Initial Considerations When Formulating Microparticle-Encapsulated Drugs

Part 1 of a 2 part seriesMicroparticle encapsulation is a formulation technique used to ensure sensitive active pharmaceutical ingredients (APIs) reach their targets with the appropriate concentration and release profile. Microparticles are sub-visible spheres (e.g. polymer, lipid, etc.) that encapsulate a drug. Depending on the ingredients used to create them, microscopic microparticles can protect drugs and regulate their dissolution in whatever biological environment they need to travel through.Microparticles are generally formed by first creating an emulsion system that utilizes polymeric compounds as the surfactants (i.e. detergents). Because these systems can become complex quickly, there are many factors that can affect the resulting microparticles: Choice of aqueous phase and organic phase, polymeric surfactant length, phase volume ratios, surfactant Hydrophilic-Lipophilic-Balance (HLB) values, amount of shear when processing the emulsion system, etc.It’s a fascinating problem with many technical challenges. Singota’s R&D Department has been tackling it, working on a novel microparticle formulation for a large protein molecule. The biodegradable particles we use are not novel in themselves, but using different ingredients to create them can produce therapeutic agents with novel properties, encapsulating drug products of arbitrary size. Based on our first experiences, we’ve outlined below some of the critical factors to consider when beginning work with these types of formulations.

Polymer choices

Longer polymers will pack more tightly when lyophilized, as is common practice to ensure stability. Alternatively, we can use shorter polymers that will leave larger gaps and thus release the API somewhat more rapidly (although not as rapidly as the unencapsulated, freeze-dried API).The microparticles don’t just control the release of the API. They also confer protection for the drug in the patient’s body. For example, if you wanted to target an oral drug for release in the intestine, you might use a set of polymers that are acid resistant, so they can get through the stomach intact before releasing in the slightly alkaline conditions in the intestine.The first hurdle will be to decide formulation type — the form of the drug in its base state (liquid, frozen or lyophilized). Lyophilization is often chosen for APIs that are less stable to ensure that they remain homogeneous before being reconstituted and administered to patients. Many protein drugs are lyophilized, to protect them from water, temperature extremes, and oxidation. Alternatively, a drug that can remain stable for a long period of time at room temperature could make sense in a liquid formulation.The next challenge is to create an emulsion system that gives the microparticles a chemical reason to form spheres. The polymer you choose also must act as a surfactant, one that will dissolve, depending on conditions, either in water or in a fatty phase like oil. (Think of a salad dressing; it contains bubbles of oil suspended in vinegar (i.e. water phase), which is why you have to “shake it up to break it up.”) The surfactant quality of the polymer microparticle allows it to be suspended in the water phase without actually breaking up and releasing the API.The way you produce the emulsion gives you control over the size of the microparticles. The higher the mixing pressure and shear during emulsification, the smaller the particles. Generally, in formulating microparticle drugs, small is good — for oral drugs, and especially for parenterals.Many of our particles are less than 10 microns in diameter. The smaller the particles and the more uniform the size, the easier it is to achieve a homogeneous solution before lyophilization.

Buffers and pH adjustments

Another variable that can be controlled in formulation is pH. Our team experimented with micro-encapsulation and emulsion at neutral pH (7) and over a range of acidic and alkaline conditions. At highly acidic or alkaline pH, unacceptably large particles tended to form. It turns out, however, that the ideal condition for emulsification and API solubility is not at neutral pH, but rather at slightly acid or base conditions, where some of the amino acid groups in the protein will carry a charge (at least with respect to our large protein, molecules that are slightly charged, either positively or negatively, are more readily encapsulated by the microparticles). Buffering the system with some phosphate buffered saline or other salts can help with these minor pH adjustments and ultimately with efficient encapsulation.That optimal formulation pH is unrelated to the pH at which the particles release the drug in the body. Formulation and release conditions are separate problems to solve in drug development.Microparticle encapsulation of large proteins is a highly nuanced, specialized scientific challenge. Formulation chemists taking it on should be prepared to experiment and to recognize that the experiment will contain multiple points of failure. Once you have a stable formulation that successfully encapsulates drug, the next problem will be to characterize that product and understand its release kinetics, so that it can be labeled and prepared for clinical study. View our next post where we discuss the characterization problem.Formulation is a component of Singota’s drug development service capability. For more details, visit our Development page.