Post on 06-Apr-2018
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Topical Dermatological Formulation Development
Put your molecule in good hands.
Things You Should Know
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Formulation Development o Topicals is Dierent Pg 1
Developing a Target Product Profle is Important Pg 2
How to Select the Topical Dosage Form Pg 3
Defnition o a Successul Formulation Pg 4
The Need or Multiple Excipients Pg 5
The Formulation Development Process Pgs 6-7
Challenging Analytical Method Development Pg 8
Prototype Screening Using In Vitro Skin Penetration Studies Pg 9
Selection o The Lead Formulation Pg 10
Clinical Manuacturing, Tech Transer & Scale Up Pg 11
About Dow Pgs 12-13
Dermatological Product Development Flowchart Back Cover
Things You Should Know
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There are important issues to consider as you contemplate develop-
ment o a topical dermatological product. You may already have
experience with oral or parenteral products, but there are challenges
and issues which are unique to development o topical ormulations.
A topical ormulation must be aesthetically pleasing, in addition to
being both physically and chemically stable, and this may require
numerous excipients. The ormulation must allow or optimal
penetration o the drug into the skin, a complex tissue. Skin pH is
approximately 5.5; thus the pH o the ormulation may change ollow-
ing application to the skin. This brochure is based on our experience
and exclusive ocus at Dow Pharmaceutical Sciences in developing
topical dermatological ormulations since 1977.
Formulation Development o Topicals is Dierent
Pg 1
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The frst step in a successul topical ormulation program is todevelop a Target Product Profle, describing the key desired product
attributes. The profle will include the intended therapeutic indication,
the preerred dosage orm (cream, gel, ointment, spray, e.g.), the
anticipated product strength (% active pharmaceutical ingredient or
API), the desired release profle and skin penetration goals, packaging,
target shel lie, and the desired cosmetic/aesthetic properties. While
not true or orals and parenterals, the cosmetic elegance o a topicalormulation (i.e., eel, color, scent, spreadibility, absorbability, etc.) is
o great importance in topical dermatologic products and is oten key
to the success o the product. The ease and/or speed with which a
topical product can be rubbed in, or avoidance o a greasy or sticky
eel, or example, can be key. Managing these actors is one o the arts
o topical ormulation development.
Pg 2
Developing a Target Product Profle is Important
Intended Therapeutic Indication
Preerred Dosage Form
Anticipated Product Strength
Desired Release Profle and Skin Penetration Goals
Cosmetic/Aesthetic Properties
Target Shel Lie
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Flexibility regarding dosage orms enhances the chance o success
or development o a stable and elegant ormulation. During early
development, the target product profle is oten refned based on
solubility, stability and/or compatibility data, as these data may
determine the dosage orm. I the API is amenable to dierent dosage
orms rom a solubility and stability standpoint, the dosage orm may
which ormulation allows or optimal penetration o the API to the
the therapeutic indication. I all dosage orms developed are similar
in their stability and skin penetration characteristics, the dosage
orm may ie selected based on compatibility with the disease state,
cosmetic properties, consumer testing and marketing considerations.
Pg 3
How to Select the Topical Dosage Form
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Deinition o a Successul Formulation
A successul topical dermatological ormulation can be considered
to be one that satisies the target product proile and is 1) physically
and chemically stable (adequate shel lie), 2) releases API rom the
ormulation and delivers it into the skin as required or the target
indication, 3) is cosmetically elegant and acceptable to patients,4) contains only excipients that are necessary, FDA-approved or
acceptable rom a regulatory perspective, and acceptable or the
disease state, 5) is easy to apply and compatible with the desired
packaging, and 6) can be manuactured with a process that is
scalable to commercial levels. There are challenges during almost
every development program. It is important to be able to anticipate
problems, prevent them where possible, and to understand how tocorrect those that do occur.
Pg 4
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Unlike oral and parenteral dosage orms, topical dermatologicalormulations oten require many excipients. Each excipient should
be justifed by unction and need. Those that may have activity or
the disease state or that could inuence the vehicle eect (thereby
reducing chances o clinical success) should be avoided. A novel
excipient should not be used i an older, well-characterized, inactive
ingredient which is listed on the FDA Inactive Ingredients Database
would work just as well. I a novel excipient is used, it is probablethat FDA will require additional saety data, which will increase the
nonclinical study burden (time and cost). Solvents, preservatives,
antioxidants, suractants and other agents are used to overcome
solubility, stability, or skin penetration challenges and are selected
based on the physiochemical properties o the API. Cosmetic elegance
necessary or patient acceptance and compliance may require
additional excipients. With so many excipients, interactions may
occur with each other or with the API, ultimately resulting in odor,
discoloration, loss o viscosity, or loss o potency. In addition, it is also
important to select well-characterized excipients whenever possible,
in order to avoid uture issues with variability.
The Need or Multiple Excipients
Pg 5
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Dow Pharmaceutical Sciences has developed a ormulation
development process which has proved to be very successul or
our clients. A team rom our Formulations, Analytical Sciences,Drug Delivery, and Project Management groups (with consultation
rom Nonclinical Toxicology, and Regulatory & Clinical Aairs) work
together to custom design ormulations based on the physio-
chemical properties o the API, with one eye on the desired cosmetic
attributes required or the clinical indication and the other on potential
regulatory considerations.
Pre-ormulation studies are conducted initially and orm the basis
or rational ormulation design. The solubility o the API in dierent
solvents (water, water miscTe p-
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Based on this data, multiple dierent prototype ormulations based
on dierent solvent and excipient systems are developed. This is done
in order to minimize the need or additional ormulation developmentat a later stage. Each topical dosage orm has its special challenges.
