Biomedical Engineering Reference
In-Depth Information
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the existence of extracellular nasal proteases/peptidases;
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low uptake rates for larger peptides/polypeptides.
Peptide/protein uptake rates across the nasal epithelia are dependent upon molecular mass.
Relatively small peptides (such as oxytocin, desmopressin and luteinizing hormone-releasing hor-
mone analogues) cross relatively easily, and several such products used medically are routinely
delivered nasally. Larger molecules (of molecular mass greater than 10 kDa) generally do not
cross the epithelial barrier without the concurrent administration of detergent-like uptake enhanc-
ers. Long-term use of enhancers is prohibited due to their damaging cellular effects.
Research efforts also continue to explore mucosal delivery of peptides/proteins via the buccal,
vaginal and rectal routes. Again, bioavailabilities recorded are low, with modest increases ob-
served upon inclusion of permeation enhancers. Additional barriers also exist relating, for exam-
ple, to low surface areas, relatively rapid clearance from the mouth (buccal) cavity and the cyclic
changes characteristic of vaginal tissue. Various strategies have been adopted in an attempt to
achieve biopharmaceutical delivery across the skin (transdermal systems). Most have met with, at
best, modest success thus far. Strategies employed include the use of a jet of helium or the applica-
tion of a low voltage to accelerate proteins through the skin.
4.11 Preclinical studies
In order to gain approval for general medical use, the quality, safety and effi cacy of any product
must be demonstrated. Demonstration of conformance to these requirements, particularly safety
and effi cacy, is largely attained by undertaking clinical trials. However, preliminary data, espe-
cially safety data, must be obtained prior to the drug's administration to human volunteers. Regu-
latory authority approval to commence clinical trials is based largely upon preclinical pharmaco-
logical and toxicological assessment of the potential new drug in animals. Such preclinical studies
can take up to 3 years to complete, and at a cost of anywhere between US$10 million and US$30
million. On average, approximately 10 per cent of potential new drugs survive preclinical trials.
In many instances, there is no strict set of rules governing the range of tests that must be
undertaken during preclinical studies. However, guidelines are usually provided by regulatory
authorities. The range of studies generally undertaken with regard to traditional chemical-based
pharmaceuticals is summarized in Table 4.2. Most of these tests are equally applicable to biop-
harmaceutical products.
4.12 Pharmacokinetics and pharmacodynamics
Pharmacology may be described as the study of the properties of drugs and how they interact
with/affect the body. Within this broad discipline exist (somewhat artifi cial) subdisciplines, in-
cluding pharmacokinetics and pharmacodynamics.
Pharmacokinetics relates to the fate of a drug in the body, particularly its ADME, i.e. its absorp-
tion into the body, its distribution within the body, its metabolism by the body, and its excretion
from the body.
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