by formulating the drug in an amorphous state (Hancock and Parks, 2000, Sarkari et al., 2002). As the amorphous solid-state form has higher energy than its crystalline counterparts, its saturation solubility is also larger (Hancock and Parks, 2000, Muller et al., 2001). Unfortunately, amorphous drug materials, especially if they consist of nanosized particles, show a strong tendency towards aggregation and crystal growth. This tendency to recrystallise as function of time is governed mainly by thermodynamic factors, as the system tries to reach the most stable crystal state (Buckton and Darcy, 1999, Yu, 2001). One method to overcome this problem in instability is to sterically stabilise the particles using suitable stabilising agents, which will prevent particle coalescence and growth. In addition, if drug molecules present in the amorphous form are embedded in a glassy matrix forming a nanoparticle, the crystallisation of the drug can be possibly prevented, thus making amorphous drugs stable over long periods of time. The stabilising matrix can consist, for example, of polymeric material, which is in glassy state at ambient temperature. Several different film-forming polymers have been widely used in pharmaceutical industry for various coating applications as well as for microencapsulation and nanoparticle synthesis purposes. For example, poly(methacrylate)-based polymers, known under the trade name Eudragits, have been used in microcapsules fabricated by spray-drying, as well as in nanoparticles manufactured by various solvent processes (Dittgen et al., 1997, Pignatello et al., 1997, Pignatello et al., 2002, De Jaeghere et al., 2001, Esposito et al., 2002). Eudragits have been accepted as pharmaceutical excipients for oral use and are generally regarded as non-toxic.

Two different Eudragit materials, namely, Eudragit E 100 and Eudragit L 100 were used as stabilisation materials in this study. The model drug used was beclomethasone dipropionate (BDP), which is an example of a poorly water soluble corticosteroid. It was studied whether the nanoparticle composition, relative amounts of drug and polymer, or Eudragit type used had an effect on the properties of the resulting nanoparticles. Eudragit E 100 is a co-polymer consisting of 1:2:1 ratio of methyl methacrylate, N,N-dimethylaminoethyl methacrylate, and butyl methacrylate monomers. Due to tertiary amino groups, which are ionised in the acidic pH, Eudragit E is soluble in gastric fluid when pH<5 (Shukla, 1994, Dittgen et al., 1997). Thus, it has commonly been used as a plain or insulating film-former. Eudragit L 100 consists of 1:1 ratio of methacrylic acid and methyl methacrylate. The acidic groups are resistant to gastric fluid, but are ionised when pH>6, thus this material is soluble in the physiological conditions of small intestine (Shukla, 1994, Dittgen et al., 1997), and accordingly, it has been used as an enteric coating. The structural formulas of the Eudragit materials are shown in Scheme 1.

The aim of the current study was to prepare drug nanoparticles using a novel aerosol flow reactor method. This method is a simple and efficient one-step process that can directly produce particles within a desirable particle size range with consistent and controlled properties. In this method, both the drug and the stabiliser material are dissolved into a common solvent or solvent mixture, which is atomised as small droplets into a carrier gas. The solvent is evaporated in a controlled manner using a heated tubular laminar flow reactor, and the particles produced are collected as dry powder using a low-pressure impactor.