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Chapter 9
Foam: A Unique Delivery
Vehicle for Topically
Applied Formulations
Dov Tamarkin, PhD
Foamix Ltd.
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Key Words:
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Foam, Hydrophilic Emulsion Foam, Lipophilic Emulsion Foam, Nanoemulsion
Foam, Aqueous Foam, Hydroethanolic Foam, Potent-Solvent Foam, Suspension
Foam, Ointment Foam, Hydrophilic Ointment Foam, Oil Foam, Saccharide Foam
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Introduction
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The paramount objective of pharmaceutical and skin care product development
is to create effective products based on state-of-the-art active ingredients with
improved patient compliance and usability. The vehicle used to deliver topical active
ingredients can considerably influence the performance of the active ingredients.
The vehicle can have a direct effect on the condition of the skin as a barrier, as it
can enhance or retard the delivery of the active agent to the target site of action. In
addition it can affect the skin’s physical appearance and sensory properties, attributes
that can influence patient compliance. While semi-solid compositions, such as
creams, lotions, gels, and ointments are commonly used by consumers, new forms
are desirable, in order to achieve improved control of the application, increased
skin absorption, and to maintain or bestow the skin promised beneficial properties.
Foam is becoming a prominent delivery system for topical active agents in skin
treatment. This platform provides an innovative, easy to apply, modern alternative
to creams and ointments. A significant advantage of the foam formulation is that
it spreads easily on large skin areas, does not leave a greasy or oily film on the skin
after application and does not impart a greasy feeling upon and after application.
The use of foam in dermatology was first reported in 1977 by Woodward
and Berry who studied the therapeutic benefit of Betamethasone benzoate, in
hydroalcoholic “quick-break” foam in comparison with a corresponding semisolid dosage form.1 The activity of the foam, as determined by a vasoconstriction
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Source: Tamarkin D. Foam: A Unique Delivery Vehicle for Topically Applied Formulations, in Formulating
Topical Applications - a Practical Guide, Dayan N, Ed., Carol Stream, IL: CT Books, Chapter 9 (2013), pp.
233-260.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
test, was similar to the corresponding ointment and better than a cream. In 1995,
Deaffontio et al. investigated the anti-inflammatory and analgesic profile of a topical
foam formulation of ketoprofen lysine salt, which exhibited anti-inflammatory and
analgesic effectiveness and favorable usability properties.2,3
A comprehensive review on foam drug delivery in dermatology was written by
Carryn et al. in 2003.4 Tamarkin et al. published a broad review, titled “Emollient
foam in topical drug delivery,” in 2006;5 and an additional review, titled “Foam:
The Future of Effective Cosmeceuticals,” was published in Cosmetics & Toiletries
magazine in 2006.6 More recently, in 2010, Steckel et al. wrote a review on foam
technology, titled ”Foams for pharmaceutical and cosmetic application.”7
Overview of the Market: Current Foam Technologies
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Currently, only a few dermatological foam products are commercially available.
EpiFoam (Alaven Pharmaceutical LLC), which contains hydrocortisone
acetate 1% and pramoxine hydrochloride 1%, is based on an aqueous foam vehicle.
It is indicated for the relief of the inflammatory and pruritic manifestations of
corticosteroid-responsive dermatoses.8
Olux Foam and Luxiq Foam (Stiefel, a Glaxo SmithKline (GSK) company),
which contain 0.05% clobetasol propionate and 0.12% betamethasone valerate,
respectively, are both thermolabile (temperature-sensitive) steroid hydroethanolic
foams (containing about 60% ethanol).9,10 Evoclin (Stiefel) is another hydroethanolic
foam, comprising 1% clindamycin, which is indicated for acne.11-12
Stiefel, a GSK company further markets four emollient foams, namely Olux-E
(0.05% clobetasol propionate) Foam and Verdeso (0.05% desonide) Foam for
corticosteroid-responsive dermatoses, Sorilux (0.005% calcipotriene) Foam for
psoriasis, and Fabior (0.1% tazarotene) foam for acne.13-14
Scytera (Promius Pharma, developed by Foamix), is a non-prescription foam
containing 2% coal tar for the treatment of psoriasis, which is effective and highly
convenient.15 While coal tar preparations in general are associated with poor patient
compliance as they cause skin irritation, staining to clothes, hair and skin, and are
malodorous,16 Scytera’s color intensity is off-white, and thus does not cause staining;
moreover, its fragrance is pleasant. Stiefel and Foamix are both market leaders
in foam technology and are engaged in the development of innovative foams in
collaboration with several pharmaceutical companies.
This chapter will describe what foam is, survey the various types of foam available
today commercially along with those presently under development, and exemplify
their uses in skin therapy. It will further account for the physiochemical properties of
foam products and explain how to evaluate them. Please note that the term “drug” is
used extensively throughout this chapter, as the source of much discussion is based
on such research; however, the principles of foam delivery systems apply equally well
to personal care product types and so for the purposes of this writing, the terms,
as regards their methods of application, may be considered synonymous.
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The Rosetta Stone of Foam
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To date, all foams are collectively designated as “Medicated Foams” by the
European Pharmacopoeia, and the U.S. Pharmacopoeia simply lists “Foam Aerosol”
as a sub-part of its Aerosol section.17
Most foams used in pharmacological and cosmetic applications are aerosol foams,
which comprise a semi-solid formulation, packaged in an aerosol can and pressurized
by a propellant. It is imperative to understand that while a foam preparation exhibits
distinct characteristics that differentiate it from other generically used vehicles,
not all foams are similar and they can be tailored to fulfill product properties
requirements. While in the past there were just a few types of medicated foam, i.e.,
aqueous foams, hydroethanolic foams and emulsion-based emollient foams, today
there are several new classes of foam formulations under development, mainly by
Foamix, which are distinct in their composition and functionality from each other.
Examples of new classes of foams are petrolatum-based foam, which is the foam
version of an ointment; hydrophilic solvents (such as PEG and propylene glycol)
based foam, which is the foam version of a hydrophilic ointment; and oil-based foam,
which corresponds to oil solutions or suspensions. Foams that are based on “potent”
solvents, such as dimethyl isosorbide and dimethyl sulfoxide (DMSO) contribute
to high solubility and enhanced transdermal drug delivery of active agents. Also
under development are hydroethanolic foams (containing high levels of ethanol)
which are suitable mostly for scalp treatment because they collapse easily and do not
impart greasiness to the scalp and hair. Foams can be also used to further stabilize
suspensions and there are foams that contain high levels of saccharides and honey
for wound and burn therapy.
