Microparticles produced by the hydrogel template method for sustained drug delivery

https://doi.org/10.1016/j.ijpharm.2013.11.058Get rights and content

Abstract

Polymeric microparticles have been used widely for sustained drug delivery. Current methods of microparticle production can be improved by making homogeneous particles in size and shape, increasing the drug loading, and controlling the initial burst release. In the current study, the hydrogel template method was used to produce homogeneous poly(lactide-co-glycolide) (PLGA) microparticles and to examine formulation and process-related parameters. Poly(vinyl alcohol) (PVA) was used to make hydrogel templates. The parameters examined include PVA molecular weight, type of PLGA (as characterized by lactide content, inherent viscosity), polymer concentration, drug concentration and composition of solvent system. Three model compounds studied were risperidone, methylprednisolone acetate and paclitaxel. The ability of the hydrogel template method to produce microparticles with good conformity to template was dependent on molecular weight of PVA and viscosity of the PLGA solution. Drug loading and encapsulation efficiency were found to be influenced by PLGA lactide content, polymer concentration and composition of the solvent system. The drug loading and encapsulation efficiency were 28.7% and 82% for risperidone, 31.5% and 90% for methylprednisolone acetate, and 32.2% and 92% for paclitaxel, respectively. For all three drugs, release was sustained for weeks, and the in vitro release profile of risperidone was comparable to that of microparticles prepared using the conventional emulsion method. The hydrogel template method provides a new approach of manipulating microparticles.

Introduction

Polymeric microparticle drug delivery systems have been widely explored for controlled delivery of active pharmaceutical ingredients. Microparticles provide several advantages as drug delivery vehicles, such as protection of encapsulated drug from unfavorable environmental conditions and ability to control drug release profile for a specified period of time (Tran et al., 2011a). In particular, the potential to control drug release profile over an extended period of time is one of the most desirable attributes (Wei et al., 2012). Suitable drug candidates that may benefit greatly from such controlled drug delivery systems based on polymeric microparticles include those that have a broad therapeutic window, require a low daily dose and are used for the long-term treatment of disease.

Poly(lactide-co-glycolide) (PLGA) is probably the most extensively used polymer in microparticle drug delivery systems (Tran et al., 2011a). This copolymer of lactide and glycolide degrade by simple hydrolysis when exposed to an aqueous environment such as inside the human body. PLGA has been used in a host of drug products approved by Food and Drug Administration (FDA), such as Zoladex Depot® (goserelin), Lurpon Depot® (leuprolide), Sandostatin LAR® Depot (octreotide acetate), Nutropin Depot® (somatotropin), Trelstar® (triptorelin), Somatulin® Depot (lanreotide), Risperidal® Consta® (risperidone), Vivitrol® (naltrxone) and Bydureon® (exenatide). PLGAs are available at various molecular weights (or intrinsic viscosities) and lactide/glycolide ratios with either ester end-caps or free carboxylic acid end-caps. The properties of PLGA have been shown to influence important microparticle characteristics, such as the amount of drug loading, loading efficiency and drug release both in vitro and in vivo (Yeo and Park, 2004, Su et al., 2011, Amann et al., 2010). Previous studies have demonstrated that the rate of hydrolysis, and therefore, drug release is heavily dependent on the PLGA molecular weight and monomer composition. Consequently, it is possible to design PLGA-based microparticle drug delivery systems with tailored polymer degradation characteristics and release patterns by varying the PLGA composition.

In addition to polymer composition and properties, there are other formulation- and process-related parameters that may affect microparticle performance. Formulation-related factors include type of organic solvent used, concentration of polymer used, and drug–polymer interactions (Yeo and Park, 2004, Doan et al., 2011, Cho et al., 2000). Various studies have shown that these formulation-related factors affect drug encapsulation efficiency and drug distribution within polymeric matrix, which in turn influences the initial burst release. The initial burst release is one of the major challenges in developing drug-encapsulated microparticle systems. The release of a large bolus of drugs before microparticles reach a steady state release is both therapeutically undesirable and economically ineffective. Therefore, the ability to control and limit the initial burst release is highly sought-after and extensively studied. In addition, there are process-related parameters that can affect the performance of microparticles produced using these methods. Currently, spray drying and emulsion-based methods are well-established and most commonly used to prepare drug-loaded PLGA microparticles. Process-related parameters in these methods that influence drug-loaded microparticle characteristics include the ratio of dispersed phase to continuous phase and the rate of solvent removal/extraction. The factors outlined above and their effects on microparticle performance, however, have been mostly studied in the emulsion-based methods only.

