Porous Microspheres Preparation

A special kind of porous microsphere is a patented [6,7], highly cross-linked polymer sphere having a size that can vary from about 3 to 3000 microns. The porous spheres are produced by an aqueous suspension of polymerization of monomer pairs consisting of a vinyl and a divinyl monomer, e.g., methyl methacrylate (the vinyl monomer) and ethylene glycol dimethacrylate (the divinyl monomer), or styrene and divinylbenzene. The divinyl monomer functions as a cross-linker, and because it is used in concentrations as high as 50 to 60%, the copolymer is a very highly cross-linked material. As a consequence of their chemical structure and the high cross-link density, the micrpsheres are totally inert and do not degrade in the body, nor do they dissolve or swell, when exposed to any organic solvent. They have been found to be stable between pH 1 and 11 and at temperatures as high as 135°C.

To prepare the copolymer, the vinyl and divinyl monomers, initiator, suspending agent (emulsifier), and a porogen, which produces the porous structure, are dispersed in water and the copolymerization started by thermally activating the initiator. The porogen must be miscible with the monomers and function as a precipitant for the polymer. Polymer particle size is controlled by the size of the suspended monomer droplets, which in turn is a function of the nature and amount of the suspending agent and the shear induced by the stirring process. When all variables are carefully controlled, a uniform batch of particles having the desired size and the desired porosity can be obtained. Typically, the surface area of such porous microspheres can be varied between 20 to 500 m2/g and the pore volume can be varied from 0.1 to 3.4 cm3/g.

A scanning electron micrograph of a porous microsphere magnified 5000 times is shown in Figure 2. A view of the interior, in this case magnified 6000 times and obtained by freeze fracture, is shown in Figure 3. As can be seen, the internal structure comprises small polymer particles enclosed in a porous membrane. The porosity of the microspheres

Figure 2 Electron scanning micrograph of porous microsphere. Magnification 5000x.

is attributable to the interstitial volumes between the polymer particles, and because the membrane that surrounds the solid polymer particles is porous, the interstitial volume is open to the outside.

Loading of Active Agents

These can be incorporated by two different procedures. In one procedure, referred to as the one-step procedure, the active agent functions as the porogen and is incorporated during the polymerization process. However, this method has some limitations because the active agent has to satisfy the requirements of a porogen, it must be stable towards free radicals generated during the copolymerization process, and it must not inhibit the copolymerization process. For this reason, a procedure where porous microspheres are produced first, and subsequently loaded with the active agent, is more generally applicable. Such a process is known as the two-step procedure.

Loading is achieved by stirring empty porous microspheres in a solution of the active agent, which diffuses into the microsphere particles. The solvent is then evaporated to obtain microspheres with the active agent loaded within the pores. If the agent is soluble in the polymer, some may partition into the matrix. Should a high loading be desired, or if the active agent is only sparingly soluble in the solvent, the process can be repeated a number of times. Clearly, using such a procedure, some of the active agent will also be found on the outside of the microspheres particles.

The incorporation of an active agent into these microspheres can be investigated by environmental scanning electron microscopy (ESEM). This method has the advantage over conventional scanning electron microscopy (SEM) in that no metallic coating is required and samples can be analyzed at ambient pressures in a water vapor. Samples are sprinkled lightly onto a metallic stub, 1 cm in diameter, bearing conductive double-sided adhesive tape, and then analyzed using a Phillips XL30 ESEM FEG instrument operated with greater than 99% relative humidity [Davies, M., and Patel, N., private communication]. Using this procedure, a good visualization of the microspheres and any free drug, if present, can be achieved.

Such a visualization method is important because loading efficiency depends on the nature of the active agent, primarily its solubility and the partition coefficient between the microspheres and the solvent used in the entrapment procedure. Both lipophilic and hydrophilic materials can be loaded into such microspheres, and range from water to petrolatum to silicone oil. Extensive studies have shown that the active agent is not bound to the microspheres and can be completely extracted.

Porous Microspheres

Figure 4 Schematic representation of controlled release of active agent from porous microspheres dispersed in a vehicle.

Figure 4 Schematic representation of controlled release of active agent from porous microspheres dispersed in a vehicle.

Release of Active Agents

Although porous microspheres can function in a limited way as a sustained-release delivery vehicle, they are best viewed as a reservoir. However, the combination of microspheres with incorporated active agents dispersed in a vehicle can function as a controlled-release device if a vehicle in which the drug is only poorly soluble is chosen. When such a formulation is applied to the skin, only that amount of the drug dissolved in the vehicle is presented to the skin. Then, as the drug diffuses from the vehicle into the skin, the saturation concentration of the drug in the vehicle is maintained by diffusion of drug from the microspheres into the vehicle. This process is shown schematically in Figure 4.

APPLICATIONS

Porous microspheres have been used in two major applications. One application takes advantage of the high porosity of the microspheres to entrap liquid materials, such as silicone oil, to convert a liquid into a free-flowing powder. This allows significant formulation flexibility, and a babywipe product has been developed where silicone in porous microspheres has been formulated in an aqueous medium.

In the other application, microspheres with incorporated active agents are dispersed in a suitable vehicle for topical applications. As already discussed, when active agents that are normally skin irritants are used and a vehicle in which the active agent is only poorly soluble is chosen, a significant reduction of irritation, when compared with ordinary formulation, is noted. Such a reduction in irritancy will be illustrated with two products, one incorporating benzoyl peroxide and the other incorporating trans-retinoic acid (RA).

Benzoyl Peroxide

Benzoyl peroxide (BPO) is clinically effective in acne, primarily because of its bactericidal activity against Proprionibacterium acnes and possibly also through its mild keratolytic effects [8-10]. The main site of pharmacological action is the pilosebaceous canal [11]. BPO penetrates through the follicular opening, probably by dissolving into sebaceous lipids, and then exerts its antimicrobial activity [12]. Skin irritation is a common side effect and a dose relation seems to exist between efficacy and irritation [13]. Thus, a controlled-release formulation would clearly be advantageous.

In vitro release kinetics were determined by applying formulations to silastic membranes mounted in static diffusion cells, and by using excised human skin. Release of BPO from two formualtions applied to a silastic membrane, one incorporating free BPO and one incorporating BPO entrapped in porous microspheres is shown in Figure 5. Initial release of BPO dispersed in the vehicle shows good linearity, but with further release would decline, as expected for t1/2 kinetics. The calculated flux for the initial release is 0.09 mg/cm2/h. The release of BPO entrapped in the porous microspheres shows a discontinuity. Initial flux is about 0.1 mg/cm2/h, very close to the release from BPO dispersed in the vehicle, followed by a slower release with a flux of 0.04 mg/cm2/h. These data indicate that not all BPO has been entrapped in the porous microspheres, and that the formulation contains some free BPO. Initial release is attributable to release of the free BPO, followed by the release of entrapped BPO.

The topical irritancy of a BPO controlled-release formulation has been determined in rabbits, in rhesus monkeys, and in human volunteers [14] using formulations with BPO dispersed in a vehicle and BPO entrapped in porous microspheres dispersed in a vehicle.

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  • Elanor
    How to prepare the porous microparticles?
    6 years ago

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