These versatile foam classes have been used to develop a large number of foam
products, containing a variety of active ingredients, such as antibiotic agents,
antifungals, antiviral agents, immunomodulators, corticosteroids, steroid hormones,
anti-acne agents, anti-psoriasis agents, vitamins A, B, C, D and E, a-hydroxy and
b-hydroxy acids, and skin barrier-building agents for the treatment dry skin
conditions.
It is important for the formulation scientist to understand the differences
between the above classes of foam formulations, and be able to select the right type of
formulation for a given clinical condition. The current review presents the “Rosetta
Stone” of foam. It introduces the various types of foam technology platforms and
suggests a functional transformation of their respective traditional topical dosage
forms. Table 1 lays out a series of foam classes, which correspond to their current
topical dosage forms, with a summary of the main features and attributes of each
class of foam; and the following sections will provide further features of each of
these classes.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
Table 1. Classification of foam technology platforms,
corresponding to traditional topical dosage form designations
Foam
Class
Traditional
topical dosage
Main
form designation
formulation
(USP and EP,
characteristics combined)
Attributes
Water-containing Foams
Emollient, skin conditioning
Emulsion, Cream, vehicle
Hydrophilic cream Can carry lipophilic and
hydrophilic drugs and retain
their stability
Emulsion, Cream,
Lipophilic cream Favorable usability, enhance
compliance
Oil-in-water
Hydrophilic
Emulsion Foam emulsion
Lipophilic
Water-in-oil
Emulsion Foam emulsion
Emollient, skin conditioning
vehicle
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Non-greasy
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Main
Hydroethanolic ingredients =
Foam
ethanol and
water
Gel
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Aqueous Foam
Main
ingredients =
water, gelling
agents and
surfactants
Improved solubility and skin
delivery of active agents
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Oil-in-water
nanoemulsion
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Nanoemulsion
Foam
Serves to solubilize drugs,
thereby increasing their
Solution, Tincture bioavailability
Suitable for oily skin areas
Does not require preservatives
Serves to solubilize drugs,
thereby increasing their
bioavailability
Potent-Solvent
Foam
Water and
strong solvents
Gel, solution
Induces skin penetration
Suitable for transdermal drug
delivery
Does not require preservatives
Suspension
Foam
Suspended
drug in a foam
formulation
Topical
suspension
Emollient, skin conditioning
vehicle
Can carry suspended drugs
and retain their stability
Favorable usability
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Foam
Main
formulation
characteristics
Class
Traditional
topical
dosage form
designation
(USP and EP,
combined)
Attributes
Water-free Foams
Ointment Foam
Single phase,
petrolatum
main ingredient
(up to 90%)
Ointment,
White
ointment,
Hydrophobic
ointment
Prolongs drug skin residence
Compatible with watersensitive drugs
Does not require
preservatives
Greaseless ointment base
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Single phase,
PEG, propylene
glycol, glycerin
or other
hydrophilic
solvents main
ingredients
Polyethylene
glycol
ointment,
Hydrophilic
ointment
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Hydrophilic
Ointment Foam
Occlusive, builds up skin
barrier
Humectant, provides skin
moisturization
Serves to solubilize drugs,
thus rendering them more
bioavailable
Compatible with watersensitive drugs
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Does not require
preservatives
Builds up skin barrier
Oil Foam
Single phase,
liquid oil main
ingredient
Nourishes and lubricates the
skin
Oil solution
or suspension
Prolongs drug skin residence
Compatible with watersensitive drugs
Does not require
preservatives
Saccharide Foam
Monosaccharides,
disaccharides,
honey main
ingredients (up
to 90%)
Hygroscopic, absorbs
exudates
Antibacterial
Useful for wounds and burns
treatment
Water-containing Foams
The early generation of medicated foams included the aqueous foam, the
hydroethanolic foam and the newer platform of emulsion-based foam, also termed
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
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“emollient foam,” which was initially introduced by Stiefel and is now also being
extensively developed by Foamix.
Water-containing foams have several general advantages:
(1) Usability. Foam formulations containing water offer cosmetically pleasing
advantages over traditional topical vehicles such as ointments and creams. These
include easy application, minimal residue after application, and quick absorption
into the skin. Studies have revealed that patients using foam preparations spent less
time applying medication when compared with other topical medications.18
(2) Stability. The pressurized aerosol container is an impermeable packaging
system, which prevents formulation contact with air, light, and contaminants during
storage, as well as during the use period. This differentiates foam packaging from
tubes, which, although minimally, are exposed to the environment once they are
opened. Hence, drugs prone to oxygenation or sensitive to light can have longer
shelf life and in-use life when formulated in a foam.
(3) Skin hydration and conditioning. In emulsion-based foams, the hydrophobic
components, which are primarily liquid oils, act to mitigate skin dryness through
their emollient properties. The mechanism is thought to involve increased skin
hydration (water content) and reduction in water evaporation (transepidermal water
loss, or TEWL) a process which contributes to the softening and pliability of the
external layer of the skin (epidermis). Humectants, such as alpha hydroxy acids,
propylene glycol, hexylene glycol, glycerol and urea, can be added to the aqueous
phase of the emulsion.
The following sections will review the compositions of the various watercontaining foam platforms.
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Cream Foam (Emollient Foam)
The term emollient foam relates to foams that exert soothing and moisturizing
effects when applied to the skin. Emollient foams are emulsions, comprised of water
and oil, and as such possess vehicular properties similar to traditional creams and
lotions. The emulsions can be oil-in-water (o/w) or inverted (water-in-oil; w/o)
emulsions, which correspond to “hydrophilic creams” and “hydrophobic creams,”
respectively.
The oil components of the foam contribute to improved skin condition and
provide symptomatic relief of dry skin and associated skin diseases such as psoriasis
and atopic dermatitis. 19,20
Emollient Foam Composition: The primary components of emollient foams
are water and oil, which are present in the formulation as the form of emulsion.
The composition of the oil phase can be selected from all cosmetically and
pharmaceutically acceptable oils, including mineral oil; plant-derived oils and
esters, such as capric/caprylic triglycerideisopropyl myristate, isopropyl palmitate
and diisopropyl adipate; and silicone oils, which are known for their emolliency,
wetting and spreading characteristics and ability to provide unique aesthetics.
