Note: Descriptions are shown in the official language in which they were submitted.
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ENHANCEMENT OF MACROLIDE PENETRATION THROUGH HUMAN
SKIN
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of U.S. Provisional Application No.
60/661,031 filed March 14, 2005. This application, in its entirety, is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to the field of topical drug delivery and more
specifically to the field of enhancing topical delivery of macrolides for
treatment of skin disorders. In particular, the invention relates to the
delivery
of physiologically active molecules with molecular weights between 500
Daltons and 1200 Daltons.
BACKGROUND OF THE INVENTION
[0003] The administration of drugs and other biological materials to the
bloodstream via a transdermal route of administration has received much
attention in recent years. The skin of an average adult covers more than two
square meters of surface area and receives about one-third of all blood
circulating through the body. It is elastic, rugged, and generally self-
generating. Human skin consists of two layers: the epidermis (which is a
composite of multiple layers including the stratum corneum), and the dermis.
The stratum corneum (S.C.) represents the rate-limiting step in diffusion of
chemical through the skin. The S.C. is composed of dead, keratinized,
metabolically inactive cells which are closely packed together, and consists
of
an amorphous matrix of mainly lipoid and nonfibrous protein within which
keratin filaments are distributed. The cells of the S.C. generally contain 20%
water, while the cells below, in the stratum germinativum, contain 70% water.
The S.C. does not become hydrated readily. Thus, transdermal permeation is
primarily controlled by diffusion through the S.C.
[0004] There are several major reasons for the interest in transdermal
delivery of drugs:
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[0005] elimination of uncertainties of absorption from, and irritation to, the
gastrointestinal tract which arise when drugs are administered orally;
[0006] bypassing the portal circulation, thereby eliminating first-pass
metabolism in the liver; this is extremely important for drugs with short half-
lives, or with potential unwanted actions on the liver:
[0007] localized delivery of medication to the intended target site;
[0008] delivery of medication directly into the systemic circulation at a
constant rate (similar to intravenous infusion);
[0009] infrequent dosing (daily, weekly or longer) for certain drugs;
[0010] ease of use; foster patient compliance.
[0011] However, present transdermal delivery systems often have major
drawbacks. For example, they are restricted to low-molecular weight drugs
and those with structures having the proper lipophilic/hydrophilic balance.
High molecular weight drugs or drugs with too high or low hydrophilic balance
often cannot be incorporated into current transdermal systems in
concentrations high enough to overcome their impermeability through the
stratum corneum. Specifically, the literature has shown that chemical
transdermal delivery systems, where the skin is undamaged or unaltered, are
limited to drugs having a molecular weight of less than 500 Daltons, for
example, see JD Bos and MM Meinardi, The 500 Dalton Rule for the Skin
Penetration of Chemical Compounds and Drugs 1: Exp. Dermatol. Jun 2000;
9(3): 165-9.
[0012] Transdermal delivery is generally restricted to those small molecule
medications requiring delivery rates less than 10 mg/day. In order to obtain
higher blood levels, the rate of drug delivery must be increased. There have
been many proposals to accomplish the higher rate of drug delivery via the
use of absorption promoters and by the development of prodrugs that can be
more readily absorbed. Examples of existing absorption enhancers include
dimethyl sulfoxide (DMSO), ethylene glycol, hexanol, fatty acid and esters,
and pyrrolidone derivatives, among others. One such enhancer compound
which has received much attention is Azone (N-dodecyl azacycloheptan-2-
one).
[0013] Use of such penetration enhancers has been made for a variety of
small molecule drugs as has been demonstrated. Prior art patents of
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relevance to penetrating enhancers of physiologically active agents include
U.S. Pat. Nos. 3,551,554 which describes dimethyl sulfoxide, U.S. Pat. No.
3,989,816 discloses 1-substituted azacycloheptane-2-one; U.S. Pat. No.
