Tuesday, July 20, 2010

Formulation evolves rapidly from tablets to needle-free injection

By Gina Shaw
Formula Racing

Back when I was a kid in the 1970s, there were pretty much two ways for oral drugs to be delivered, standard tablets and capsules, and capsules were still fairly novel. I remember an old TV commercial that showed a capsule splitting apart and hundreds of tiny round particles spilling forth.

Drug formulation, of course, goes back a lot farther than the 1960s and 1970s—indeed, you could take it back centuries. What was Socrates’ cup of poisoned hemlock, after all, but a fatal drug mixture?

But over the past three or four decades, the formulation of drugs—for both oral and parenteral delivery—has taken several giant leaps forward from the simple tablets and capsules of the 1960s and 1970s.

Oral Arguments

Drug tablets, of course, need a coating—to improve their appearance and stability, mask odor and taste, reduce dust, improve bulk handling, and, not least of all for the producer, help the consumer identify the brand. Back in the 1960s, most tablets were coated with sugar. But that coating had its drawbacks, said Yidan Lan, PhD, a senior scientist at BASF Pharma Solutions. “As we moved into the 1980s, film-coated tablets were developed, and with the original film coating, stability improved, and the coating process was also more consistent, less time consuming, and just better from an appearance point of view.”

Those particle-spilling capsules, usually called hard-shelled capsules, were not particularly popular in their early days, said Dr. Lan, so those, too, evolved. “We moved to the softgel approach. That was done to achieve some kind of water solubility and also to increase the bioavailability of the drug.”

The faster and much more economical film coating technology that was adopted in the 1970s could also be functionalized for time-release delivery. The immediate-release tablets and capsules of the 1970s started dissolving as soon as you swallowed them—that was that. Controlled-release dosage form technology became important in that era; most of these had first-order release patterns.

But the big goal in the 1970s was something called “zero-order release,” said Rick Soltero, PhD, president of PharmaDirections, a drug development consulting and management company. “That was the single biggest change in oral drug formulation in the 1970s and 1980s.” Zero-order release involves a mechanism that ensures that a steady amount of the drug is released over time, improving efficacy by maximizing bioavailability while minimizing side effects and peak/trough fluctuations.

Two revolutionary developments helped to make zero-order release a reality. The first was the osmotic pump—a technology patented by in the 1980s by ALZA, which would later be acquired by Johnson & Johnson. The technology, called OROS, consisted of an osmotic core and a semi-permeable membrane. As soon as you swallowed an OROS-based drug and it reached the stomach, water there would be drawn by osmotic pressure through the membrane to saturate the drug, diffusing it gradually as a liquid through tiny laser-drilled delivery orifices on the membrane of the drug. Osmotic pump tablets helped to reduce side effects and kept levels of the drug in the bloodstream at regular and predictable levels.

Figure 1. Example of Rapid Absorption of Small Molecule Drugs From  the Lung.
Figure 1. Example of Rapid Absorption of Small Molecule Drugs From the Lung. AERx Morphine (8.8 mg loaded dose) vs. IV Morphine (4 mg). Absorption is shown for a small molecule, morphine. There is rapid absorption and once in the blood stream the clearance mimicked IV. Note that the bioavailability is almost 100%. The 8.8 mg loaded dose in the packet translated into about 5 mg lung dose based upon a 60% efficiency.

Functional Polymers Emerge

This technology is still used in drug formulation today, but it has been eclipsed somewhat by the development of functional polymers, which are used to coat single-unit tablets. These polymers simply act as excipients for the drug itself and can take a number of forms, such as ion exchange resins, polymeric adsorbents, cellulosic polymers, and polymeric coatings. Functional polymers not only allow for extended release, but can also mask the taste of a drug and improve its chemical and physical stability.

As the use of functional polymers evolved, multiple layers of coatings could be used to control the drug’s release. You might, for example, have an outer release control polymer, an inner protective coating or additional release-control layer, and then the drug’s core. “With advanced technologies today, you can also make very small mini-tablets,” said Dr. Lan. “A film-coated, single-unit tablet can now achieve the same drug release profile as the osmotic pump, without the need for drilling holes in the tablet.”