Petrolatum is a less desirable hydrophobic component, due to its greasy nature.21
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Formulations that include high concentrations of petrolatum leave a greasy and
sticky feeling after application and occasionally stain clothing. The foaming agents
that are required to stabilize the emulsion and produce foam with desirable texture
include surfactants, polymers, and foam adjuvants. The surfactants should be
carefully selected. Ionic surfactants are effective as foaming agents but they are
generally known as irritants, and therefore, nonionic surfactants are preferred,
especially when the target area of treatment is inflamed or infected or is a mucosal
surface or body cavity. A gelling agent is a useful component for the creation of
foam with desirable texture and spreading properties. A variety of gelling agents
also possess film-forming properties, which serve to maintain drugs at the site
of application. Another group of components that contribute to the stability and
sensory properties of the foam are the aforementioned foam adjuvants, which assist
the surfactants in stabilizing the emulsion and forming stable foam. The adjuvants
are selected from the variety of fatty alcohols and fatty acids.22,23 Optionally, polar
solvents such as glycerol, propylene glycol, hexylene glycol, dimethyl isosorbide,
and DMSO are added to the foam composition, in order to increase the solubility
of the active agents and to enhance skin penetration.24 The propellant can be a
hydrocarbon propellant (mix of butane, propane, and isobutene) or a fluorocarbon
gas. A pharmaceutical or cosmetic emollient foam product may include a single
active agent or a combination of active agents, which can be dissolved in the water
phase or the hydrophobic phase of the carrier composition. Yet, in certain cases,
the foam as a vehicle can still allow the dispersion of the drug even when it is not
fully soluble in either the water or oil phases. Examples of drugs that have been
successfully incorporated in emollient foam formulations include antibiotics,
antifungals, antivirals, corticosteroids, non-steroidal anti-inflammatory agents,
retinoids, keratolytic agents, immunomodulators, anesthetic drugs, anti-allergic
agents, and anti-proliferative drugs.25-26
Emollient Foam Properties: Emollient foams possess several advantages, when
compared with hydroethanolic foams:
(1) Breakability. The emollient foam is thermally stable. Unlike hydroethanolic
foams, it does not readily collapse upon exposure to skin temperature. Shearforce breakability of the foam is clearly advantageous, since it allows comfortable
application and well directed administration to the target area.
(2) Skin hydration and skin barrier function. The oil components of the foam
provide skin conditioning and enhance the skin barrier function, thereby improving
the condition of damaged skin.
(3) Reduction in adverse effects. Due to the lack of alcohol and improvement
in skin barrier function, skin irritability is reduced.
(4) Usability. Foam provides significant usability advantages. When the foam
is released from its container, it expands and allows easy spreading on the target
area, and is absorbed into the skin without any extensive rubbing. This feature is
particularly important with regard to the treatment of large skin surfaces. The fact
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
that when applied to skin the foam remains on the applied area and does not leak
or drip is an additional usability advantage.
The following examples demonstrate the implications of the above mentioned
advantages.
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Betamethasone Valerate Emollient Foam
An emollient foam composition, containing 0.12% of betamethasone valerate, was
developed with the aim of treating patients with psoriasis and atopic dermatitis. The
composition includes delicate oils and nonionic surfactants, in order to minimize
skin irritation. A Phase II, randomized, blinded, right-left comparison within patient
clinical trial was carried out with 30 patients with mild to moderate psoriasis. Two
similar plaque areas of psoriasis, i.e. both knees or both elbows, were selected for
treatment for each patient. Foam was administered on one side and a commercially
available betamethasone valerate 0.12% cream was administered on the other side
for a period of six weeks. The following results were recorded:
Efficacy: Both treatments were equally effective in the treatment of the
psoriatic lesions. After three weeks of treatment, there was a statistically significant
improvement from baseline in all parameters, including thickness (4243%
improvement), redness (3644%), scaling (4956%), itch (7778%) and global score
(4244%). These clinical improvements persisted following an additional three
weeks of treatment (Figure 1).
Usability: Patients rated the foam as better than the cream in skin absorption,
oily residue, shiny look, stickiness, and odor (Figure 2). The favorable usability of
the foam is a major advantage, which contributes to enhanced patient compliance
and better clinical outcome of treatment.
Safety: No drug-related adverse effects were recorded in both treatments.
In conclusion, the emollient foam offers an attractive alternative to mid-potency
steroid cream. As such, it is more likely that psoriasis patients will use their medication
as frequently as prescribed and will gain the desirable therapeutic benefits.
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Figure 1. Betamethasone Emollient Foam—clinical improvement of
psoriasis lesions following three weeks of treatment
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Figure 2. Usability preference–Foam vs. Cream
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Metronidazole 1% Emollient Foam – Demonstration of Efficient Drug
Solubilization and Favorable Skin Bioavailability
Metronidazole, the leading topical drug for rosacea, is currently available in gel,
cream, and lotion at 0.75% and 1% concentrations. Since the saturation solubility of
metronidazole in water is relatively low (≤ 0.75%), 1% metronidazole is not expected
to fully dissolve in an aqueous vehicle.
Emollient foam compositions, including delicate emollient oils and nonionic
surfactants, were designed with the aim of dissolving 1% metronidazole. Surprisingly,
the foam fully solubilized the active ingredient, as shown in Figure 3.
An in vitro skin penetration study was conducted using excised human skin,
aiming to evaluate the penetration profile of 1% metronidazole from two types of
emollient foams. Two foam compositions were tested–one with 2.5% propylene
glycol as a penetration enhancer and the other without propylene glycol (MZPG
and MZ, respectively). These were compared to a commercial 1% metronidazole
cream. As shown in Figure 4, the total cutaneous penetration of metronidazole
following 16 hours’ exposure was two- to threefold higher for the two foams when
compared to the commercial product. Propylene glycol increased significantly the
delivery of metronidazole through the skin. The full solubility of the active agent in
the foam formulation, as shown in Figure 3, is conceivably the explanation for the
better penetration from the foam products. Particles will obviously not penetrate
the stratum corneum.
Thus, the enhanced solubility of the drug in the emollient foam is useful in
enhancing the effectiveness of topical metronidazole.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
Figure 3. Metronidazole 1% emollient foam versus commerical cream
(a) No crystals in the 1% emollient foam
(b). Metronidazole crystals in commercial product
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Figure 4. The skin penetration profile of Metronidazole 1% emollient foam
with 2.5% propylene glycol as a penetration enhancer (MZPG) and without
propylene glycol (MZ) vs. cream.
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(a) enhanced intradermal delivery and controllable transdermal delivery by
both foams; and further, induction of transdermal delivery by propylene glycol
(b) delivery of metronidazole to all skin layers
Numerous cosmetic and over-the-counter (OTC) products have been conceived
as suitable for a foam delivery format. Several such products are at various stages
of development. Table 2 describes some of these cosmetic foams, their active
ingredients and their properties.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
Table 2. Examples of Cosmetic and Nonprescription Emollient Foams
Product
Active Agent
Salicylic Acid Acne Foam
2% Salicylic Acid
BPO Anti-acne Foam
5% Benzoyl Peroxide
Scytera
2% Coal Tar
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3% Mg Ascorbyl Phosphate
(MAP)
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Skin Whitening Foam
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“Instant” Skin Whitening Foam
MAP + Titanium Oxide
Anti-cellulite and Body Firming Foam
5% Caffeine
Sunscreen Foams
Type II:
Type I: chemical
Micronized zinc oxide &
Titanium dioxide
Type II: physical
Type III: combination chemical and physical
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Properties
Comments
Non-greasy o/w emulsion
Salicylic acid is listed as an
anti-acne agent under the FDA
OTC monograph.
