APR March 2024 - 29

« INTERVIEW
solubility unless the particles are in the 10-nm diameter range, which
is exceedingly difficult to achieve. Most approaches to produce
nanoparticles result in diameters of a few 100-nm. The main benefit of
nanoparticles is a significant enhancement in dissolution rate relative
to typical crystalline API (which tend to fall in the 1-100-micron
diameter range). So, they don't really enhance solubility. However,
in some cases, for hydrophobic API, dissolution rates can be quite
slow, so this approach can lead to enhanced absorption as long as the
solubility of the crystalline drug is not too low. Typically, nanoparticle
approaches work for APIs with crystalline solubilities > 10 ug/mL. Lipid
systems are useful for classes of APIs which are lipophilic, and in these
cases can be the method of choice. Most modern active molecules
targeting novel biological targets are only slightly lipophilic, so this
approach is somewhat niche.
Spray dried dispersions appear to be the
preferred approach to enhancing solubility in
the GI tract, can you give us an overview
of how this works and the limitations of
this approach?
Spray Dried Dispersions, stable amorphous formulations of an
API, are by far the preferred approach to overcoming solubility
limited absorption in the GI tract. Typically, the API and a polymer
are combined in an organic solvent as a solution, and then spray
dried to form 5-50 um sized particles. These particles, which are a
combination of an amphiphilic polymer and the API, are physically
stable and have dissolution properties that lead to substantial
increases in bioavailability relative to crystalline API alone. There
really are no other formulation approaches that can broadly achieve
performance, stability, and manufacturability goals needed for
insoluble small molecules.
well established.
The technology is very scalable and
There are over 45 spray dried products on the
market and 100's in development today. While it is truly an amazing
technology, it isn't easy to develop or scale for those who don't
have the experience. It is critical that clients choose a CDMO with
extensive particle engineering experience and proven processes
to deliver successful spray-dried products. Our estimates are that
as much as 80% of insoluble compounds that require an enabled
approach should use spray drying as the preferred approach. There
are certainly other approaches, such as twin-screw melt-extrusion
that can produce amorphous materials, but this approach is only
applicable to 10-20% of the APIs that our clients have today.
In addition to solubility, permeability in the GI
tract is a major challenge. Could you outline the
existing approaches to improving permeability?
Permeability limited absorption is becoming a major barrier for
many novel molecules that
are being developed.
Specifically,
molecules are becoming much more complex structurally in order
to enable sufficient interaction with novel targets.
For example,
protein degraders and molecular glues are clearly a promising
class of compounds for treating a broad range of diseases, but
these molecules are generally large (800-1500 MW) and thus have
significantly reduced passive permeability across the epithelium in
the small intestine. Another class of compounds, peptides, are also
generally large and have very poor permeability.
Unfortunately,
there aren't a lot of tools that we can use to improve permeability.
There are generally two main approaches that are practical:
increasing solubility to increase the flux across the membrane,
and using excipients that modify the lipid bilayer or tight junction
between epithelial cells to allow for increased transport. We have
used both successfully, but in general, these formulation approaches
are still far from ideal in terms of enhancement in bioavailability.
It
takes a very comprehensive approach to formulation and the dosage
form to truly have an impact here, and we have ongoing research to
explore other approaches that appear promising.
Going back to complexity, and given the
challenges of permeability for oral delivery
of peptides and other larger molecules, what
other approaches do you see that might make
an impact?
Given the complexity of molecules that we see and the significant
limitations in existing formulation technologies, it is clear we need
" outside the box " approaches to obtaining acceptable PK. There are
some novel approaches that utilize nanoparticles to at least maximize
drug at the surface of the epithelium that may help, and certainly
for peptides, it is critical to protect the peptide from the enzymatic
degradation that occurs in the GI tract.
So, designing a dosage
form that transits through the gut to deliver the peptide to the right
location to maximize absorption and minimize degradation is key. It's
more than just enterically coating your tablet, one needs to design
the form to transit, protect, and dissolve at the right location. Also, we
are developing injectables (SQ and IM) that are simple to deliver and
patient friendly that should be considered when developing and drug
that has significant permeability issues.
For compounds that are complex and can't
be given orally, what needs do you see that
are unmet and how would you address
these needs?
Advanced injectable formulations and devices are likely to be adopted
more and more as a viable approach. If we are limited to a few percent
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APR March 2024