Although emulsion-based and spray-drying methods are widely used, their applicability is restricted by a number of limitations. Techniques such as spray drying may be unsuitable for substances sensitive to heating and mechanical shear of atomization, which narrows the field of applicability for this technique (Maa and Prestrelski, 2000). Low product yield due to deposition of materials on the interior surface of drying chamber is yet another common concern for spray drying. For both spray drying and emulsion-based methods particle formation is random and results in microparticles with broad size distribution (Tran et al., 2011b). Microparticle size is an important factor that affects the choice of administration route (Gaumet et al., 2009, Mohamed and van der Walle, 2008, Thomas et al., 2010), drug encapsulation within the microparticle and therefore drug release profile from the delivery vehicle (Berkland et al., 2003, Berkland et al., 2004, Siepmann et al., 2004). Another common problem with spray drying and emulsion-based methods is low drug loading, often with an average of less than 10% (Gaspar et al., 1998, Kauffman et al., 2012, Le Ray et al., 2003). Certainly there is room for improvement in microencapsulation techniques.

To address limitations associated with conventional methods of microparticle preparation, we have developed a microfabrication technique for preparation of microparticles. The approach utilizes the unique properties of physical gels that can undergo sol–gel phase transitions or water-soluble polymers that do not dissolve in organic solvents. The approach is collectively called the hydrogel template method (Acharya et al., 2010a). The hydrogel template approach allows a more precise control of microparticle size and shape, which translates into narrow size distribution and increased microparticle homogeneity. In addition, the method provides flexibility in producing microparticles of various desirable size ranges. Another improvement over existing methods is the possibility of incorporating a higher amount of drug into the polymeric matrix, since the particle formation process is no longer random, thereby allowing more control over drug encapsulation. The hydrogel template approach does not require the application of excessive heat, mechanical force or any harsh treatment conditions. It is a simple and fast process.

Early method development of the hydrogel template technology and initial study on the effect of the particle size on drug release were discussed in previous publications (Acharya et al., 2010a, Acharya et al., 2010b). The main objective of the present study is to evaluate the hydrogel template method for producing drug-loaded polymeric microparticles, with the goal of gaining a better understanding of this method that will ultimately aid in method optimization. Three drugs with different physicochemical properties were used as model compounds in this study. The data obtained were compared and contrasted to microparticles prepared using the conventional emulsion-based technique.

Section snippets

Materials

Risperidone (RIS) and methylprednisolone acetate (MPA) were purchase from Sigma–Aldrich (St. Louis, MO), paclitaxel (PTX) was supplied by Samyang Genex Corporation (Republic of Korea). Poly(d,l-lactide-co-glycolide) (PLGA) 5050, 6535, 7525 and 8515 (corresponding to lactide:glycolide ratio of 50:50, 65:35, 75:25 and 85:15, respectively) were purchased from Lactel (Pelham, AL). Poly(vinyl alcohol) (PVA, 87–89%, 96%, 98–99% and >99% hydrolyzed) of various typical molecular weight was purchased

Development of the hydrogel template method

The ability to precisely control and manipulate microparticle geometry is highly valuable as the shape and size of drug carriers have been shown to have an impact on biological processes such as vasculature, circulation time, targeting efficiency, cellular uptake and subsequent intracellular transport for therapeutic delivery (Decuzzi et al., 2010). While the hydrogel template approach produces microparticles of pre-defined size and shape, it requires further development for practical

Conclusion

Drug-loaded PLGA microparticles prepared using the hydrogel template method were characterized and evaluated using three poorly water soluble, model drugs: RIS, MPA and PTX. The microparticles were characterized based on size, shape, morphology, drug loading, encapsulation efficiency as well as in vitro release. Among the formulation and process-related parameters studied, it was found that the ability of produced microparticles to retain the designed shape was dependent on molecular weight of

Acknowledgements

This work was supported by the Showalter Research Trust Fund and National Institute of Health through CA129287, HL062552, and GM095879.

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