Alcohol-free (no skin drying or irritation)
Moisturizing effect, to mitigate the drying effect of
the active agent
Non-greasy o/w emulsion
Contains the Natural Moisturizing Factor (NMF) ,
to mitigate the drying effect of the active agent
Benzoyl peroxide is a highly
effective anti-acne agent,
approved by FDA for OTC use.
Alcohol-free
Preservative-free
Non-greasy o/w emulsion
The foam presentation decreases color intensity
of coal tar from dark brown to off-white, making it
stain-free
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The unique formulation neutralizes the typical
smell of coal tar.
Suitable for the treatment of scalp and whole body
psoriasis.
Coal Tar is a highly effective
anti-psoriasis and antiseborrheic agent, approved by
FDA for OTC use.
The product is currently
marketed in the United States
and will become available
worldwide.
O/W emulsion
Alcohol-free
Proprietary product.
Drip-free
Cosmetically elegant
Active approved in Japan for
skin whitening.
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Skin lubricating and conditioning effect
Based on the emollient foam
technology platform.
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Moisturizing effect
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Suitable for the treatment of dandruff and
seborrheic dermatitis.
As above with instant “cosmetic” whitening
provided by titanium oxide
Based on the emollient foam
technology platform.
Sun protection as an added benefit
Proprietary product.
Unique combination product.
Alcohol-free (no skin drying or irritation)
Based on the emollient foam
technology platform.
Moisturizing effect (builds skin barrier)
Proprietary product.
Refatting effect
Uses penetration enhancers,
to increase efficacy.
O/W emulsion
Drip-free
Cosmetically elegant–spreads easily on large areas
Alcohol-free (no skin drying or irritation)
O/W or w/o emulsion foams.
Moisturizing effect (builds skin barrier)
Proprietary products.
Ability to include solids in
Cosmetically elegant–spreads easily on large areas foam based on Foamix’s
suspension foam technology.
Drip-free
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
Nanoemulsion Foam
Nanoemulsion foam is a thermodynamically stable system with a typical droplet
size in the range of 20–200 nm. Nanoemulsions show great promise for the future
of topical drug therapies and cosmetics. They enable the solubilization of hard-todissolve active agents and increase their bioavailability, resulting in improved efficacy.
The technology is suitable for a variety of actives, including water-soluble and
oil-soluble molecules, vitamins, hydroxyl acids, peptides and proteins, retinoids,
antimicrobial, antifungal and antiviral agents, NSAIDs and hormones.
Hydroethanolic Foam
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Hydroethanolic foams are the foam version of alcohol solutions and tinctures.
Olux Foam and Luxiq Foam (Stiefel Laboratories), which contain 0.05% clobetasol
propionate and 0.12% betamethasone valerate, respectively, were the first
commercially available dermatological foams, and they gained high acceptance
by physicians and patients. These are thermolabile foams, consisting of ethanol
(about 60%), water, propylene glycol, cetyl alcohol, stearyl alcohol, polysorbate
60, citric acid, potassium citrate, and a hydrocarbon propellant. The launch of
these products was followed by Extina Foam (ketoconazole foam 2%) and Evoclin
Foam (clindamycin foam 1%). Studies conducted in vitro demonstrated that drugs,
formulated in hydroethanolic foam exhibit delivery at an increased rate compared
with other vehicles. For example, an in vitro skin penetration study, using Franz
cells, demonstrated that the hydroethanolic foam vehicle delivered more clobetasol
propionate through the skin (5.3%) than the comparator solution, cream and lotion
vehicles (2.8%, 2.7%, 2.1% and 1.8% respectively).11 These findings suggest that
components within the foam (probably the alcohol) act as penetration enhancers,
and alter the barrier properties of the outer stratum corneum, thus driving the
delivered drug across the skin membrane via the intracellular route.
Since alcohol evaporates quickly from the skin, it also promotes fast drying of
the skin and therefore is used to ameliorate the sticky feeling left by many topical
formulations after application. However, alcohol extracts stratum corneum and sebum
lipids that naturally moisturize the skin and therefore may cause skin to become
dry and cracked. Due to this undesirable property, hydroethanolic foams have not
been proposed for the treatment of atopic dermatitis, a childhood inflammatory
skin disorder that involves dry, itchy skin and rashes on various body areas. Atopic
dermatitis is also characterized by impaired skin barrier and enhanced penetration,
and the use of ethanol can further promote percutaneous absorption instead of
targeted delivery to skin layers.
The high incidence of skin irritation (burning, itching and stinging) as noted,
for example, in the package insert of Luxiq Foam (54% ethanol content) is probably
due to the high content of alcohol content, in combination with surfactants which
are known skin irritants. Moreover, an even higher incidence of skin irritation was
reportedly caused by this foam vehicle (75%); 27% of the population tested/using
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the product reported moderate-to-severe irritation. Furthermore, since alcohol is
an irritant to mucosal surfaces, the label of these products states, “Avoid getting the
foam in or near your eyes, mouth, lips, or broken skin.”
In addition, the current hydroethanolic foams are thermolabile and their usage
is hindered by the recommendation not to dispense them directly onto the hands,
as the foam melts immediately upon contact with skin temperature. Instead, the
foam is to be dispensed onto a cool surface, and then small amounts of foam should
be picked up using the fingers and gently massaged into affected area.27
Thus, while alcohol is useful in solubilizing an active agent and enabling effective
dermal penetration of drugs, the development of less irritable foam vehicles, which
overcome the evident skin drying and irritation caused by the combination of alcohol
and surfactants, was warranted. One of the means to achieve this goal is adding
emollient oils to the foam composition. Such emollients provide skin conditioning
effects, build up the skin barrier properties, and reduce skin irritation. An example
of such commercially available foam is Scytera (Promius Pharma, developed by
Foamix), a product containing 2% coal tar for the treatment of psoriasis. Scytera
contains alcohol, but it also contains emollients. This novel foam vehicle is versatile
and may be used to treat psoriasis even in areas of the body where the application
is challenging, such as the scalp, palms, and soles.28,29
An additional way to overcome the usability limitations of the traditional
hydroethanolic foams, which was developed by Foamix, is to omit the surfactants
or to replace them by polymeric agents, resulting in foams which are thermally
stable.30,31 The absence of surfactants in the formulation further decreases the
irritation potential of such formulations.
