Calling the Shots: Innovation in Controlled-Release Injectables

July 2, 2011
Pharmaceutical Technology
Volume 35, Issue 7

High demand could lead to innovation in controlled-release injectables.

Sustained-release injectable biologics are popular among patients who suffer chronic illnesses. Injectable products that offer controlled drug release can reduce the frequency of injections, which makes it easier for patients to remain compliant. Sustained-release injectables also can offer therapeutic advantages and enhance the quality of patients' lives. Demand for these medicines is increasing, and the desire to extend the patents of branded biologics likely will lead to innovations in controlled-release applications.


Polymeric microspheres

One controlled-release technique suitable for biopharmaceuticals is based on polymeric microspheres. In this method, manufacturers use polymers to construct a biodegradable matrix within which a drug can be encapsulated. By choosing polymers with the proper characteristics, and by modifying the matrix properties, manufacturers can establish the desired release profile for the drug. Biodegradable microsphere systems can deliver peptides, proteins, nucleic-acid-based drugs, and even small molecules, says Ramin Darvari, senior principal scientist for novel delivery technologies at Pfizer.

Drugmakers can form the microspheres by creating oil–water emulsions. The process uses an immiscible aqueous–organic solvent system that formulators can design to accommodate various presentations of the drug compound, including aqueous solutions and dry particles. "Although traditional emulsion-based processes rely on exerting high shear on the system to generate the desired particle-size distribution, recent advances in emulsion-based particle-engineering processes have made it possible to achieve more precise control of the particle-size distribution" without the high shear that could denature a therapeutic protein, says Darvari.

Manufacturers must extract solvents such as methylene chloride and ethyl acetate from the emulsion to form the particles and remove the residual solvent through freeze-drying or spray-drying. An alternative approach to avoid solvents is to use hot-melt encapsulation to create microspheres for heat-tolerant molecules.

Manufacturers can choose among various synthetic and natural biodegradable polymers to create injectable microspheres. Most often, formulators opt for synthetic polymers, such as polyesters, poly(orthoesters), polyanhydrides, and polyphosphazenes, says Darvari.

In particular, the poly(lactide-co-glycolide) (PLGA) family of polyester copolymers is used extensively in drug delivery. PLGA might have some undesirable attributes, however. The compound exhibits bulk degradation, rather than surface degradation, which fosters the formation of the polymer's acidic degradation byproducts, lactic acid and glycolic acid. These byproducts, in turn, reduce the pH of the microenvironment within the matrix. This effect might cause drug degradation within the matrix, as well as irritation and discomfort at the site of injection, says Darvari. This problem can be mitigated by adding buffering or neutralizing agents to the formulation, thus allowing PLGA to be used safely and successfully in controlled-release injectables.

The polymeric matrix controls drug release by acting as a diffusion barrier that determines the rate at which the drug payload dissolves. The barrier also controls the rate at which the dissolved payload diffuses from the matrix. Formulators could modify the polymeric matrix to create release mechanisms that range from diffusion-based to degradation-based systems.

The release rate from a microsphere partly depends on the composition of the polymer. For example, the release rate from a PLGA microsphere is affected by the ratio of lactide to glycolide, says Darvari. Molecular weight is an important factor, too. Polymers with high molecular weights generally release their payloads at a slower rate, says Mathew Cherian, director of global research and development for Hospira. The polymers' hydrophilicity, hydrophobicity, particle morphology, and surface charge also can affect the drug's release profile.

Polymeric microsphere systems allow for a broad range of release profiles, including sustained release with zero-order and first-order kinetics, delayed release, and pulsatile release. The polymer composition also can be modified to provide an initial release of drug substance before the delivery rate stabilizes at a lower rate. "The degree of polymerization, and consequently the molecular weight, modulates the release rate," says Cherian. "By using two or more molecular-weight ranges in separate steps, during formulation, multiple release rates can be obtained."

The most common goal, especially for treating chronic diseases, is a constant- or sustained-release profile. Polymeric microspheres can provide sustained drug release for one week, or for as long as a month. Some companies are developing products with release profiles of three months or more. Life-science company Peptron has a three-month formulation of leuprolide in clinical trials. Eligard (leuprolide) from Atrix Laboratories has a three-month profile. Debiopharm has a triptorelin-embonate formulation capable of delivering for as long as six months.

In addition to the wide range of release profiles that they enable, polymeric microspheres have other advantages. The synthetic polymers can be readily synthesized in a narrow range of properties (e.g., molecular weight, viscosity, and comonomer ratio). Then the classification and adherence to standards could be reliably achieved by common methods of analysis.

PLGA polymers also are nonimmunogenic. Because they eventually degrade to their original monomeric components, the microsphere can act as an injectable depot system without the need for removing the matrix once the depot is depleted.

Microspheres also can enhance the safety of potent drugs by preventing an initial dosage spike upon administration. By encapsulating the drug and controlling its release, microspheres avoid the spike in blood levels seen after the injection of unencapsulated drugs.

The PRINT technique

The pharmaceutical industry has frequently benefited from technologies developed in other industries. The method called Particle Replication in Nonwetting Templates (PRINT), which is based on technologies used to make transistors for the computer industry, potentially could be applied to making controlled-release injectable drugs. A team led by Joseph DeSimone, a chemistry professor at the University of North Carolina at Chapel Hill, developed PRINT, which gives companies increased control of the size and shape of drug particles.

In this technique, scientists pour a drug solution into a template that forms particles with the desired dimensions and form. The solution is sometimes formulated with surfactants or lipids, and the resulting particles are colloids that are either stabilized sterically (e.g., through the incorporation of polyethylene glycol) or electrostatically (i.e., though a charge), says DeSimone. Formulators disperse these particles in phosphate buffer.

