3 Unusual Approaches To Sustained-Release Injectables
With the exponential growth of injectables (parenteral products), an explosion of recent advances in sustaining the delivery of injectable drugs has occurred. Specifically, polymeric implant, microsphere, and liposomal technologies have been developed to support the controlled release of injectable medications. All three of these technologies and their applications to parenteral products are further described below. Learn why sustained-release injectables are preferred.
Sustained- or controlled-release injectable delivery systems are desirable for three main reasons:
- Due to prolonged drug release, a smaller number of injections are needed for therapy which improves patient compliance and therapeutic results.
- Therapeutic agents are locally delivered where needed instead of throughout the entire body. Local drug delivery is particularly useful for cancer therapies and vaccinations.
- Medication(s) and active ingredients are protected from degradation when in the body, unlike oral products.
Polymeric implants for sustained-release parenteral products
Polymeric implants are products that have a drug combined with a biodegradable polymer matrix. The degradation of the polymer matrix controls the rate at which the drug is released to local tissues. Most polymeric implants are manufactured through compression, melting, or sintering processes. In some cases, the biodegradable polymer matrix is instead a replaceable polymeric system that slowly releases the drug in a controlled manner. In other cases, the polymeric implant is an injectable system that polymerizes into a solid upon implantation to form a drug delivery system. The later polymeric implantation system is the only system that allows for sustained drug release with an injection.
Though polymeric implants are highly advantageous for sustained drug release, there are a few drawbacks. Firstly, polymeric implants are challenging to manufacture because the biodegradable matrix must perform various functions reliably. The biodegradable matrix must degrade with a consistent profile over time, must be able to contain or incorporate the drug of interest compatibly, and must provide stability for the medication before and after implantation. In addition to development challenges, surgical procedures are often required to implant (and in some cases remove) polymeric implants.
Here are some examples of polymeric implants already on the market:
- Norplant ® — Levonorgestrel in silastic capsules inserted sub-dermally into the upper arm. Drug delivery can last up to five years.
- Duros ® — A titanium cylindrical osmotic pump implanted in the upper arm that can deliver the drug in a matter of weeks or months, as needed.
- Gliadel ® wafer — A wafer composed of carmustine medication combined with a biodegradable polyanhydride copolymer. The wafer is implanted into the cavity created by a brain tumor resection. Eight implanted wafers (61.6 mg carmustine) provide up to three weeks of antineoplastic therapy.
- Compudose ® — Silicone rubber subcutaneous implant inserted behind the ear of cattle that releases the hormone estradiol.
Microspheres for sustained-release parenteral products
Microspheres are injectable suspensions of micro-sized particles (microparticles). Most microsphere injectables are stored as dry powder. This dry powder is mixed with an appropriate liquid before injection to create the microparticle suspension used for treatment. The microparticles release drug at different rates depending upon the degradation or drug diffusion of the polymers used to encapsulate the active drug ingredient. The degradation or diffusion rates determine whether a drug is released for days, weeks, or months within the body. Microspheres can encapsulate peptides and proteins and are not limited to use with small molecules drugs. Indeed, dextran-based microspheres have been used to encapsulate liposomes and proteins using an aqueous-based emulsion technique. For dextran-based microspheres, microspheres containing substances such as dextran sulfate, hydroxyethyl starch, and albumin are formed through adjustments of ionic strength, pH, active and polymer concentrations, and temperature.
Injectable gel formulations are another approach to microsphere technologies for parenteral products. Injectables such as Atrigel R, and other formulations containing natural materials such as alginates, chitosans, or collagens, will turn from a liquid at room temperature to a gel upon injection into the body. Once the injectable formulation has gelled due to the change from room temperature to body temperature, the active pharmaceutical ingredient is slowly released as the natural gel, or polymeric matrix degrades. Common biodegradable polymers, such as poly(DL-lactide), lactide-glycolide copolymers, or lactide-caprolactone copolymers, are used for these injectable formulations. These polymers can be paired with solvents such as -methyl-2-pyrrolidone (primary), polyethylene glycol (PEG), tetraglycol, glycofurol, triacetin, ethyl acetate, and benzyl benzoate to increase biodegradable polymer degradation.
Liposomes for sustained-release parenteral products
Liposomal formulations have recently grown in popularity due to their ability to support drug stability and penetrate the drug into deep tissues. In 1995, Sequus marketed the first stealth liposome (Doxil). Stealth liposomes are nanoparticles that allow the liposome to avoid detection by the reticuloendothelial system. The reticuloendothelial system acts like a drug shield and limits the amount of drug freely circulating in the body. Thus, reducing the amount of medicine that gets to the tissues and provides therapy. Liposomes have been used to deliver genetically engineered treatments, such as inference RNA (RNAi), across the blood-brain barrier and provide other genetically engineered therapies.
Summary
Overall, the rapid growth of parenteral products has led to an explosion of recent advances in sustaining the delivery of injectable drugs. Sustained-release injectables are advantageous over traditional injectable formulations as they provide localized delivery of therapeutic agents, protect active ingredients from immediate degradation in the body, and reduce the number of injections needed for the treatment of various diseases. All of these factors reduce patient side effects and increase patient compliance for treatments.
There are three primary approaches to creating a sustained-release injectable for your drug product. These approaches are creating a polymeric implant, using polymeric microspheres, and using liposomal technologies.
When deciding which method is best for your product, it is essential to recognize that polymeric implants often require implantation and increased development time. That being said, all of these approaches support the reliable and sustained release of injectable medications that can result in drug therapies lasting from days to months instead of hours.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Sterilization Validations, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, Cytotoxicity Testing, Bacterial Endotoxin Testing, EO Residual Testing, Package Integrity Testing & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
