Biomedical Engineering Reference
In-Depth Information
3.3 The Material Excipientability and Production
Process Scale-Up Ability
The 2R2S capability for nanocarriers discussed in the previous sections
determines the adsorption, distribution, metabolism, and excretion (ADME)
of the carried drug. Such a nanocarrier simultaneously having 2R2S capability
can deliver a high cytosolic drug concentration and give rise to high
therapeutic efficacy. However, this is not sufficient for it to be trans-
lational.
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The nanocarrier itself should also have proper ADME.
According to Choi and Frangioni, safety and clearance (renal or hepatic)
and a proper stealth surface should be included among the basic criteria for
clinical translation of formulation/materials administered to humans,
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''from
the benchtop to the bedside'' translation. Thus, a nanocarrier must meet the
requirements for the pharmaceutical excipient for i.v. uses. For simplicity, this
ability of the nanocarrier material(s) to be used or approved to be an excipient,
herein denoted as excipientability, is the second element for a nanocarrier to be
translational (see Figure 3.2). It goes without saying that the production of the
nanocarrier and the resulting nanomedicine should be able to be scaled-up and
establish the required GMP, or scale-up ability, for short. Some of these
important points of the two key elements are summarized as follows.
1) Safety. The nanocarrier itself should have proper ADME and no
nanotoxicity, and should be nontoxic and easy to excrete completely from the
body via the liver (into bile) or the kidneys (into urine) or both. This is because
retention of polymers or nanosized materials in the body, even inert polymers
like polyvinylpyrrolidone (PVP),
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can cause health problems. The
threshold for rapid renal excretion is about 5.5 nm in hydrodynamic diameter.
This corresponds to a molecular weight of about y 45 kDa for HPMA
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and
40 kDa for PEG.
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2) Approval. In order to expedite and increase the probability of the
approval success, the carrier should have a clear and simple structure with
known degradation products. An even better case would be that it is made of
FDA-approved building blocks.
3) Production scale-up. This involves the feasibility of making large volumes
of consistently reproducible quality to establish GMP. For instance, because
the molecular weight of a polymer-drug conjugate strongly affects its
pharmacokinetics, the polymer itself must have consistently low polydispersity
and reproducible average molecular weight from batch to batch. The same
applies to drug-loaded micelles made of block copolymers, such as PEG-PCL,
in addition to reproducible particle size, particle-size distribution, and drug-
loading efficiency and content. As the micelle structure becomes more and
more complicated, the number of quality control parameters drastically
increases,
14,210
which makes it more and more difficult to produce an
acceptably consistent formulation. Also, although not crucial to clinical
success, it is also worth considering a high, ideally close to 100%, drug-loading
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