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.
Logistics come into play if the biopharmaceutical company is partnering with a medical device company for its final dosage
form. Development of the bulk product formulation will have to take into account interim storage conditions and shipping to
the device company that will load it into devices in a fill and finish operation. Preservatives or different stabilizers may
be required, and sterility is always a concern for liquid formulations. Liquid formulations for pulmonary delivery are stored
frozen (requiring freeze-thaw testing) or at a controlled temperature (typically 2-8° C). Powder formulations are spray-dried
or lyophilized and then micronized.
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.
So why are protein pills so difficult to develop? Our digestive systems evolved to do one thing well — break down food into
usable raw materials. Proteins are some of the main nutrients we eat, so our gastrointestinal tract is pretty good at breaking
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.