4,132,781 discloses a topical antibiotic plus 2-pyrrolidone or an n-lower
alkyl-
2-pyrrolidone, U.S. Pat. No. 4,017,641 also describes 2-pyrrolidone but with
propylene glycol; others of interest are U.S. Pat. Nos. 3,903,256, 4,343,798,
4,046,886, 3,934,013; 4,070,462; 4,130,643, 4,130,667, 4,289,764;
4,070,462; 3,527,864; 3,535,422, 3,598,123, 3,952,099, 4,379,454,
4,286,592; 4,299,826; 4,314,557; 4,343,798; 4,335,115; 3,598,122;
4,405,616, 3,896,238, 3,472,931 and 4,557,934.
[0014] Applicants have previously developed a new class of compounds
which are derivatives of 1,3-dioxanes and 1,3-dioxolanes for use as skin
penetration enhancing compounds. These compounds, which have been
made commercially available under the trademark SEPA , are described in
detail in U.S. Pat. No. 4,861,764. Work with the dioxolane enhancers has
been described in several literature and patent publications. For example,
Samour, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16: 183-184
(1989); Marty, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 16:179-
180
(1989); Marty, et al., Proc. Int. Symp. Control. Rel. Bioact. Mater. 17:415-
416
(1990); Michniak, et al., Drug Delivery 2:117-122 (1995); Marty, et al., -
Abstract of Paper Presented at American Association of Pharmaceutical
Scientists, Washington, D.C., Mar. 26-28, 1990.
[0015] Specific examples of SEPAO enhancers can be found in U.S.
Patents 5,976,566 and 5,968,919 where the topical delivery of non-steroidal
anti-inflammatory drugs and hormones are demonstrated. The active
molecules for each of these examples have molecular weights that range from
approximately 200 Daltons to about 400 Daltons. In an article published in
the June/July 2004 issue of Pharmaceutical Formulation and Quality, delivery,
via SEPAO, of fat- and water-soluble small molecules, and proteins and
biologics is discussed. In addition this article discusses delivery of a
peptiae
of 1200 mol. wt. through the skin. Unexpectedly, Applicants have discovered
that the SEPAO enhancers can enhance delivery of macrolides with molecular
weights larger than the 500 MW upper limit previously believed to exist for
chemical penetration enhancement.
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SUMMARY OF THE INVENTION
[0016] The present invention has as a principal object to provide a stable
topical composition effective for the treatment of skin disorders with a
macrolide. In one embodiment, the invention can include a corticosteroid in
addition to the macrolide.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The compositions of the invention are intended for topical non-
invasive application to the skin, providing non-systemic, localized absorption
of the macrolide active ingredient, and any other co-active ingredients for
treatment of skin disorders. The composition of the present invention can be
applied as needed to the affected part of the skin. For example it can be
applied one to four times a day.
[0016] Examples of the macrolide.active ingredient which is
advantageously administered by the topical formulations of this invention
include macrolides with molecular weights greater than 500 Daltons, for
example 600 Daltons, and more preferably 700 Daltons and less than 1200
Daltons, for example 1100 Daltons, and more prefereably 1050 Daltons.
Specifically, these macrolides can include tacrolimus, pimecrolimus,
sirolimus,
ascrolimus, everolimus, ascomycins such as ascomycin, dunaimycins such as
dunaimycin, rapamycins such as rapamycin, prolylrapamycin, 32-
desmethylrapamycin, 32-desmethoxyrapamycin and other lactone based
compounds. Suitable macrolides include the chemical whose structure is:
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H
"3C!D, CHg
IC1H
H ...
~ .. "S'H2O
~ ON
C0a,
R#gC0= 4QHg
[0019] Additional suitable macrolides include 17-allyl-1,14-dihydroxy-12-[2-
(4-hyd roxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-d imethoxy-
13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1 Ø4,9]octacos-18-
ene-2,3,10,16-tetraone and FK 506.
[0020] The macrolide can be present in amounts ranging from 0.01-5.0
wt.% relative to the weight of the composition, preferably 0.01-2.0 wt.%
relative to the total composition. For example, the macrolide can be present
in the follow wt. % relative to the weight of the composition: 0.01, 0.05,
0.1,
0.5, 1, or 1.5.
[0021] Examples of some of the skin disorders that can be treated with the
composition include psoriasis, eczema, atopic dermatitis, erythema, pelagra,
allergic contact dermatitis, poison ivy, poison oak, poison sumac and other
skin disorders.