Another advance in this field, in the 1990s, involved the development of multi-particle drugs. “Originally, people were always trying to make it simple. The drug is included in a single tablet, it’s released, that’s it,” said Dr. Lan. “But multiple-unit dosage forms allow for increased uniformity of plasma levels and better reproducible bioavailability. Mini-matrix tablets combine the advantages of multiple unit dosage with those of matrix tablets, as their manufacturing technique is well established.”

“If you have multiple small particles, even if some have problems, the rest are still good, so you prevent ‘drug dumping,’ which is another advantage over single-unit tablets,” Dr. Lan said.

Another relatively recent method of controlled release is the “floating” tablet. Floating tablets have relatively low density—about the same as water—prolonging the drug’s contact with small intestinal mucosa. This is particularly useful for drugs that are poorly soluble and those that have poor bioavailability.

Yet another advance in oral delivery that came about in the early 1990s was the use of penetration enhancers—generally, combinations of fatty acids—to help enhance the bioavailability of poorly soluble drugs. “Elan was a propagator of a fair amount of that,” said Dr. Soltero. “It was based on a capric acid moiety and was used to get poorly soluble drugs, even some small peptides, into the bloodstream. Emisphere even claimed they had something that would get proteins through the GI tract, as did Novex, but I always thought that was more magic than reality.”

In oral delivery today, that’s still the biggest need, Dr. Soltero said: for poorly soluble drugs to be delivered successfully with good bioavailability. “There’s only one easy method for doing that that’s been successful so far, and that’s been increasing the number of particles by decreasing the particle size and thus increasing the total surface area. For that, nanotechnology is opening things up. Another thing that’s been effective has involved micelles, using things like surfactants or other ingredients to try to utilize the oil/water properties of the drug so that it can get across the GI tract.”

Figure 2. AERx Morphine Post-Op Pain Result: Pain Intensity Visual  Analog Scale (VAS).
Figure 2. AERx Morphine Post-Op Pain Result: Pain Intensity Visual Analog Scale (VAS). This figure shows that if you achieve similar pharmacokinetic profiles via inhalation, then you also achieve an effective pharmacodynamic response. (LOCF stands for last observation carried forward.)

Piercing Needs

Of course, not all drugs are orally delivered. For parenteral formulations, particularly given the recent growth of biologics such as proteins and peptides, the past several decades have seen an evolution toward convenience for the patient.

“We started out with a lot of lyophilized products, which addressed the concerns about stability at room temperature,” said David Cipolla, PhD, senior director of pharmaceutical sciences for Aradigm Corporation. “However, these weren’t very convenient. Patients or healthcare professionals needed to reconstitute them, add saline or another buffer, and mix—sometimes for many minutes—to get the drug to dissolve. Then they had to transfer it into a syringe or injection device. When I was at Genentech, we developed the first growth hormone liquid formulation, Nutropin hGH, which removes the reconstitution step. Now most biological products are in liquid formats to provide greater convenience.”

For regular users of injectable medications, such as diabetics who need insulin, the past two decades have been marked by the development of pen-based injection systems. “There are now systems that have their own cartridges, designed especially for short-term duration; the drugs can spend a couple of weeks or a month in an injection system. To do that, preservatives had to be added to ensure that the formulation would remain stable and to maintain sterility,” Dr. Cipolla said.

Today, some injection devices shield the patient from ever seeing the needle—and some don’t use needles at all. In July 2009, the Food and Drug Administration (FDA) approved Sumavel DosePro, Zogenix’s needle-free sumatriptan injection for acute migraine and cluster headaches. “The liquid is in a half-milliliter container, a small glass vial, powered by a nitrogen cylinder,” Dr. Cipolla said. “The patient pushes the device up against their skin, the cylinder expels nitrogen gas and presses on the plunger, shooting liquid out through a tiny orifice in the device at such high force that it enters the skin and flows into the subcutaneous fat space. They’re not advertising it as pain-free. There’s still some sensation but it’s faster than human reaction time, so by the time you hear it actuated, the injection is complete.”

Another approach is the use of inhalation. Aradigm Corporation, for example, has developed the AERx pulmonary drug delivery platform for drugs such as as morphine (see Figs. 1-3, pgs. 11-13).