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Potent Solvent Foam
A new platform of foam formulation is intended to promote transdermal
skin delivery of drugs via the addition of high concentrations of skin penetration
enhancers. Following the recent FDA approval of products containing up to 40%
DMSO, an aqueous foam comprising 40% DMSO was developed by Foamix, which
is suitable as a carrier for non-steroidal anti-inflammatory drugs that are intended to
treat osteoarthritis, as well as other drugs that can be administered transdermally.32
Water-free Foams
The creation of foam formulations without water is counterintuitive. It is known
in the art that foams can easily be formulated based on high amounts of water, in
combination with surface active agents, foam adjuvants, and polymeric agents. As
described in the literature, hydrophobic excipients, such as petrolatum, oils, and
hydrophilic solvents, can have a de-foaming effect which makes the formulation of
foams based on such solvents challenging. To overcome this challenge, substantial
levels of surfactants that act as foaming agents have been used in the past; however,
many surface active agents are known to be irritating to skin, especially ionic surface
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active agents, and repeated application to the skin or mucosa in high concentrations
can damage the integrity of the skin barrier and cause dryness and irritation.
Newly-developed water-free foams, which contain limited amounts of surfactants
or no surfactants at all, are currently under development. While water-free foams
are as-yet unavailable commercially, several products based on such foams that are
under development are described in following sections.
Water-free foams have several advantages:
(1) Stability. The first and foremost advantage is that water-free foams are
perfect vehicles for drugs and cosmetic active agents that undergo decomposition
or are unstable in water. Many active agents, including corticosteroids, steroid
hormones, immunomodulators, antibiotics, and water-soluble vitamins such as
vitamin C, as well as other actives that contain ester groups, tend to degrade in the
presence of water, so a vehicle that does not contain water is preferred. Moreover,
the pressurized aerosol container is an impermeable packaging system, and as such,
it prevents contact of the formulation with ambient moisture even during the use
period, unlike tubes which are exposed to the environment once they are opened.
(2) Self-preservation. Microorganisms require water to grow and reproduce. A
water-free foam formulation prevents the growth of bacteria, molds and fungi during
storage, and, as mentioned, the entry of moisture into the aerosol pressurized can
is prevented during the use period, so water-free foams do not require the inclusion
of preservatives.
(3) Usability. Today’s water-free topical formulations are primarily ointments,
which are characterized by being thick and greasy, and they require extensive
rubbing for efficient topical application. In contrast, foams are structurally soft and
their application is facile. They spread easily onto the skin and absorb quickly.
(4) Skin hydration & conditioning. Hydrophobic excipients such as petrolatum
and liquid oils act to mitigate skin dryness and ameliorate inflammation through
their emollient and humectant properties. They make the external layers of the skin
(epidermis) softer and more pliable, thereby increasing the skin’s hydration (water
content) by reducing water evaporation. Hydrophilic excipients, such as polyethylene
glycol, propylene glycol, and glycerin are hygroscopic—they attract ambient water
and retain skin moisture. Water-free foams are rich with such emollients and
humectants, so they maximize skin hydration and conditioning.
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Ointment Foam – Petrolatum-based Foam
Ointment foam is the foam version of traditional petrolatum-based ointments.33
When applied to skin, petrolatum can generate an occlusive layer and lower TEWL.
Petrolatum-based foam formulations may be complicated to make, especially due
to the high viscosity of the hydrocarbon; however, there are now under development
ointment foams that contain up to 90% petrolatum. The foaming agents in such
formulations include small amounts of foam adjuvants and nonionic surfactants.
The propellant is typically hydrocarbon.
Due to the unique texture of the foam, it instantly liquefies and spreads easily
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onto the skin upon application, and no extensive rubbing is required. Thus, the
benefit of petrolatum’s occlusive shield is retained without the thick texture and
greasy feel of traditional ointments. This usability feature is especially valuable in
the treatment of infants and children who suffer from dry skin conditions like atopic
dermatitis. In such cases, the effect of the drug is accompanied by the synergistic
skin barrier buildup, and lubricating and protective properties of the vehicle.
Examples of drugs that can benefit from this type of formulation include
corticosteroids, which are typically applied to large areas of dry, inflamed and
damaged skin, anti-infective agents (antibacterial, antifungal, and antiviral drugs)
and immunomodulators (such as pimecrolimus and tacrolimus) which are used to
treat atopic dermatitis. An illustrative example is a unique petrolatum-zinc oxide
foam (petrolatum and natural oils, 91%; zinc oxide, 15%). Petrolatum is approved
by FDA as an OTC active ingredient that helps treat and prevent diaper dermatitis,
seal out wetness, and temporarily protect against and provide relief from chapped
or cracked skin, as well as minor cuts, scrapes, and burns. Likewise, zinc oxide,
the active ingredient in many diaper dermatitis products, is a skin protectant and
an antimicrobial agent. It protects by forming a protective barrier on the skin,
preventing wetness and other irritants from reaching the skin underneath. Unlike
traditional petrolatum-based pastes for diaper dermatitis, which are very thick and
hard to apply to the baby’s sensitive skin, the petrolatum-zinc oxide foam is easy
to apply, and still provides the same protective and healing effects. This synergistic
composition can be further enhanced by the addition of an antimycotic agent (such
as miconazole, ketoconazole, clotrimazole, or nystatin) to eradicate yeast infections.
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Oil Foam
Oil foam is the foam version of traditional oil-based solutions and suspensions.34
Oil foam is one of the most promising foam platforms for use in dermatology, as it
can utilize a broad range of pharmaceutical liquid oils, including mineral oil, plantderived oils (e.g., olive oil, soybean oil, and castor oil), emollient esters and alcohols
(e.g., isopropyl myristate, isopropyl palmitate, diisopropyl adipate, isostearic acid,
and oleyl alcohol), and silicone oils.
Despite the fact that oils are generally known as de-foaming agents and their
incorporation in foam formulations is challenging, studies have shown that use of
a unique proprietary technique can yield a foamable composition containing more
than 90% oil content. Such a composition contains very small amounts of foaming
agents and no water whatsoever. The foaming agents include lipophilic surfactants
with low HLB, foam adjuvants (fatty acids and fatty alcohols), waxes, and polymers.
In certain cases, when a drug is to be included in the vehicle that is incompatible
with surfactants, the aforementioned technique even allows the creation of foam
compositions with no surfactants at all. 35-36 The most suitable propellants for such
foams are hydrocarbon propellants.
Oil foams have a very soft and airy texture; they spread effortlessly on the target
surface and quickly absorb into the skin, leaving no greasiness at all. In fact, oil
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foams are so cosmetically elegant that they can be used for the treatment of facial
conditions, even if those conditions are associated with oily or sensitive skin, as in
the cases of acne and rosacea.
