Delivering With Depot Formulations
(Dr. Thomas Tice) Issue Date: Vol. 4 No. 1 January/February 2004, Posted On: 3/28/2008
Usually, we read about and become intrigued with new and novel drug delivery technologies and rightly so. This article, however, is different because it focuses on “tried and true” drug delivery technologies. Although not always in the limelight, tried and true technologies are more attractive to product developers until a novel technology demonstrates feasibility, clinical efficacy, and commercial viability. Tried and true technologies decrease the reliance on technical unknowns, have proven clinical experience and commercialization strategies, have examples of products on the market, and increase the chance of product success in today’s demanding and shorter development timelines.
“TRIED & TRUE” DEPOT FORMULATIONS
Parenteral depot formulations are tried and true. These formulations have been investigated for more than 30 years. They are administered to the patient and then release their active pharmaceutical ingredient for days, weeks, months, and for some products, even years. Many products are on the market; some of the first depot products appeared on the market in the 1980s and most are still available. And new products continue to be launched. Today, product development activity continues as laboratories are formulating to extend the duration of existing depot products, to make generic depot products, and to produce the next generation of new chemical entity products in depot form.
Depot formulations can be in the form of microparticles, implants (rod-shaped) (Figure 1), or solid boluses that form in situ. Most depot formulations comprise biodegradable polymer excipients. The polymer excipient controls the rate of drug release and resorbs during and/or after drug release. One class of biodegradable polymers that has been around for a while and still is attractive today is lactide/glycolide polymers. These resorbable polymers are biocompatible and have a long safety record in humans. They resorb solely by hydrolysis, initially to lactic acid and glycolic acid, and eventually to carbon dioxide and water.
LACTIDE/GLYCOLIDE BIODEGRADABLE POLYMERS
Southern Research Institute was one of the original groups to work with lactide/glycolide polymers. Our experience began in the 1960s when we developed the first synthetic, resorbable suture (Dexon° suture/launched 1970). This is a polyglycolide suture made by melt spinning. The first patent claiming depot compositions with lactide/glycolide polymers issued in 1973 with a priority date of October 1969. The claims speak to dosage forms consisting of lactide/glycolide particles and pellets. The inventors were George Boswell and Richard Scribner, and the patent was assigned to E.I du Pont de Nemours (US Patent No. 3,773,919). The classes of drugs listed in this patent include small molecules and peptides. Throughout the 1970s, several investigators looked at a variety of drugs to formulate with lactide/glycolide polymers. For example, much effort was put into delivering steroids because they are potent, so they can be released for long periods of time (1 to 6 months) with a single administration. The first clinical trials with steroid depot formulations began in the late 1970s.
Depot formulation activity with lactide/glycolide polymers accelerated when these polymers became commercially available in the mid to late 1980s. Today, these polymers are available in gram to kilogram quantities (up to 100-kg lots). Larger lot sizes and better polymerization process control affords polymer properties that are more reproducible as compared to the early days. Good reproducibility means polymers with the same lot-to-lot solubility and polymers that afford reproducible release profiles. For instance, improved and more consistent solubility is achieved by incorporating monomers into the polymer backbone more randomly, thus decreasing the occurrence of blocks of glycolide and lactide.
Lactide/glycolide polymers for medical devices and drug delivery formulations are typically made by meltpolymerization through a ring opening of lactide and glycolide monomers. Commercially, these polymers are made with inherent viscositites as high as 6.5 dL/gm to as low as 0.15 dL/gm. Some polymers are available with or without acid end groups. Linear lactide/glycolide polymers are applied the most, but star polymers are used as well. Higher-molecular-weight polymers are typically used for medical devices, for example, to meet strength requirements. Lower-molecular-weight polymers are typically used for drug delivery and vaccine delivery products in which resorption time and not material strength is more important. The lactide portion of the polymer has an asymmetric carbon. Commercially, racemic DL- and L-polymers are provided, but not D-polymers. The L-polymers are more crystalline and resorb slower than DL- polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are available. And of course, homopolymers of lactide or glycolide are available. For drug delivery, lactide/glycolide copolymers are available primarily in the mole ratio range of about 50% lactide / 50% glycolide to 100% lactide. Polymers in this mole ratio range are soluble in regulatory useful solvents; copolymers with higher ratios of glycolide are not. Choice of useful solvents, however, is limited in number. Key commercial suppliers of lactide/glycolide polymers include:
- Boehinger-Ingelheim (Resomer°)
- PURAC (Purasorb°)
- Absorbable Polymers International (Lactel°)
- Alkermes (Medisorb°)
Figure 2 shows the resorption of C14 labeled DL-lactide/glycolide polymers all having the same molecular weight (inherent viscosity of about 0.7 dL/gm). The polymers used in this resorption study were tested as microparticles injected intramuscularly in rats. The data show that increasing the ratio of lactide into the polymer backbone from about 50 mole% to 100 mole%, significantly extends the resorption time. Because lactide/glycolide polymers are bulk-eroding polymers (not surface-eroding polymers), the polymer hydrolyzes throughout the microparticle matrix as water enters and decreases in molecular weight, but does not leave the site of injection until the polymer is of very low molecular weight. The initial flat portion of the curve is when the polymer is reducing in molecular weight. As the curve downturns, the polymer is leaving the site of injection. It is possible to shift the resorption curves to longer times by increasing the polymer molecular weight, using L-polymers and decreasing the surface area by increasing the size of the microparticles, or using larger rod-shaped, implant formulations. The resorption curves will shift to shorter times by making the formulations more porous to increase water uptake, by using polymers with acid end groups, and when the formulations are exposed to ionizing radiation to achieve sterility (a decrease in polymer molecular weight occurs).
