Silicones in Pharmaceutical Applications. Part 2

Silicones in Pharmaceutical Applications.
Part 2: Silicone Excipients
Andre Colas
Jason Siang
Kathy Ulman
Dow Corning Corporation
Midland, MI 48686
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Abstract
Silicones are currently used in
many different registered pharmaceutical products, both as actives
(e.g. simethicones for anti-flatulent applications) and as inactives or excipients (e.g. fluids,
gums and gels for topical pharmaceutical creams, ointments and
lotions). Silicones are often used
in these applications because of
some of their unique physicochemical and performance properties, such as low surface tension, non-greasy feel, high substantivity, high permeability and
controlled delivery. This article is intended to provide the
reader with an understanding of
where silicones have traditionally been use, or might potentially be used as excipients in
pharmaceutical applications.
Kompendium (Switzerland) and
AGIM® (Belgium). The search
was complicated by silicone listings under compendia names (e.g.
Dimethicone or Simethicone)
as well as other common chemical names (e.g. silicone, siloxane, methylsiloxane, polydimethylsiloxane) and even trademarks
(e.g. Silastic®). In many instances silicone (a polymer) was also
confused with silicon (a metal) or silica (an inorganic compound). Some databases allowed
for “word search” as in the PDR
or for “list of non active substances” as in the BIAM, where others did not. The presence of silicone was found in many registered drugs, including familiar
ones such as Augmentin® , Maalox
®, Prozac®, Tagamet®, Vicks
VapoSteam®, just to name a few.
Introduction
As the functional properties of
excipients become more critical to
the performance of pharmaceutical products (e.g. impact on bioavailability for drug products) the
pharmaceutical industry needs
to develop a good understanding of their role and select excipients based on their ability to provide intended functionality and
perform throughout the intended shelf-life of the drug product.
The purpose of this article is to
provide a review of pharmaceutical products currently available
that contain silicones, what form
of silicone(s) were most often
used and what attribute(s) silicones brought to the formulations.
Although it is well known that
silicones are used as actives,
such as Dimethicone or more
often as Simethicone (a blend of
Dimethicone and silicon dioxide), surprisingly, they are more
often used as excipients (table 1).
Topical Formulations
More than 358 registered products containing silicones were
retrieved using CD Rom or internet databases such as the PDR®
(USA), Rote Liste® and Gelbe
Liste (Germany), MediaVidal®
and BIAM (France), BNF® (UK),
While the use of silicones as
“pharmaceutical actives” is well
documented as antifoam in antigas or anti-acid formulations, the
use of silicones as excipients is
more difficult to understand. In
many cases, information about
excipients is limited and it is not
always possible to identify which
silicones are used. However, several references indicated that silicones have been used as excipients in pharmaceutical formulations for siliconization (lubrication of syringe barrels, pistons,
needles or lubrication of stoppers), as skin adhesives (drug
permeable), as elastomers (drug
release control membrane), as
release liner coatings for transdermal patch (release coating), and,
in topical skin products as polymers, volatiles/non-volatiles and
as copolymers to carry actives
or to improve spreading and aesthetic qualities. The latter is not
surprising as silicones are widely used in Personal Care products, with around 50 % of today’s
skin care products containing silicones(2) because they are recognized as safe, and known to provide for a pleasant “silky touch”
non-greasy and non-staining feel.
It is also worth noting that a substantial number of registered products contain silicones that are not
described in any Compendia, e.g.
methylpolysiloxane, silicone for
powder treatment, silicone or fluo-
Table 1: Silicone occurrence as actives or excipients and physical form in
registered drugs expressed as percentage of the 358 products identified in above
databases(1).
Silicone in composition
%
Form
%
As active
24
Simethicone
Dimethicone
13
1
As excipient
70
Simethicone
Simethicone emulsion
Dimethicone
Elastomer
Silicone Oil
Silicone Polymer
Others
14
11
10
6
5
5
19
Unknown
6
2
ro silicone for polyester film coating, silicone copolyol, hexamethyldisiloxane (HMDS), Silastic®,
silicone wax, …: in these registered product formulations, the
benefits brought by silicones were
obviously offsetting the regulatory hurdle to file a drug formulation with a new excipient.