Oil foam is the most suitable form to accommodate unstable drugs. For example,
it has been used as a vehicle for calcipotriene and calcitriene, two vitamin D3 analogs
to treat psoriasis and atopic dermatitis, resulting in stable drugs with more than two
years of shelf life. The most advanced oil foam product in private development is
Minocycline Foam (1% and 4%).37,38 Minocycline is an antibiotic known to be very
unstable, since it is degraded by a wide range of commonly used pharmaceutical
excipients. For example, it degrades readily in the presence of hydrophilic solvents
(such as water, glycerin, sodium PCA, propylene glycol and polyethylene glycols),
polymers (such as xanthan gum, poloxamers, carbomers, and methocel), and
surfactants (such as polysorbates, sorbitan esters, polyoxyalkyl esters, and lanolinbased surfactants). Hence, the development challenge was to attain a stable foam
composition without the hydrophilic compounds, which are usually used as foaming
agents. A series of development efforts resulted in a water-free, alcohol-free, and
surfactant-free formulation which contains more than 80% liquid oils, where the
foaming agents are fatty alcohols, fatty acids, and waxes.
The Minocycline foam has the following features:
Stability: Minocycline Foam 1% and 4% exhibit high stability. They remain
within the designated specifications following 12 months’ storage at 40 ºC and over
24 months at 25ºC.
Antibacterial effects: In vitro studies have demonstrated that Minocycline Foam
1% and 4% effectively inhibited the growth of Streptococcus pyogenes, Pseudomonas
aeruginosa, Staphylococcus aureus, a methicillin-resistant strain of Staphylococcus
aureus (MRSA), and Propionbacterium acnes, the causative microorganism in acne.
Inhibition of inflammation and apoptosis: UVB irradiation of the skin is known
to decrease cell viability and total antioxidant capacity, while increasing the levels of
inflammation (pro-inflammatory cytokines secretion) and epidermal cell apoptosis.
Exploratory studies have revealed the beneficial effects of Minocycline foam on cell
viability and apoptosis of skin cells: treatment prior to irradiation results in more
than 50% inhibition of apoptosis, as measured by caspase 3 activity; and treatment
after irradiation results in 60% inhibition of apoptosis, as measured by caspase
3 activity. Capsase 3 is a cytokine that plays a key role in apoptosis, defined as
programmed cell death that is accelerated in inflamed tissues.44
Targeted delivery of Minocycline into the skin: The transdermal penetration of
Minocycline was tested using the Franz cell in vitro diffusion system, with porcine
ear skin. Approximately 500 mg of product was placed in each cell; the receiver
compartments were sampled at baseline and 3, 6, 9 and 24 hours following application,
respectively. After 24 hours the amounts of Minocycline in the upper and lower
stratum corneum layers (SC1 and SC2) and viable skin were analyzed. As shown
in Table 3, the drug was delivered exclusively into the skin. The mean amount of
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Minocycline in the skin following 24 hours of exposure was 9.5 g/cm2 for the 1%
formulation and 43 g/cm2 for the 4% formulation. The weight of skin at the delivery
area is about 100 mg, which implies that the concentration of Minocycline in the
skin following 24 hours of exposure is about 168 g/gr of skin for the 1% formulation
and about 760 g/gr for the 4% formulation. This amount is an effective dose for
the treatment of bacterial skin infections. No transdermal passage of Minocycline
was observed, indicating that Minocycline foam should not generate any systemic
adverse effects.44
Table 3. Minocycline Foam 1% and 4%; Measure Skin Delivery
Comparison
Minocycline Foam 1%
(n=5)
Minocycline Foam 4%
(n=6)
Minocycline g/cm2 STD Minocycline g/cm2 STD
C
Stratum Corneum SC1
7.77
4.32
33.63
20.41
0.93
0.77
7.49
8.67
8.70
4.97
41.12
16.89
Receiving Compartment
(Transdermal Delivery)
0.79
0.19
2.00
0.81
9.49
4.99
43.12
17.48
-
0.00
-
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Total Intradermal Delivery
IG
Viable Skin
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Stratum Corneum SC2
Total Stratum Corneum
0.00
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Figure 5. Percent reduction of inflammatory, non-inflammatory and total
count of acne lesions
Minocycline foam is safe and effective in the treatment of acne:39 A randomized
double-blind dose-ranging Phase II clinical study was conducted to assess the
efficacy and safety of Minocycline foam in 150 patients with moderate to severe
acne who received placebo or one of two Minocycline foams (1% or 4%) once daily.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
As shown in Figure 5, six weeks’ treatment was enough to reach more than
70% reduction in the inflammatory lesions. Even after three weeks of treatment the
reduction of inflammatory lesions was 53% and statistically significant. The effects
were dose-dependent, as demonstrated by the higher effects of the 4% foam and
the placebo. Figure 6 exemplifies an acne patient who had 49 lesions at baseline (23
inflammatory lesions, 26 non-inflammatory lesions) and who improved dramatically
after nine weeks of treatment.
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Figure 6. Photographic documentation of the effect of Minocycline foam in
a severe acne patient. Dramatic improvement is observed after 9 weeks of
treatment.
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Minocycline foam is safe and effective in the treatment of impetigo39: A randomized
double blind dose-ranging Phase II clinical study was designed to assess the efficacy,
safety, and tolerability of two strengths of the Minocycline foam in pediatric patients
with impetigo. Impetigo is a highly contagious bacterial skin infection. The study
enrolled 32 pediatric patients ages 2 to 15 with at least two impetigo lesions. Patients
applied the foam twice daily for 7 days; and they were checked again on day 14.
Strong efficacy was demonstrated in both 1% and 4% levels. Clinical effectiveness
was defined as the absence of treated lesions, or treated lesions that had become dry
without crusts with or without erythema compared to baseline, or had improved
(defined as a decline in the size of the affected area, number of lesions, or both)
such that no further antimicrobial therapy was required. Notably, about 80% of
the patients in both groups saw improvement, or disappearance of the lesions, and
met the efficacy criteria after 3 days of treatment. Clinical response at the end of the
treatment was 92% and 100% respectively for the low or high doses; and all patients
(100%) demonstrated improvement on day 14 (Table 4 and Figure7).
Eleven of the study patients had methicillin-resistant Staphylococcus aureus
(MRSA) infection at baseline, and in all cases the infection was eradicated on day 7.
Minocycline foam was well-tolerated and no drug related side effects were
recorded in any of the patients throughout the study. Questionnaires, filled by the
patients’ caregivers revealed high satisfaction from treatment.