Particle replication in nonwetting templates can produce shapes that mimic (left) red blood cells and (right) metastatic cancer cells. (IMAGES ARE COURTESY OF JOSEPH DESIMONE AND TIMOTHY MERKEL OF THE UNIVERSITY OF NORTH CAROLINA)

When an emulsion is used to create PLGA microspheres, a fraction of the drug usually separates into the polymer, thus trapping it and preventing it from being released. The amount of drug loaded into PLGA microspheres is consequently limited because it is difficult to control partition coefficients. In contrast, the PRINT technique enables manufacturers to make PLGA particles that contain 40% drug. "That's three or four times higher than anyone in the literature has been able to achieve," says DeSimone.

One way that scientists can control drug release from a PRINT particle is by using degradable polymers, such as PLGA, as the particle matrix. The polymer's properties can be exploited or modified to achieve the desired release profile. The electrostatic interactions and the solubility characteristics between the particle matrix and the drug cargo that it contains can be adjusted. The more similar the polymer's characteristics are to those of the drug, the higher solubility the drug will have in the polymer. Another method would be to incorporate prodrugs into the PRINT particles. Formulators choose prodrug linkers with the appropriate rates of degradation to ensure that the drug is released from the carriers at the desired rate.

Particle size and shape also can affect a drug's release rate because different sizes and shapes have different surface-area-to-volume ratios. "Generally, if one has a set volume of particle, decreasing particle size will increase the available surface area for water contact, and thus increase the release rate," says DeSimone. Shapes, such as spheres, which minimize surface area to volume, have decreased drug-release rates, he adds. Through the PRINT technique, surface-area-to-volume ratios can be adjusted to achieve the required release rate for the product.

PRINT also can help extend a drug carrier's elimination half life, thus keeping it in the body longer (1). The more deformable a drug particle is, the more easily it can bypass biological barriers such as the lung and spleen, and the longer its elimination half-life. Rigid particles tend to get stuck in small capillaries.

DeSimone's team made particles that were 1.5 µm thick and 6 µm in diameter to mimic the properties of red blood cells. "We systematically varied the degree of deformability. When we matched the degree of deformability of a red blood cell, we had a 30-fold increase in elimination half life. We had a four-day elimination half-life for a 6-µm diameter particle, which is really unheard of," says DeSimone.

Because the PRINT technique offers enhanced control over particle properties, including size, shape, chemistry, and surface area, it could enable a wider range of release rates for injectable drugs compared with manufacturing techniques, such as emulsions, says DeSimone. The method also allows manufacturers to load particles with more types of drugs than other techniques do, including hydrophilic, hydrophobic, and biomacromolecules. He adds that PRINT can modify the particle matrix easily, thus establishing the desired release profile. "The precise control over numerous particle parameters is what makes PRINT so versatile," says DeSimone.

Solid-dose injection

Several options for controlled-release injectable dosage forms, though effective, require somewhat complicated formulations that present unique manufacturing challenges. Injectable controlled-release drugs are traditionally in liquid form because of the constraints of the standard needle-and-syringe delivery method, which limits formulation options.

The ability to retain a solid formulation offers several advantages, not least in terms of stability. The injection of solid doses is not a new concept; drug implants have been around for some time. AstraZeneca's Zoladex (goserelin), for example, was introduced more than 20 years ago. Used to treat prostate cancer, the 10.8-mg implant must be injected by a healthcare professional through a 14-gauge needle with an aseptic technique. "Not particularly pleasant," says Charles Potter, chief technical officer at specialty pharmaceutical company Glide Pharma. However, the formulation does offer sustained release over a 12-week period and makes such injections relatively infrequent.

Taking the idea of an implant one step further, Potter asked, "Why not use the drug as the needle? If the formulation can be made solid enough, it can be formed into a sharp point." That premise is the basis of Glide Pharma's Solid Dose Injector (SDI) technology, which uses a solid, homogenous mixture of drug and excipient.

In controlled-release formulations, the excipients used are biodegradable polymeric compounds, such as PLGA or polyethylene glycol, that are compatible with the Glide implant manufacturing process. By blending various grades of polymer, changing the ratio of drug to polymer, and manipulating process conditions, varied release profiles can be created with Glide formulations. On the other hand, if immediate release is required, the formulation would require quick-dissolving excipients, such as a single sugar or a blend of sugars that provide the physical strength required, but dissolve within seconds in the tissue. And although other excipients may be required to increase stability, such as for thermally labile biological macromolecules, formulations remain relatively simple.

The manufacturing process for the solid dosage form is also simple: the active ingredient and a blend of selected excipients are mixed together and passed through a standard twin-screw extruder, usually at room temperature to ensure that the active ingredient is not damaged. The spaghetti-like extrudate is then cut into individual doses that are pointed at one end and flat at the other. The drug implant is loaded into a sterile cassette and pushed directly into the tissue using a simple, reusable spring-driven actuator. The rate of degradation of the polymeric matrix within the tissue controls the release of the drug.

Potent drugs are good candidates for the company's solid-dose injection technology because they are administered in small doses that can be delivered easily as small implants. Beyond dosage size, Glide's technology does not seem limited by drug type. "We've got some very exciting vaccine data where we've shown the potential for better efficacy than a needle and syringe, and we've worked with several peptides and proteins," says Potter.

Looking to the future, Potter sees a potential market in the treatment of Type II diabetes because of Glide SDI's suitability to self-administered drugs. "Type II diabetics need a basal layer of insulin across the day. We can address Type II diabetes with our system, but different people need different levels, so we would need several dose levels for our formulations."


Scientists are refining current technologies and developing new means of controlling the release of injectable drugs. Patients seem likely to benefit from further innovations.


1. T.J. Merkel et al., Proc. Natl. Acad. Sci. USA 108 (2), 586–591 (2011).