DRUG DELIVERY & MEDICAL PRODUCTS
Lactide/glycolide homopolymers and copolymers have been used in biodegradable surgical products for more than 30 years. Among these products include surgical sutures, interference screws (Figure 3), suture anchors, clips, angioseal/angioplastic plugs, pins, rods, staples, surgical meshes, and dental materials for guided tissue regeneration. The first drug delivery product using lactide/glycolide polymers took place in 1986 with the launch of Decapeptyl LP in Europe. This was the first injectable, long-acting microparticle product on the market. When administered, the formulation delivers a LHRH peptide analog (the agonist triptorelin) for a duration of 1 month for the treatment of prostate cancer. This product is still being sold today. A 3-month product is available as well. Three years later, Lupron Depot° was launched. Like Decapeptyl LP, Lupron Depot is indicated for treatment of advanced prostate cancer. Doses are available as 1-, 3-, and 4-month products. Lupron Depot is also indicated for endometriosis, uterine fibroids, and for the treatment of children with central precocious puberty. Risperdal° ConstaTM is the most recently approved depot formulation. It was approved in the US on October 29, 2003 (earlier in other countries). This is an injectable, microparticle formulation that provides a 2-week release of the antipsychotic risperidone. It is indicated for the treatment of schizophrenia. Interestingly, more than 30 years ago, the Boswell patent cited the use of antipsychotic agents in lactide/glycolide polymers.
Table 1 provides a list of 15 of the lactide/glycolide depot formulations on the market today. A key driver for developing these products was to ensure patient compliance. The active pharmaceutical ingredients in these products include small molecules, peptides, and a protein. These products are manufactured aseptically or employ terminal sterilization (ionizing radiation).
THE FUTURE FOR DEPOT FORMULATIONS
Many lactide/glycolide depot formulations are being developed today. Products at preclinical and clinical stages include formulations of naltrexone and buprenorphine for alcoholism/drug abuse, GLP-1 peptides for diabetes, r-hFSH for fertility, dopamine for nerve growth, dexamethasone for ocular treatment, melanotan for cancer prevention, plasmid DNA for cancer prevention, a variety of vaccines, octreotide generics, luprorelin generics, and drug eluting devices like cardiovascular stents. Another trend is drug discovery groups optimizing the chemical and physical properties of new chemical entities to facilitate their use in lactide/glycolide depot formulations.
Although this article has focused on parenteral lactide/glycolide depot formulations, there are other depot formulations based on other biodegradable polymers. And there are depot products based on non-biodegradable polymers, such as Organon’s Implanon°, a single-rod formulation made with an ethylene vinylacetate copolymer excipient. Implanon releases etonogestrel for 3 years. It is indicated for contraception. Also non-biodegradable, steroid-releasing fibers are being developed for local delivery. Depot formulations have also appeared in the veterinary sector. An example is Fort Dodge’s ProHeart° 6 microparticle formulation. This is a 6-month moxidectin formulation formulated to prevent heartworm in dogs.
In summary, there is a lot to be said for tried and true depot formulations. These formulations have been researched for more than 30 years, and products have been appearing in the marketplace since the 1980s. These dosage forms comprise microparticles, implants, and solid boluses, and many are based on the class of resorbable, biocompatible lactide/glycolide polymers known for their long safety record. Just based on the number of publicized products in preclinical and clinical development, many more depot formulations will inevitably be on the market in the near future. These high-value products will help ensure patient compliance, deliver the increasing number of biotech pharmaceuticals, and release drugs at specific sites with increased efficacy for extended periods of time.