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Table 4. Minocycline Foam 1% and 4%: Success rate at Day 3, Day
7 (End of Treatment) and Day 14 (Follow-up)
1%
4%
All
Day 3
81.3%
78.6%
80.0%
Day 7 (EOT)
92.3%
100.0%
95.8%
Day 14 (FU)
100.0%
100.0%
100.0%
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Figure 7. Photographic documentation of the effect of Minocycline foam in
pediatric patients with impetigo, demonstrating visible improvement or
clearance of lesions within 3 to 7 days of treatment.
Hydrophilic Waterless Foam
Hydrophilic waterless foam is the foam version of traditional hydrophilic
ointments.
This foam can contain up to 98% polar hydrophilic solvent, which may be selected
from the following groups of compounds: (1) polyols (organic solvents that contain
at least two hydroxy groups in their molecular structure); and (2) polyethylene
glycols (PEGs). The polyols can be selected from the group of di-alcohols, such as
propylene glycol, butanediol and diethylene glycol, and tri-alcohols, such as glycerin.
The PEGs can be primarily low-molecular weight liquid PEGs, such as PEG 200,
PEG 400, PEG 600 and PEG 1000; however, mixes of the liquid PEGs with higher
molecular weight such as PEG 4000, PEG 6000, and PEG 8000 may be used as long
as the viscosity, prior to filling of the composition into aerosol canisters, is less
than about 10,000 CPs. The addition of secondary polar solvents, such as dimethyl
isosorbide, ethoxydiglycol, DMSO, and alpha hydroxy acids, such as lactic acid and
glycolic acid, is sometimes warranted in order to enhance solubilization and skin
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
permeation of the drug.40 These properties enable increased permeability across the
skin, resulting in an enhanced therapeutic effect.
The foaming agents include up to 5% surfactants and small amounts of polymers,
and the propellants can be hydrocarbon propellants and fluorocarbons.
Polyols, PEGs, and other polar solvents have a great affinity for water; as such, they
exhibit hygroscopic properties. Microorganisms require water to grow and reproduce,
thus the high concentration of polar solvents that absorb and hold free water in
order that it be unavailable for bacterial population, the result being an inhibition
of the growth of bacteria and fungi. Consequently, waterless hydrophilic foams do
not require preservatives in their composition; furthermore, their application onto
an infected skin surface can be used as a topical treatment for superficial infectious
conditions. It is further possible to add an anti-infective (antibacterial or antifungal)
element that may enhance the formulation’s effect and, consequently, render higher
treatment success.41,42
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Saccharide Foam
Saccharide foam, which contains up to 90% monosaccharides, disaccharides,
or honey was developed for the treatment of wounds and burns.43 The foam is soft
and easy to apply on the target site of treatment, with no need for extensive rubbing.
It is hygroscopic, and thus it has anti-infective attributes and absorbs exudates. In
addition, high percentages of sugars in the formulation are known to generate a
high-osmolality environment that is hostile to microbial proliferation.
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How to Formulate Foam Products
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Most foams used in pharmacological and cosmetic applications are aerosol
foams, which comprise a semi-solid formulation, packaged in an aerosol can and
pressurized by a propellant.
An aerosol is made up of several basic components:
•An aerosol can
•The bulk product (semi-solid formulation)
•The propellant
•A valve
•An actuator
•A dust cap
The preparation of the semi-solid bulk (termed pre-foam formulation or PFF)
depends on the type of composition used. For example, emollient (emulsion-based)
foams are produced in the following sequence:
1. PFF production
(a) Aqueous Phase preparation: Gelling agents and surface-active agents are
dissolved in water with agitation. The solution is warmed to 50–70°C. Water-soluble
cosmetic or pharmaceutical active ingredients and optional water-soluble ingredients
are added with agitation to the aqueous phase mixture.
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(b) Hydrophobic phase preparation: The hydrophobic solvent is heated to
50–70°C. Foam adjuvants (e.g., fatty alcohols and/or fatty acids) are added to the
hydrophobic solvent with agitation; followed by the addition of oil-soluble cosmetic
or pharmaceutical active ingredients and other optional oil-soluble formulation
ingredients.
(c) The warm hydrophobic phase is gradually poured into the warm aqueous
phase, with agitation, followed by homogenization. The mixture is allowed to cool
down to ambient temperature. In case of heat-sensitive active ingredients, they can
be added with agitation to the mixture after cooling to ambient temperature.
2. Packaging and pressurization
The mixture, at ambient temperature, is added to an aerosol container, the
container is sealed with a valve and an appropriate amount of propellant (typically
6–12% of the composition) is added under pressure into the container.
The most commonly used propellants are hydrocarbon mixtures, which
comprise n-butane, isobutane, and n-propane in various ratios. These hydrocarbons
are gasses at ambient temperature; however, when stored under pressure, they are
liquefied. Alternatively, fluorocarbon propellants, such as 1,1,1,2 tetrafluorethane
and 1,1,1,2,3,3,3 heptafluoropropane, can be used.
When single-phase foams are prepared, such as aqueous foams and hydroethanolic
foams, as well as oil foam and waterless hydrophilic foams, the primary solvents
and foaming agents are mixed together to form a uniform bulk PFF, which is in
turn added to the aerosol can and pressurized as described above.
W hile the preparation of PFFs can be performed in any formulation laboratory,
the stages of packaging into the aerosol cans and the pressurization require specialized
equipment. The assembly of the valve to the can is carried out using a specialized
crimper, which compresses the edges of the valve and secures tight attachment of
the valve to the can. This is a very critical operation and the crimping machinery has
to be carefully set up to ensure that the can/valve seal does not leak. The preferred
crimper for this operation is a “vacuum crimper,” which is capable of drawing the
air from the can prior to sealing it with the valve.
The pressurization of the product also requires specialized equipment, as the
propellant is injected into the can under pressure, through the valve. The propellant
may be in the form of a liquefied gas, or a compressed gas. When a liquefied gas is used
it will exist as both a liquid, and vapor in the aerosol can head space. A significant
part of the propellant will be dissolved in the PFF, resulting in an increase of the
volume of the semi-solid bulk. To ensure product integrity, each can is immersed
in a water bath at 50°C to check for any leaks. Any cans that leak are rejected.
Once the process of preparing the PFF, packaging it in the aerosol can, and
pressurizing it is completed in laboratory scale, it is usually readily scalable to
commercial amounts, using industrial manufacturers.
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
Methods of Evaluation of Foam Products
The following section provides test methods for the evaluation of foam products.
The chemical analysis is important to ensure the compliance of a product with the
specified concentration of active ingredients, and to follow-up the stability of the
active agents. The physical parameters are also related to the integrity, uniformity,
and stability of the product; moreover, they are important properties in terms of
the usability of the product.