For example, emulsions (creams and lotions) can be thermodynamic-
ally unstable lat96(elo(der t)5.9(o)-separrmula. A varie.9(ot)-9 o(der t)echniquesns) ca.9(.)9.9( )]TJ
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Topical ormulations oten contain multiple excipients and
preservatives, as well as potentially low levels o API, sometimes making
the development o stability-indicating and impurity-tracking methods
challenging. The semisolid environment can accelerate degradation or
other reactions. Rates o degradation can vary signifcantly based on
the ormulation matrix. Extractions can also present challenges dur-
ing topical ormulation development. An API method must oten be
modifed in order to be appropriate or assay o a topical ormulation
containing the API. R&D methods can be developed, qualifed or GLP
nonclinical studies, and then validated as appropriate or GMP supplies
or Proo o Concept (POC) clinical studies in a step-wise ashion, as
needed or the particular stage o development. Full validation can
then be completed at Phase III.
Challenging Analytical Method Development
Pg 8
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In vitro penetration studies are used to screen prototypes to ensure
that the API is released rom the ormulation and penetrates the
target tissue as required or your clinical indication. A ormulation
optimized or drug penetration is more e cient and requires lower
concentrations o API, thus reducing cost o goods. This can also result
in a product o lower irritation potential, and maximum opportunity
or clinical e cacy. At Dow, human abdominal skin rom elective
surgery rom a single donor is used or these studies. This provides test
results superior to cadaver skin and avoids donor-to-donor variation.
Multiple prototypes can be compared in one study using Diusion Cell
Systems (Franz Static or Bronaugh Flow-Thru, depending on desired
study design).
Prototype Screening Using In Vitro Skin Penetration Studies
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A lead ormulation is selected based on the chemical and physical
stability data rom accelerated stability studies, on in vitro skin
penetration data, on the assessment o cosmetic elegance and
aesthetic properties, and on results o animal e cacy testing that
may be conducted (dependent on availability o predictive animal
models).
In topical dermatological product development programs, it ispreerable that the lead ormulation selected or non-clinical and
clinical studies be very close to the fnal commercial ormulation.
Signifcant ormulation changes made later in development will likely
trigger the need or bridging studies or an FDA request to repeat
potentially expensive and time consuming non-clinical studies.
Thereore, i optimization o the ormulation (beyond minor changes)
is considered necessary, it should be conducted at this stage, prior toentering into potentially costly GLP nonclinical studies.
Selection o the Lead Formulation
Pg 10
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During ormulation development a process should be developed
which will later allow the ormulation to be scaled up to large batch
sizes at a commercial manuacturing site. With topical ormulations,
the manuacturing process can inuence both stability and product
perormance. When a ormulation is transerred to a commercial
manuacturer, depending on the type, size and mixing capacity o the
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Experience With Many Indications and Dosage Forms
Since 1977, Dow has ocused exclusively on topicals and has developed
more Rx topical ormulations than any other company in the world.
Most projects are or NCEs which can be di cult to ormulate. From
this ocused experience we understand the issues and challenges
and we know how to lead you through the process. By working with
Dow, you gain access to all our experience and this provides your best
chance or success. While other companies may provide dermatological
ormulation development services, most do not have the same ocus
on topicals, wealth o experience and history o success.
Dow has developed topical ormulations or psoriasis, acne, atopic
dermatitis, actinic keratosis, rosacea, wrinkles, ungal inections,womens health, topical pain, wound healing, warts and other
dermatological conditions. A range o disease-compatible dosage
orms are developed as part o our ormulation process, so we have
considerable experience developing aqueous and non-aqueous gels,
ointments, creams, lotions, oams, sprays, shampoos, solutions, and
suspensions.
Topical Dermatological Formulation Experience
About Dow
Pg 12
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Each year we develop ormulations or 20-25 new clients, including
many start-ups. We understand the needs o small and large comp-
anies. Dow clients come rom the USA, Europe, Australia, Canada,
China, Israel, Japan, and Taiwan. Several clients are now selling
products ormulated at Dow including ClindagelTM, Clobex SprayTM,
Cutivate LotionTM, Desonate GelTM, MetroGel 1%TM, ZianaTM and AcanyaTM
to name a ew.
All services needed to progress your topical ormulation through
development, testing, manuacturing, labeling and delivery to clinical
sites are available at our acility in Petaluma, Caliornia. Coordinated
by a Dow project manager, in one location you have a ull team ospecialists to provide ormulation development and optimization, in
vitro skin penetration studies, analytical method development and
validation, scale-up and process development, stability, manuacturing
o toxicology and clinical supplies, labeling and distribution to your
clinical sites, and regulatory support. Our goal is to save you time and
to provide your best chance or success.
Pg 13
Experience Working With a Broad Range o Clients
Everything You Need in One Location
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Dow Pharmaceutical Sciences, Inc.
1330 Redwood Way
Petaluma, CA 94954-1169
Tel: 707.793.2600www.dowpharmsci.com
2009 Dow Pharmaceutical Sciences, Inc. All rights reserved.
Drug Discovery
API Selection
API Synthesis
Pre-FormulationStudies
Selection oLead Formulation
Conduct o GLPTox Studies
Preparation andSubmission o IND
TopicalFormulation
Development
RegulatoryConsulting orIND-EnablingTox Studies
Manuacture oGLP Supplies or
Tox Studies
Screening(stability & in vitrotissue penetration
studies)
Manuacture andLabeling o GMP
Supplies(PhI and PhII)
Conduct oPhase II (Other)Phase I (Saety)
clinical trials
GMP Manuactureo Phase III
RegistrationBatches
Tech Transer toCMO (commerical
manuacturer)
Phase IIIClinical Trials
Manuacturing oCommercial Product
DowCapabilities
Dermatological Product Development Flowchart
Submission oNDA & Approval