Table of Contents for the Digital Edition of APR March 2024

Message from the Editor
Editorial Advisory Board
BIOPHARMACEUTICALS - Getting to GMP-Quality Biotherapeutics From Today’s Bench-Scale Continuous Manufacturing Systems: A Gap Analysis
MICROBIOLOGY - Critical Behavioral Attributes and the Application of COM-B Framework in Aseptic Processing
FORMULATION AND DEVELOPMENT - Use of AUC in AAV Analysis in a GMP Setting
FORMULATION AND DEVELOPMENT - Precision Medicine in Clinical Trials: A Statistical Perspective
An Interview with Dan Smithey, PhD President & CEO, Serán
FORMULATION AND DEVELOPMENT - Still Early Days for AI in Drug Discovery...Says Who?
QC Corner - Enhancing Material and Equipment Availability in Production Isolators
BIOPHARMACEUTICALS - Technologies for Aseptic Filling: The Choice is Clear
Vendor Viewpoint - Data Integrity and Rapid Micro Methods: Transforming to a Modern Microbiology Lab
MICROBIOLOGY - Bacterial Spore Formers in Disinfectant Efficacy Testing
Partner Perspective - Nanoparticle Technologies: Enablers for Ocular Drug Delivery
DRUG DELIVERY - Your Nails and You
DRUG DEVELOPMENT - Battling Exorbitance: High Costs in Sickle Cell Gene Therapies and the Imperative of Global Patient Registries for Equity
FORMULATION AND DEVELOPMENT - How Pharma Companies Are Solving Regulatory Challenges with AI-based Technology
Event Preview - CPHI North America
Event Preview - Excipient World 2024
P.I.N. Points
Advertiser's Index
APR March 2024 - CoverTip01
APR March 2024 - CoverTip02
APR March 2024 - Cover1
APR March 2024 - Cover2
APR March 2024 - 1
APR March 2024 - 2
APR March 2024 - 3
APR March 2024 - 4
APR March 2024 - 5
APR March 2024 - Message from the Editor
APR March 2024 - Editorial Advisory Board
APR March 2024 - BIOPHARMACEUTICALS - Getting to GMP-Quality Biotherapeutics From Today’s Bench-Scale Continuous Manufacturing Systems: A Gap Analysis
APR March 2024 - 9
APR March 2024 - 10
APR March 2024 - 11
APR March 2024 - 12
APR March 2024 - 13
APR March 2024 - MICROBIOLOGY - Critical Behavioral Attributes and the Application of COM-B Framework in Aseptic Processing
APR March 2024 - 15
APR March 2024 - 16
APR March 2024 - 17
APR March 2024 - 18
APR March 2024 - FORMULATION AND DEVELOPMENT - Use of AUC in AAV Analysis in a GMP Setting
APR March 2024 - 20
APR March 2024 - 21
APR March 2024 - 22
APR March 2024 - 23
APR March 2024 - FORMULATION AND DEVELOPMENT - Precision Medicine in Clinical Trials: A Statistical Perspective
APR March 2024 - 25
APR March 2024 - 26
APR March 2024 - 27
APR March 2024 - An Interview with Dan Smithey, PhD President & CEO, Serán
APR March 2024 - 29
APR March 2024 - 30
APR March 2024 - FORMULATION AND DEVELOPMENT - Still Early Days for AI in Drug Discovery...Says Who?
APR March 2024 - 32
APR March 2024 - 33
APR March 2024 - QC Corner - Enhancing Material and Equipment Availability in Production Isolators
APR March 2024 - 35
APR March 2024 - BIOPHARMACEUTICALS - Technologies for Aseptic Filling: The Choice is Clear
APR March 2024 - 37
APR March 2024 - 38
APR March 2024 - 39
APR March 2024 - Vendor Viewpoint - Data Integrity and Rapid Micro Methods: Transforming to a Modern Microbiology Lab
APR March 2024 - 41
APR March 2024 - MICROBIOLOGY - Bacterial Spore Formers in Disinfectant Efficacy Testing
APR March 2024 - 43
APR March 2024 - Partner Perspective - Nanoparticle Technologies: Enablers for Ocular Drug Delivery
APR March 2024 - 45
APR March 2024 - 46
APR March 2024 - 47
APR March 2024 - DRUG DELIVERY - Your Nails and You
APR March 2024 - 49
APR March 2024 - 50
APR March 2024 - 51
APR March 2024 - DRUG DEVELOPMENT - Battling Exorbitance: High Costs in Sickle Cell Gene Therapies and the Imperative of Global Patient Registries for Equity
APR March 2024 - 53
APR March 2024 - 54
APR March 2024 - 55
APR March 2024 - FORMULATION AND DEVELOPMENT - How Pharma Companies Are Solving Regulatory Challenges with AI-based Technology
APR March 2024 - 57
APR March 2024 - Event Preview - CPHI North America
APR March 2024 - 59
APR March 2024 - Event Preview - Excipient World 2024
APR March 2024 - 61
APR March 2024 - P.I.N. Points
APR March 2024 - 63
APR March 2024 - Advertiser's Index
APR March 2024 - Cover3
APR March 2024 - Cover4
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