In the above databases, 36 products (10 % of the retrieved registered products) identified silicone use as an excipient in topical products. Silicones were also
declared as one of the actives in
product targeted at both treatment
of acne and skin ulceration prevention. The latter case may be
related to the fact that NF grade
Dimethicone is recognized as an
OTC active for skin protectancy(3).
The highest level of silicones were
noted in products intended to treat
skin diseases, mainly as creams
followed by gels and lotions for
the treatment of acne, fungal diseases or psoriasis. The non-comedogenic nature of silicone probably accounts for their use in antiacne formulations(4). Other topical applications included contact
with fragile mucosa in the treatment of haemorrhoids, anal dermatoses or itch relief as well as
for the delivery of antibiotics in
gynecological capsules or creams.
Although Dimethicones and
Simethicones accounted for most
of the occurrences, other specific silicones used as excipients in
registered products were retrieved
using the above databases:
- Cyclomethicones [(Me2SiO)4,
D4; (Me2SiO)5, D5; (Me2SiO)6,
D6, etc], registered in Diprolene® (Schering Plough) or as
decamethylpentacyclosiloxane
(Me2SiO)5 in Dexeryl Crème®
(Pierre Fabre Santé). Although
the reason for their use is not
well known, cyclomethicones
are widely used in personal
care because of their volatility,
“aesthetic” and safety profile;
- Hexamethyldisiloxane (HMDS),
where recent work(5) has shown
that HMDS, Me3SiOSi Me3
(Bp. = 100°C), can be used as a
volatile excipient in spray pump
systems for topical applications.
The low surface tension of
HMDS improves skin coverage
and may increases bio-availability of the active drug. One
advantage of HMDS, despite
its flammability, is its very low
heat of vaporization, which
allows a film to dry quickly;
- Stearyloxytrimethylsilane,
CH3(CH2)17OSiMe3, a wax
with occlusive properties that
provides the pleasant silky feel
normally associated with silicones, is registered in Retinova®
(Roc - Johnson and Johnson);
- Dimethicone copolyol used
in conjunction with cyclomethicones is found in Retin-A
Micro® (Ortho Dermatological - Johnson and Johnson),
yet the exact structure of the
silicone glycol copolymer was
not found in databases used.
While the above silicones were
certainly used as a result of their
biocompatibility and probably
their aesthetic benefits, emerging evidence suggests that silicones may also affect the
bio-availability of actives.
The substantivity of actives on the
skin can be increased by adding
high molecular weight silicone
polymers, linear or branched,
which provide better cohesion of
the formed film. These substantive agents, when combined with
volatile silicones such as HMDS
or cyclomethicones, reduce blend
viscosity and may lead to oversaturated solutions. Improved
3
substantivity of cosmetic products
was demonstrated using attenuated total reflectance FTIR spectroscopy, where UV sunscreen
substantivity on the skin was
increased in presence of PDMS
gums of very high molecular
weight (Mw = 700,000): the diving resistant sun cream(6) ! High
molecular weight silicone gums
have also been shown to improve
substantivity on the skin of a
pharmaceutical active, ketoprofen, when dispensed from a volatile-based silicone spray(7). After
8 hours, the presence of ketoprofen was detected on the skin surface using formulations containing a silicone gum, while it was
no longer detected in the control after 6 hours. It is not clear
yet if this occurred because abrasion resistance was improved or
because the gum had an influence
of the skin penetration rate, e.g.
acting as a reservoir delaying penetration. Abrasion resistance was
certainly improved: consecutive
attempts, immediately after spraying, to remove the film from the
skin with an adhesive tape indicated that the presence of gum
made it more difficult and drug
loaded films were more resistant
to removal(7). Silicone gums are
very substantive on their own and
studies have shown that more than
25 % remains on the skin after 8
hours(8). Interesting to note is that
improved substantivity was even
observed when very low concentrations of silicone gum (1 to 3 %
by weight) were used, thus providing a low viscosity formulation
which could be easily applied by
spraying and which did not unreasonably increase drying time(7).
Using different actives, trials on
rat skin have shown skin penetration rates and compartmental distributions between the
stratum corneum, the epidermis and the dermis were affected by the presence of silicone
gum in the applied formulation;
however, too few actives have
been evaluated to rationalize the
results (table 2 and 3).
