Search Continues for Injection Alternatives

Most biopharmaceutical drugs cannot, at present, be taken orally. Since patients do not like injections, there is a need for new ways to deliver medications. More effective delivery systems also offer big pharma increased opportunities to create new products at a time when many blockbusters are coming off patents and competition from biosimilars is looming.

At Bharatbook.com’s “4th Annual Drug Delivery Systems” conference held recently in London, representatives from big pharma and specialist biotechs discussed the latest drug delivery technologies for biopharmaceuticals.

Some of these advances facilitate delivery of drugs through the skin in nontraditional ways. Glide Pharma is already making its mark in this arena; it recently signed a deal with a leading pharma company to evaluate the SDI™ solid-dose injector for delivery of a branded peptide. This is the third agreement the firm has signed for a biological product. “People normally think an injection involves a syringe, needle, and liquid,” said Charles Potter, Ph.D., CEO of Glide.

Solid-dose formulation has advantages over liquid. It is more stable, eliminates the need for cold-chain storage, and allows for controlled release. Current solid-dose injection technologies as listed and reviewed by Dr. Potter at the meeting include microspheres, implants, PowderJect technology, as well as SDI. There are also dual-chamber devices in which a drug is stored as a solid and injected as a liquid.

Microspheres, which are typically polymer based, allow controlled release of drugs and vaccines. They do work, Dr. Potter reported, but they are not perfect as it can be hard to control release and the microspheres can cause needle clogging.

Implants are invasive as they have to be surgically applied and removed. They do, however, have uses such as the delivery of Zoladex, the luteinizing, hormone-releasing hormone analog used to treat hormone-sensitive prostate cancer.

PowderJect technology is based on the high-velocity delivery of particles into the skin. It has been applied to the delivery of drug particles with diameters of 20–40 micrometers (e.g., lidocaine hydrochloride) or DNA vaccines on gold particles with a diameter of 2 micrometers. The technology is complicated, Dr. Potter explained, and it is hard to provide accurate and repeatable injection as particle size varies and many particles actually bounce off the skin. These drawbacks affect drugs more so than vaccines, he noted.

Drug applications for the PowderJect technology now reside with Anesiva, which in 2007 received FDA approval for Zingo, a needle-free system to treat pain associated with venous-access procedures in children.

The use of PowderJect for vaccines was acquired by Chiron and spun out as PowderMed, which was bought by Pfizer.

SDI consists of a reusable actuator containing a disposable drug cassette with the dosage inside. The dosage itself is a tiny rod of the drug with a point at the end. The device works by a “push-click-dose” action. It is simple and stable, and patients prefer it to an injection, Dr. Potter claimed.

Applications suitable for SDI include the delivery of biologics, vaccines, and small molecules. As far as biologics go, the technology will be used for peptides and proteins intended for long-term administration such as interferon and insulin. For vaccines, it can be used in industrialized and developing countries and for emergency use. “We believe we can address all three of these vaccine applications,” said Dr. Potter. In the case of small molecules, SDI will be a needle-free alternative for injectable generics as well as branded products.

Supercritical Fluid Technology

There are two ways in which companies can use advances in drug delivery to continuously improve and differentiate their products from the competition, said Joel Richard, Ph.D., head of pharmaceutical development for biotech products at Merck-Serono.

First, they can increase convenience and comfort for the patient by decreasing the frequency of injection. Second, they can improve pharmacokinetic and pharmacodynamic properties, which could result in a higher safety and efficacy profile for these products.

Dr. Richard went on to describe the role of supercritical fluid (SCF) technology in drug formulation and delivery, an approach that is of interest to Merck-Serono. Fluids in the supercritical state, which is between liquid and gas, combine high-solvent power with low viscosity. Using these fluids as solvents and as excipients may replace the use of organic solvents, which often cause denaturation of protein drugs.

“This is one of the drivers for supercritical fluids,” Dr. Richard explained. Aqueous-based processes may have similar benefits, only their use tends to lead to the formation of gel-containing proteins, whereas SCF-based processes are used to form nanoparticles or microparticles, which are more tractable.

Carbon dioxide is the most frequently used SCF. It has been successfully used in industrial-scale extraction processes in the food industry (the extracting of caffeine for instance) and also in the pharmaceutical industry.

“The most interesting SCF applications are those that do not use any organic solvents to produce protein particles, which allows the release of the protein over a period of time, a target for many companies,” said Dr. Richard. Applications relevant to the formulation of biopharmaceutical products include using SCFs as antisolvents for protein-particle engineering and as gas-dispersing agents for nebulization drying. SCFs can also be used as plasticizers or swelling agents to make composite protein-loaded microparticles and as solvents in fluidized bed-particle coating.

SCF is a technology that is now maturing. “At first, people thought you could do everything with it, but it does have limitations,” added Dr. Richard. There are now SCF applications being developed for both biopharmaceuticals and small molecules in which nano- and microparticles with controlled morphology are being made. “SCF offers some real opportunities for the formulation of proteins.”

Ophthalmology

Delivering medicines to the eye poses an interesting challenge, which OphthalmoPharma (OPPH) was founded to address.

“At OphthalmoPharma, we are actively involved in front-of-the-eye delivery using eye drops with trans-corneal penetration into the eye, which circumvents the need for intravitreal injections,” explained Richard White, Ph.D., director of toxicology and pharmacology. “Delivery of pharmaceuticals to the back of the eye following front-of-the-eye administration would be a major breakthrough in the treatment of diseases such as AMD and inflammatory retinitis.”

To this end, OPPH is using cyclodextrins—complex, water-soluble glucose oligomers with hydrophobic cores that can bind other molecules—as drug delivery vehicles. Cyclodextrins are ideal for the delivery of insoluble or poorly water-soluble compounds, according to Dr. White.

By identifying suitable cyclodextrin derivatives and defining the optimal molar ratio of cyclodextrin to drug candidate, the aqueous solubility of certain drug candidates can be enhanced hundred-fold and more, he added. Candidates for capture include steroids, peptides, natural compounds, and a host of small to large molecular-weight drug substances.

In a concentrated solution, the on-off kinetics of the complex favor capture of the drug. Once diluted in a complex fluid like tears, the on-off equilibrium favors slow release, increasing the half-life of the drug, which allows better penetration through the cornea and the reduction of unwanted side effects. Cyclodextrins themselves are practically inert. They are nontoxic, nonirritating, and are therefore ideally suited for the formulation of eye drops, Dr. White said.

“We have successfully developed a water-soluble latanoprost formulation using our patented monosubstituted cyclodextrin core technology,” Dr. White noted. “The new formulation, a clear aqueous solution, is stable over several months at physiological temperatures. This product shows superior ocular retention and intra-ocular penetration. We are at an early stage of development but we believe that this innovative formulation should have a good safety profile with fewer side effects than those of currently marketed products for the treatment of glaucoma.”

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Susan Aldridge, Ph.D., is a freelance science and medical writer specializing in biotechnology, pharmaceuticals, chemistry, medicine, and health.
E-mail: susaldr@aol.com.