Step 3: Determining manufacturing issues. Small doses are better than large doses, so high concentrations (>50 mg/mL) are desirable for inhaled biopharmaceuticals if they don't lead to solubility or aggregation problems. Whereas asthma drugs are typically given by the microgram, many proteins are dosed by the milligram.

The Oral Route Pills are sort of a Holy Grail for drug formulators, especially those involved with biopharmaceuticals. Many successful therapeutics are delivered to patients by way of a tablet, capsule, or pill. Oral delivery is preferable for several reasons, and patient compliance is near the top of the list. Patients are much happier swallowing a pill than getting an injection, using an inhaler, or spending time hooked up to an IV unit. Pills are also highly stable and typically have long shelf lives.

Built-in barriers to protein and peptide uptake by the oral route include enzymatic membrane mechanisms, protein biocompatibility, chemical breakdown, and physical clearance. Transport of the large molecules is controlled by enzymatic breakdown, particularly in the stomach and small intestines.

Many research laboratories are working on oral delivery systems, specifically protection against degradation and other approaches to oral delivery. For peptide or protein drugs to make it through the digestive system intact, they must be protected from enzymatic degradation and get into the bloodstream. They must be maintained at maximum solubility until they get to the intestines, where proteins are best absorbed into the bloodstream. Recall Ganderton's comment that even low bioavailability might be acceptable if it is reliable.

Buccal delivery. Other companies are developing buccal delivery formulations for biopharmaceuticals. The drug is delivered to the body by way of the mucosal membranes, in this case those inside the mouth. Biopharmaceuticals may be incorporated into patches that stick to the roof of the mouth or underneath the tongue. Buccal delivery requires absorption enhancers.

Other Delivery Methods Transmucosal drug delivery (including suppositories, which suffer from a poor reputation with patients) usually falls into the "miscellaneous" category of drug delivery technologies for therapeutic proteins, and only a few are in development. Several biopharmaceutical companies and companies that specialize in drug delivery are trying to create new methods of delivering large protein molecules to the body.

Sometimes the method of delivery depends on the indication, as with intraocular drugs (those delivered through the mucosal membranes surrounding the eye) and topical formulations, such as Regranex Gel for treating diabetics' skin wounds.

Nasal delivery. Doctors and patients want methods of drug delivery that are more convenient than parenterals. Nasal delivery is transmucosal delivery through the nose, which has good protective mechanisms for keeping proteins and infectious agents from crossing its mucosal barriers. For nasal delivery of biopharmaceuticals to be a viable therapeutic option, therefore, such mechanisms must be overcome, which may involve adding absorption enhancers. Even so, the nose offers low bioavailability (<5%) for proteins, but its mucosa are permeable to many peptides. Several peptide drugs are currently on the market as nasal drops or sprays. Sprays work best, but as with certain inhaled formulations, device development and manufacturing may become an issue. For patient compliance, sprays are preferable because nasal drops require special directions (to move the head in a particular way, for example), and the tickle causes many patients to sneeze.

Nasal delivery requires larger particles than pulmonary delivery. Droplets <10 µm are so light they go right past the nose and into the respiratory tract. Also nasal dosages must be high to make up for the low bioavailability. Absorption enhancers are being studied to address this problem.