While most silicones are hydrophobic and often used to formulate lipophilic drugs, low molecular weight OH endblocked fluids, HO-(SiMe2O)n-H (n ~ 12)
, have been shown to dissolve
hydrophilic actives like polyethyleneoxyalkylphenols, e.g.
for the preparation of spermicidal condom lubricants(9).
While polydimethylsiloxanes are
highly permeable to moisture,
some silicones display occlusive
properties like stearyloxytrimethylsilane wax (partially silylated stearyl alcohol) and yet retain
the silky touch feel usually associated with silicones (table 4).
Although silicone elastomers
are solids, it is possible to prepare paste like products with
them when polymer crosslinking is carried out in the presence of a large concentration of
a non-reactive fluid, e.g. a volatile silicone. These products can
be applied to the skin in large
Table 2: Comparison of the penetration rates of different actives through hairless
rat skin in Franz diffusion cells from silicone gum (2 % by weight) in silicone
volatile formulations versus commercial products (without silicone)(8).
Active
Cumulative amount after 24 h
without silicone (µg/cm2)
Cumulative amount after 24 h
with silicone (µg/cm2 )
Ibuprofen
80
180
Econazole nitrate
0.7
0.5
Hydrocortisone
0.4
0.4
Table 3: Comparison of the compartimental distribution in hairless rat skin of
different actives after 24 h from silicone gum (2 % by weight) in silicone volatile
formulations versus commercial products (without silicone)(8).
Active
Ibuprofen
Drug distribution for formulations
w/o silicone (% of initial drug load)
str.corn. epidermis dermis
1
0.2
0.3
Drug distribution for formulations
w silicone (% of initial drug load)
str.corn. Epidermis dermis
1
0.2
1.5
Econazole nitrate
3.5
1
1
4
1
1
Hydrocortisone
0.2
2.5
0.5
7
2
0.8
Table 4: Comparison of oil-in-water emulsion occlusivity of Vaseline and/or stea
ryloxytrimethylsilane wax via gravimetric water loss through gelatin membranes
using the following formulations: oily ingredient: 20 %; silicone glycol copolymer
emulsifier: 2 %; HMDS 10 %; EtOH: 10 %; water + 2 % NaCl: qsp(8).
Oily ingredient
Occlusivity Power (%)
Vaseline emulsion
93.4
Vaseline / silicone wax 50 - 50 emulsion
84.7
Silicone wax emulsion
72.9
4
quantities while maintaining an
exceptional feel. They are widely used in Personal Care products
and it has recently been shown
that they can be used as carrier for the release of actives(9).
Conclusions
Silicones have a history of more
than 50 years of safety and efficiency in health care related applications and polydimethylsiloxanes are globally recognized both
for their proven biocompatibility as well as for being one of the
most tested materials for their
safety. As excipients, many of
the unique properties of PDMS
have been exploited in controlled
release drug delivery systems due
to their: chemical stability, high
level of purity (absence of organic solvent or heavy metal contamination; low level of residual polydimethylcyclosiloxanes),
ease of use to manufacture different designs and very high permeability to many active drugs.
Because of their unique physicochemical properties, silicones are
especially suitable for providing
aesthetics and bioavailability of
actives for topical formulations.
Note: Parts of this article were
originally published in Chimie
Nouvelle, 15 (58), 1779 (1997)
by A. Colas and L. Aguadisch
of Dow Corning Europe and
is reproduced here with the
permission of the Editor.
References
1. A. Colas, “Silicones Polymers
and Elastomers as Excipients
in Pharmaceuticals”, Belg.
Plast. Rub. Inst. conference,‘t
Gravenends, Belgium (2000).
2. M. Delvaux, private communication (2001)
3. United States Food and Drug
Administration Skin Protectant
Drug Products for Over-theCounter Human Use; Final
Monograph, 21 CFR 347.
4. C. E. Creamer, Pharm. Technol., 6 (3), 79 (1982).
5. J.M. Aiache, Aerosol and SprayReport, 35 (4), 190 (1996).
6. G. Chandra and H. Klimisch, J. Soc. Cosmet.
Chem., 37 (2), 73 (1986)
7. L. Aguadisch and coll.,
EP 0 966 972 (1999)
8. C Mallard and L. Aguadisch, Interchimie (1999).
9. A. Etienne and L. Aguadisch, EP 0 475 664 (1992)
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