[0022] The penetration of the active ingredient through the skin is
preferably enhanced to an acceptable level by including in the composition an
effective amount of a skin penetration enhancing compound in the form of a
skin modifying agent of the substituted 1,3-dioxacyclopentane and substituted
1,3-dioxacyclohexane types disclosed in U.S. Pat. No. 4,861,764, the
disclosure of which is incorporated herein in its entirety by reference
thereto,
or the corresponding substituted acetal compound. Representative examples
of the skin penetration enhancing compounds include:
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[0023] 2-substituted 1,3-dioxolanes of the formula (I):
R1
R2
R Ro
O R
3
R4
1. (I)
2-substituted 1,3-dioxanes of the formula (II):
R1 R2
O
R3
R Ro
0 R4
R6 R5
2. (II)
substituted-acetals of the formula (III):
O R'1
R
O R'2
3. (III)
[0024] In the above formulas (I), (II) and (III) R preferably represents a C7
to
C14 hydrocarbyl group, Ro, Ri, R2, R3, R4, R5, and R6, each, independently,
represent hydrogen or a C, to C4 alkyl group. R', and R'2, each,
independently, represent C, to C4 alkyl group.
[0025] The hydrocarbyl group for R may be a straight or branched chain
alkyl, alkenyl or alkynyl group, especially alkyl or alkenyl. Preferably, R
represents a C7 to C12 aliphatic group; especially C7 to Clo aliphatic group.
Examples of suitable alkyl groups include, for example, n-hexyl, n-heptyl, n-
octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, 2-methyl-octyl, 4-ethyl-decyl,
8-
methyl-decyl, and the like. The straight chain alkyl groups, such as n-heptyl,
n-octyl, n-nonyl and n-decyl, are especially preferred. Examples of alkenyl
groups include, for example, 2-hexenyl, 2-heptenyl, 2-octenyl, 2-nonenyl,
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2',6'-dimethyl-2',6'-heptadienyl, 2',6'-dimethyl-2'heptaenyl, and the like.
The R
group may also be substituted by, for example, halo, hydroxy, carboxy,
carboxamide and carboalkoxy.
[0026] The C, to C4 alkyl group may be, for example, methyl, ethyl, n-
propyl, isopropyl, n-butyl, tert-butyl, and the like. The preferred alkyl
groups
for Ro, and for R, to R6 and for R', and R'2 are alkyl having 1 or 2 carbon
atoms, most especially ethyl. Ro, and R, to R6 may also, preferably, all be
hydrogen.
[0027] Specific skin modifying agents include, for example, 2-n-pentyl-1,3-
dioxolane, 2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2-n-undecyl-1,3-
dioxolane, 2-n-nonyl-1,3-dioxane, 2-n-undecyl-1,3-dioxane, 2-n-
heptylaldehyde-acetal, 2-n-octyl-aldehyde-acetal, 2-n-nonylaldehyde-acetal,
2-n-decylaldehyde-acetal, 3,7-dimethyl-2,6-octadienal (citral), citronal and
the
like. 2-n-nonyl-1,3-dioxolane is especially preferred and is commercially
available from MacroChem Corporation of Lexington, Mass., under the
trademark SEPAO.
[0028] Examples of other skin penetration enhancers and co-solvents that
may be added in addition to the skin modifying agent include dimethyl
sulfoxide (DMSO), polyethylene glycol monolaurate, ethylene glycol, alkyl
lactams, long chain amides, hexanol, fatty acids and their esters, and
pyrrolidone derivatives.
[0029] The solubilizing and/or absorption-promoting agents that can be
used in the present invention means an agent which can dissolve the active or
actives or their pharmaceutically acceptable salts with a concentration of at
least 0.01 % relative to the total weight of the composition, and further
promote the absorption of the active(s) or their pharmaceutically acceptable
salts through skin. In other words, the solubilizing and/or absorption-
promoting agent affords solubilizing and absorbing abilities to the active(s)
or
their pharmaceutically acceptable salts. Examples of absorption promoters
and/or solubilizers inciude: alkane dicarboxylic esters such as alkane
dicarboxylic dialkyl esters (dimethyl adipate, diethyl adipate, diisopropyl
adipate, diethyl pimelate, diethyl sebacate, dipropyl sebacate etc.); and
higher
alkane carboxylic alkyl esters (isopropyl myristate, ethyl myristate, etc.).