Figure 3. Aerosol Particle Size Influence on Lung Deposition Using  the AERx System.
Figure 3. Aerosol Particle Size Influence on Lung Deposition Using the AERx System. Gamma scintigraphic studies are often used to determine the amount of (labeled) drug delivered to the lung and to some extent the deposition within the lungs. Three-dimensional single-photon emission computerized tomography studies like those above can give a clear picture of deposition in the lung (same subject across the four images using various AERx configurations). Clearly, at constant inhalation flow rates, with near monodisperse aerosols (GSD ~ 1.3), particle size affects deposition site.

The Solubility Challenge

As peptides, proteins, and now monoclonal antibodies have become increasingly important, drug formulators have been challenged to increase their solubility, because for many of those drugs, the required dose is very high. “The challenge has been, how do you get it all into a volume of formulation small enough to inject?” Dr. Cipolla asked. “If the viscosity becomes too high, it’s very hard to push the drug through the syringe. If you use a very wide-bore needle, that’s not too comfortable for the patient.”

That’s what happened with Nutropin Depot, a sustained-release growth hormone designed using Alkermes’ ProLease technology and brought to market by Genentech and Alkermes in December 1999. “It would be delivered once or twice monthly instead of daily or every few days, using microspheres that released the hormone over a long-time duration,” said Dr. Cipolla. “It sounded great, but the 21-gauge, half-inch needle was not well accepted. The manufacturing COGs [cost of goods] and market economics weren’t working well, either—so it was eventually withdrawn in 2004.” Alkermes has had greater success applying their sustained-release microsphere technology to deliver risperidone for schizophrenia and naltrexone for alcohol dependence.

Another innovation in parenteral delivery over the past 10 to 15 years has been reduced particle size in suspensions. “In the past, material was lyophilized, then jet-milled down to a few microns in size. But now you can create nanoparticles that are submicron in size,” Dr. Cipolla said.

“One of the leading early technologies was ALZA’s. They were able to create high concentrations of nanosuspensions, and with the smaller particles, have much greater surface area relative to the volume of the drug. For something that’s poorly soluble, the surface area guides how rapidly the drug can be dissolved. This approach is being used in nanoparticles for pills as well as nanosuspensions for injection,” he added. (One of the first nanosuspension products was, in fact, oral—Wyeth’s Rapamune [sirolimus] oral solution, approved by the FDA in 1999.)

In the early 2000s, the development of Captisol (cyclodextran) gave solubility another great leap forward. “These look like little donuts,” said Dr. Cipolla. “If you have a drug that’s poorly soluble, the cyclodextran can help solubilize it. The hydrophobic region of the drug can position itself within the ‘donut’ and increase its solubility by a factor of 10 to 100.” The first two drugs using the Captisol formulation that were approved were Zeldox/Geodon for injection (ziprasidone mesylate), a Pfizer therapy for schizophrenia approved in Europe in 2002, and Vfend I.V. (voriconazole), an antifungal from Pfizer that became the first U.S. regulatory approval of a Captisol-enabled drug in the same year.

The challenge has been, how do you get it all into a volume of formulation small enough to inject? If the viscosity becomes too high, it's very hard to push the drug through the syringe. If you use a very wide-bore needle, that’s not too comfortable for the patient.
—David Cipolla, PhD, Aradigm Corporation


In the early 2000s, pegylation swept the market. This covalent attachment of polyethylene glycol polymer chains to a drug, helps to shield the agent from the host’s immune system, prolongs its circulatory time by reducing renal clearance, and can improve the water solubility of hydrophobic drugs.

“The drug you saw pegylation first applied to was interferon alpha. PegIntron and Pegasys were the first two versions,” said Dr. Cipolla. “They reduced the frequency of administration from every other day to once a week, because the systemic half-life is increased and the drug stays in the bloodstream much longer.”

“Other polymer chains are also being added to proteins and peptides to keep them around longer,” said Dr. Soltero. “They’re changing the formulations by modifying the molecule itself. In terms of drug delivery, that means we’re going full circle in a way—back to how do we change the drug itself so that it has the characteristics of a long-term formulation, without worrying about the formulation itself to make it happen.”

Shaw is a freelance writer based in Montclair, N.J. Reach her at ginashaw@vagabondmedia.com.

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