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Chemical Analysis
Active ingredients and preservatives are commonly quantified in pharmaceutical
and cosmetic preparations as part of the quality control and stability evaluation of
such products. Foams are unique in the sense that the composition within the aerosol
container includes a propellant, which evaporates immediately upon dispensing.
Therefore, it has been accepted that the quantitation should be done in the absence
of the propellant to mimic real “in use” conditions.
Accordingly, the testing sample preparation includes (1) shaking the canister well
and dispensing an initial quantity to waste; (2) transferring to a beaker a sufficient
quantity for duplicate preparation; (3) de-aerating the dispensed foam by mixing
with a glass rod. Aliquots of the de-aerated sample are then weighed accurately
and processed for analysis by chromatography (e.g., GC, HPLC or UPLC) using
customary methods.
The method of analysis of preservatives in Scytera was recently published by Dr
Reddy.44
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Physical Foam Properties
The physical characteristics of the foam are important for ensuring acceptance
and facile usability of the product by the consumer. The principal physical properties
of foam are presented below, alongside with the methods to quantify them.
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Foam quality:
Foam quality can be graded as follows:
Grade E (excellent): Very rich and creamy in appearance; does not show any
bubble structure or demonstrates a very fine (small) bubble structure; does not
rapidly become dull; upon spreading on the skin, the foam retains the creaminess
property and does not appear watery.
Grade G (good): Rich and creamy in appearance; very small bubble size; “dulls”
more rapidly than an excellent foam; retains creaminess upon spreading on the skin
and does not become watery.
Grade FG (fairly good): A moderate amount of creaminess is noticeable; bubble
structure is noticeable; upon spreading on the skin, the product dulls rapidly and
becomes somewhat lower in apparent viscosity.
Grade F (fair): Very little creaminess is noticeable; larger bubble structure than
a FG foam; upon spreading on the skin, it becomes thin in appearance and watery.
Grade P (poor): No creaminess is noticeable; large bubble structure; when spread
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on the skin, it becomes very thin and watery in appearance.
Grade VP (very poor): Dry foam, large very dull bubbles; difficult to spread
on the skin.
Topically administrable foams are typically of quality grade E or G, when
released from the aerosol container. Smaller bubbles are indicative of more stable
foam, which does not collapse spontaneously immediately upon discharge from
the container. The finer foam structure looks and feels smoother, thus increasing
its usability and appeal.
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Foam density:
Density is also a distinguishing factor in at the assessment of the quality of foams.
The density of a foam product is quantified by dispensing into vessels (including
dishes or tubes) a known volume and weight of the foam product, as follows:
The foam product is allowed to reach room temperature. The canister is then
shaken well to mix the contents and 5–10 g of product are dispensed and discarded
thereafter. Then, foam is dispensed into a pre-weighed tube, filling it until excess
is extruded from the other side of the tube. The excess of foam at both ends is
removed and then the tube, filled with foam, is weighed on an analytical balance.
The density is calculated by dividing the net weight of the foam by the volume of
the tube. Replicate measurements are recommended.
The density of the foam is related to the foam class, as provided above. Watercontaining foams are less dense and their density is typically less than 0.1 g/mL.
Frequently, the density of hydroethanolic foams and emollient foams is in the range
of 0.03–0.06 g/mL, which makes their application very easy.
Water-free foams are “heavier” when applied and their density can range from
0.1–0.25 g/mL. Even such dense foams spread very easily and absorb quickly into
the skin.
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Breakability and collapse time:
An important property of foams is breakability, i.e., the way the foam breaks
down or collapses upon release from the aerosol can. Foams can be classified into
three classes: stable, quick breaking foam, and breakable.
A typical example of stable foam is shaving foam. Shaving foams possess
remarkable stability upon release from the aerosol can, and they do not break down
even upon extensive rubbing onto the skin. Such stable foams are not suitable for
topical therapy of skin conditions as they do not absorb into the skin upon application.
By contrast, quick breaking foams are inherently unstable and thermolabile, i.e.,
they readily collapse or melt upon exposure to body temperature.45 The quick breaking
property is usually caused by the presence of ethanol in the foam composition, and
the breaking temperature can be somewhat modulated by changing the alcohol
to water ratio in the quick-breaking temperature sensitive foam composition. The
usability of quick breaking foams is hindered by the fact that the foam quickly
collapses upon dispensing to one’s fingers prior to application to the target area.
Breakable foams are thermally stable, yet break under shear force. Shear force
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Foam: A Unique Delivery Vehicle for Topically Applied Formulations
breakability of the foam is clearly advantageous over thermally induced breakability.
The breakable foam does not collapse quickly upon expulsion, and it does not readily
collapse or melt upon exposure to skin temperature, allowing for comfortable
application and well directed administration of the preparation to the target area.
The difference between quick breaking thermolabile foam and breakable foam is
illustrated in Figur8. In the figure, the breakable foam is stable, resulting in facile
application and spreading, while the hydroethanolic foam instantly melts on the
fingers, which makes the application to the target site challenging and difficult
spreading over large skin areas.
The tendency of a foam to collapse upon exposure to skin temperature is examined
by dispensing a given quantity of foam and photographing sequentially its appearance
over time at 36°C. This “collapse time” is determined as the time that elapses until
the height of the foam is reduced to 50% of its original value. Preferably, to ensure
convenient application, the foam should maintain its structural stability at skin
temperature for at least 1 minute and, more preferably, more than 2 or 3 minutes.
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Figure 8. Breakable emollient foam vs. quick breaking hydroethanolic
foam
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Summary
Creams and ointments have been used historically in skin care and dermatology.
Foams offer an innovative and more convenient means of topical treatment of the
skin. The continuing development of versatile foam technology platforms will
facilitate achieving new topical products, including valuable drugs for the treatment
of dermatological mucosal and body cavity conditions. The advantages of foam in
terms of enhanced usability and compliance, improved clinical safety, tolerability
and efficacy, stability, and targeted drug delivery will enhance therapy and the future
development of therapeutic and topical treatments and products.
References
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1. R Woodford and BW Barry, Bioavailability and activity of topical corticosteroids from a novel
drug delivery system, the aerosol quick-break foam, J Pharm Sci, 66 1, 99-103 (1977).
2. M Parrini et al, Efficacy and tolerability of ketoprofen lysine salt foam for topical use in the
treatment of traumatic pathologies of the locomotor apparatus, Clin Ter, 141 9, 199-204
(1992).
3. L Daffonchio et al, Effects of a new foam formulation of ketoprofen lysine salt in experimental
models of inflammation and hyperalgesia, Arzneimittelforschung, 45 5, 590-4 (1995).
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