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[0030] The amount of the skin modifying agent is selected to provide the
desired delivery rate for the active compound by taking into consideration
such additional factors as, product stability, side effects, carrier system
and
the like. Generally, depending on the particular delivered compound and
other vehicles, amounts of the skin modifying agent in the range of from about
2.0 to 25%, preferably from about 2 or 3 or 4 to 12 or 15 or 20 percent,
especially from about 5 to 10 percent, of the composition, will provide
optimal
flux rate and 24 hour payload of the active ingredient. Usually, for gel
formulations the amount of enhancer compound may be lower than for cream
formulations, such as from about 2 to 10 percent of the formulation.
[0031] The compositions are generally formulated as gels, especially
aqueous-alcoholic gels. However, other forms, such as, for example, lotions,
creams, mousses, aerosols, ointments, lubricants, lacquers, patches,
solutions, tinctures, and the like, may be used so long as when applied to the
affected area of the skin the formulation will stay in place, i.e., without
run-off,
for sufficient time, to permit an individual to spread and retain the
composition
over and on the affected area.
[0032] The vehicle for any of the forms of the compositions of the invention
may also include glycol, e.g., propylene glycol, butylene glycol, hexylene
glycol, etc. (except in the case of the third embodiment described above),
lower alcohol, e.g., ethanol, isopropanol, and, usually, water. In addition,
of
course, the skin penetration enhancing dioxolane, dioxane or acetal is
included in the formulations in an amount effective to enhance the penetration
of the active ingredient through the skin, including the stratum corneum.
[0033] Accordingly, a suitable vehicle or carrier system for a composition
comprising a macrolide and a skin modifying agent can be an aqueous or
non-aqueous alcoholic carrier containing sufficient alcohol, especially
ethanol
and/or isopropanol and, often, glycol, e.g., propylene glycol, to solubilize
the
macrolide and be miscible with the skin modifying agent. Generally, however,
depending on the amounts of agent and macrolide in the formulations an
aqueous or non aqueous alcoholic carrier can contain from about 1 to about
99% by weight, for example 15 to about 85%, or 30 to about 70%, or 35 to
about 55% by weight of the composition of ethyl alcohol and/or isopropyl
alcohol. Mixtures of ethanol and isopropanol in proportions providing the
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desired solubility of the macrolide and compatibility with the enhancer can
also be used.
[0034] Again, the total amount of the aqueous or non-aqueous, alcoholic
carrier will depend on the amount of macrolide, amount and type of enhancer,
and the form of the composition, e.g., gel, cream, ointment, etc. Usually
amounts of the aqueous or non-aqueous alcoholic carrier within the range of
from about 1% to about 98% such as between about 20 and 95%, or between
70% and 90% by weight may be used. For example, in one embodiment, the
aqueous carrier can contain water between 15 and about 89% by weight, for
example 20 to about 80%, or from 25 to about 70% or from about 30 to about
60 % by weight of the composition. Mixtures of water and alcohol, e.g.
ethanol, propanol, ethylene glycol, propylene glycol can be used in ratios of
water:alcohol ranging from 20:80 to about 90:10, such as about 40:60, about
45:55, about 50:50 about 55:45 about 60:40.
[0035] In some compositions which are in the form of a gel, a thickening
agent, such as hydroxypropyl cellulose, can be included as a gelling agent.
However, any other pharmaceutically acceptable thickening/gelling agent may
be used. For example, mention may be made of other cellulosic ethers,
polymeric thickening agents, e.g., acrylic acid polymers, Carbopol®
thickeners, etc., xanthan gum, guar gum, and the like, as well as inorganic
thickeners/gelling agents. The amount of the thickening agent is not
particularly critical and can be selected to provide the desired product
consistency or viscosity to allow for easy application to the skin but which
will
not be too watery or loose so that it will stay where applied. Generally,
depending on its molecular weight, amounts of thickening agent up to about
5%, such as, for example, from 0.1 to about 2%, of the composition will
provide the desired effect.
[0036] As is well known in this art, it is possible to include other
ingredients
in the formulations for particular aesthetic and/or functional effects. For
example, the formulations may, optionally, include one or more moisturizers
for hydrating the skin and emollients for softening and smoothing the skin.
