Drug Delivery Underestimated Drug Formulation: So Much Potential in Pellets

Related Vendors

Glatt GmbH

Glatt Ingenieurtechnik GmbH

Italvacuum, Srl

TRM Filter d.o.o.

Before new active ingredients can achieve market success, comes drug delivery. OSDs continue to rank highly as the formulation of choice. Why the pellet is probably the most versatile active ingredient formulation, but at the same time the most underestimated.

Active ingredient formulation is a fine art and a matter for specialists. Albeit many pharmaceutical companies like to take the path of least resistance when launching a drug and, for the sake of simplicity, press the active ingredient into a tablet along with a few excipients. However, at least by the time the topic of life cycle management is broached, good advice can prove expensive, and that is when Glatt Pharmaceuticals comes to the fore.

The Glatt subsidiary has now been on the market for more than 25 years, and Dr. Norbert Pöllinger has been there from the very beginning. In the meantime, the initial team of five employees has grown to over 150.

Pöllinger emphasizes that, as a manufacturer of process technology, Glatt enjoys a good reputation among pharmaceutical customers worldwide, and the service subsidiary certainly benefits from the machine manufacturer's reputation. The developers, who are based in Binzen, Germany, specialize in multiparticulate dosage forms, i.e. powders, granules and pellets. Here the focus is on optimized bioavailability, taste masking, and improving the solubility or stabilization of the dosage form. Pöllinger is a real pellet fan and, over the decades, has become a sought-after specialist in this field. His special flair for this dosage form probably dates back to the days when the pharmacist worked in galenic development at Bayer. At some point, the call from Binzen ensued and he began to build up the team that today accompanies pharmaceutical companies worldwide from development to market supply.

Despite New Therapy Options — People Still Swallow Pills

Speaking of market supply: According to Pöllinger, the majority of active ingredients confronting Pharmaceutical Services are “small molecules”. Despite all the hype about new forms of therapy, almost 90 percent of the drugs developed and manufactured by the pharmaceutical industry are still small molecules with a molecular weight of 0.1 to 1 kilodalton, which are swallowed as capsules or tablets. The preferred site of absorption of such active ingredients is the gastrointestinal tract. This is yet another reason why oral formulations are still the workhorses of drug delivery.

However, there are additional reasons why Binzen will not be running out of work anytime soon. “People come to us with complex requirements when the active ingredients are difficult because the uptake kinetics are poor, the active ingredients are extremely bitter, or there are special requirements for the uptake site. It is also about life cycle management and the question: What comes after the initial formulation?” says Pöllinger, immediately providing the explanation: "Many companies work with a rapid-release formulation for market approval in new NCEs, and then figure out how to design the rest of the drug’s life cycle later.”

Children are Special Patients

The EU created a special challenge for pharmaceutical companies a few years ago: The authority will only grant approvals if there is also a formulation suitable for children. Since 2007, an EU regulation has been in force that requires pharmaceutical companies to submit a pediatric investigation plan for new marketing authorizations and to conduct studies with children. To make this development effort worthwhile for the companies, the EU has promised benefits such as an extension of patent protection for another six months. Since then, many things have changed, but the problem has remained that children, especially infants, find bitter medicine very hard to keep down. Child-friendly formulations are needed so that the child does not spit out the medicine in disgust. This is a broad playing field for Glatt experts, whose expertise includes the formulation of the antibiotic clarithromycin, which is given to children to treat middle ear infections or pneumonia.

Glatt was and is also involved in another exciting project: Together with Diurnal, a spin-off of the University of Sheffield and Berlin Charité, the experts have developed pellets that are filled in transport capsules for the treatment of a congenital hormone deficiency in newborns. Babies who suffer from this cannot produce their own cortisone and have to take the hormone for the rest of their lives.

For years, only tablets were available, which could only be dosed very imprecisely for newborns and infants. That was until bioavailability studies showed that hydrocortisone-loaded pellets not only worked just as well, but could also be precisely adjusted to the weight of the young patients.

Now the EU-funded project has entered its second round: To reduce the number of adult intakes, pellets with a special coating will soon be available – a “controlled-release formulation” that mimics the natural progression of cortisone levels.

Which Dosage Form do You Prefer?

Anyone developing a dosage form for a new active ingredient is first faced with a few very fundamental questions:

• What is the molecular nature of the drug?

• Where should it be absorbed?

• How high does the dosage have to be?

• How often is it to be administered?

“We've been focusing predominantly on multiparticulate dosage forms, mainly pellets, for the last 25 years,” Pöllinger says. In his opinion, pellets are particularly suitable for clinical studies. If you want to test ascending dosages, e.g. for tolerance, the beads coated with active ingredient are much easier to dose than tablets, which quickly become unwieldy. “That's why we're trying to convince companies to use the pellet form,” the pharmaceutical expert explains. But multiparticulate forms also offer advantages for subsequent life cycle management. Starting from a basic concept, it would be possible to control the release kinetics of the drug and/or the site of resorption in the second and third attempts.

Medicines for pediatrics and geriatrics – all of this is easily possible with pellets, according to Pöllinger.

It's All a Question of Absorption

Many issues revolve around drug absorption and solubility enhancement. Whether the transport to the site of action is successful is decisive for the existence or non-existence of new developments. “For example, self-emulsifying surfactant mixtures improve the absorption of hydrophobic active ingredients quite decisively,” Pöllinger explains. The experts also have processes such as “solid dispersion” in their repertoire. This refers to the conversion of crystalline to amorphous molecular structures, which dramatically increases the solubility of active ingredients in combination with suitable polymers such as polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP).

Pellets may contain the solid dispersion in the form of a layer on a starter bead – or may consist entirely of the solid dispersion, as matrix pellets. Pöllinger also sees potential in processing highly active ingredients.

Toxic dusts would not be produced at all with coated pellets, and the number of transfer steps and the risk of contamination are also reduced compared to tablet production.

What's Next?

There are also ideas for the future: Pellets could enable individualized medicines that contain different drug pellets for multiple ailments. The background should be familiar to many people who care for their mother or father. Elderly people often suffer from several diseases, have to take statins, blood pressure lowering drugs and much more. This can often come to up to ten tablets a day.

“The point here is to make medication more intelligently, more thoughtfully and with more individualization, because people often suffer from side effects that cancel out the positive effects,” Pöllinger explains. He believes the range of possibilities offered by pellets is far from exhausted. The art of active ingredient formulation still offers great potential for innovation.

(ID:48518394)