Glycerin is an example of such a suitable moisturizing additive. When present
the additive will usually be incorporated in an amount of up to about 5
percent
by weight of the composition, for example, from about 0.1 to 5%.
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[0037] The carrier can also include a lipophilic component which can
comprise from about 1% to about 60% of the total weight of the composition,
such as about I to about 30% or about 1 to about 10%.
[0038] Lipophilic components of the formulation can be fatty acid material.
"Fatty acid material" may include blends of fatty acids, typically containing
fatty acid moieties with chain lengths of from C8 to C30. The fatty acid
material may also contain relatively pure amounts of one chain length fatty
acid moiety. Suitable fatty acids from which fatty acid/nonionic surfactant
base mixtures may be derived include pelargonic, lauric, myristic, palmitic,
stearic, isostearic, oleic, linoleic, ricinoleic, arachidic, behenic and
erucic
acids. Although normally saturated, suitable fatty acid materials may contain
unsaturated fatty acid moieties, and may contain fatty acid moieties having a
degree of substitution, such as e.g. hydroxy fatty acids. The chain length of
the components of the fatty acid material also determines the rheological
properties of the resultant skin composition base. A fatty acid material mix
containing relatively high proportions of stearic and palmitic acid moieties
has
been found to be particularly suitable for use for manufacturing skin creams
and lotions which may be used in temperate to hot climates, while fatty acid
material mixtures containing relatively high amounts of lower chain length
fatty
acid moieties (e.g. more than 50% of the fatty acid moiety having a chain
length of C8-C14) may also be suitable for the preparation of skin
compositions for use in relatively cold climates.
[0039] Additional additives in the compositions can include skin care
actives which are acidic in aqueous solution, such as for example fatty acids,
such as alpha hydroxy fatty acids including lactic acid and glycolic acid; as
well as peroxides such as hydrogen peroxide, vitamins such as vitamin B3,
and polysaccharides such as chitosan; particularly preferred alpha hydroxy
fatty acids are lactic acid and glycolic acid.
[0040] Emollient materials may also serve as cosmetically acceptable
additives. These may be in the form of silicone oils and synthetic esters.
The*
emollient material may be a silicone oil, an ester or a mixture of these.
Amounts of the emollients may range anywhere from 0.1 to 20%, such as
between I and 5% by weight of the final composition.
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[0041] Silicone oils may be divided into the volatile and non- volatile
variety.
The term "volatile" as used herein refers to those materials which have a
measurable vapour pressure at ambient temperature. Volatile silicone oils are
preferably chosen from cyclic or linear polydimethyl siloxanes containing from
3 to 9, preferably from 4 to 5 silicon atoms. Linear volatile silicone
materials
generally have viscosities less than about 5 centistokes at 25 C., while
cyclic
materials typically have viscosities of less than about 10 centistokes.
[0042] Non-volatile silicone oils useful as an emollient material include
polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane
copolymers. The essentially non-volatile polyalkyl siloxanies useful herein
include, for example, polydimethyl siloxanes with viscosities of from about 5
to
about 25 million centistokes at 25 C.
[0043] Silicone emulsifying agents can include dimethicone copolyols.
These can include polydimethylsiloxanes modified to include polyether side
chains. Other modifications to the side chains can result in nonionic,
anionic,
cationic, amphoteric, and zwitterionic pendant moieties.
[0044] Among the ester emollients are:
1. Alkenyl or alkyl esters of fatty acids having 10 to 20 carbon
atoms. Examples thereof include isoarachidyl neopentanoate,
isononyl isononanoate, oleyl myristate, oleyl stearate, and oleyl
oleate.
2. Ether-esters such as fatty acid esters of ethoxylated fatty
alcohols.
3. Polyhydric alcohol esters. Ethylene glycol mono and di-fatty
acid esters, diethylene glycol mono- and di-fatty acid esters,
polyethylene glycol (200-6000) mono- and di-fatty acid esters,
propylene glycol mono- and di-fatty acid esters, polypropylene
glycol 2000 monooleate, polypropylene glycol 2000
monostearate, ethoxylated propylene glycol monostearate,
glyceryl mono- and di-fatty acid esters, polyglycerol poly- fatty
acid esters, ethoxylated glyceryl monostearate, 1,3-butylene
glycol monostearate, 1,3-butylene glycol distearate,
polyoxyethylene polyol fatty acid ester, sorbitan fatty acid
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esters, and polyoxyethylene sorbitan fatty acid esters are
satisfactory polyhydric alcohol esters.
4. Wax esters such as beeswax, spermaceti, myristyl myristate,
stearyl stearate and arachidyl behenate.
5. Sterol esters of which cholesterol fatty acid esters are
examples thereof.
[0045] The compositions of the present invention may be prepared and
formulated as emulsions. Emulsions are typically heterogenous systems of
one liquid dispersed in another in the form of droplets usually exceeding 0.1
,um in diameter. (Idson, in "Pharmaceutical Dosage Forms," Lieberman,
Rieger and Banker (Eds.), 1988, volume 1, p. 199; Rosoff, in "Pharmaceutical
Dosage Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p.
245; Block in "Pharmaceutical Dosage Forms," Lieberman, Rieger and Banker
(Eds.), 1988, volume 2, p. 335; Higuchi et al., in "Remington's Pharmaceutical
Sciences," Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are
often biphasic systems comprising of two immiscible liquid phases intimately
mixed and dispersed with each other. In general, emulsions may be either
water in oil (w/o) or of the oil in water (o/w) variety. When an aqueous phase
is finely divided into and dispersed as minute droplets into a bulk oily phase
the resulting composition is called a water in oil (w/o) emulsion.
Alternatively,
when an oily phase is finely divided into and dispersed as minute droplets
into
a bulk aqueous phase the resulting composition is called an oil in water (o/w)
emulsion. Emulsions may contain additional components in addition to the
dispersed phases and the active drug which may be present as a solution in
either the aqueous phase, oily phase or itself as a separate phase.
Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-
oxidants may also be present in emulsions as needed. Pharmaceutical
emulsions may also be multiple emulsions that are comprised of more than
two phases such as, for example, in the case of oil in water in oil (o/w/o)
and
water in oil in water (w/o/w) emulsions. Such complex forrriuiatioi-is o-fien
provide certain advantages that simple binary emulsions do not. Multiple
emulsions in which individual oil droplets of an o/w emulsion enclose small
water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets
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enclosed in globules of water stabilized in an oily continuous provides an
o/w/o emulsion.
[0046] Emulsions are characterized by little or no thermodynamic stability.
Often, the dispersed or discontinuous phase of the emulsion is well dispersed
into the external or continuous phase and maintained in this form through the
means of emulsifiers or the viscosity of the formulation. Either of the phases
of the emulsion may be a semisolid or a solid, as is the case of emulsion-
style
ointment bases and creams. Other means of stabilizing emulsions entail the
use of emulsifiers that may be incorporated into either phase of the emulsion.
Emulsifiers may broadly be classified into four categories: synthetic
surfactants, naturally occurring emulsifiers, absorption bases, and finely
dispersed solids (Idson, in "Pharmaceutical Dosage Forms," Lieberman,
Rieger and Banker (Eds.), 1988, volume 1, p. 199).
[0047] Useful oils can include vegetable and hydrogenated vegetable oils
including safflower oil, castor oil, coconut oil, cottonseed oil, menhaden
oil,
apim kernel oil, palm oil, peanut oil, soybean oil, jojoba oil, linseed oil,
rice
bran oil, pine oil, sesame oil, and sunflower seed oil and their hydrogenated
varieties. Additional useful oils can include animal fats and oils such as cod
liver oil, and lanolin and its derivatives, mineral oil and petrolatum.
[0048] Synthetic surfactants, also known as surface active agents, can be
used in the carrier in forming emulsions and have been reviewed in the
literature (Rieger, in "Pharmaceutical Dosage Forms," Lieberman, Rieger and
Banker (Eds.), 1988, volume 1, p. 285; Idson, in "Pharmaceutical Dosage
Forms," Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199).
Surfactants are typically amphiphilic and comprise a hydrophilic and a
hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of
the surfactant has been termed the hydrophile/lipophile balance (HLB) and is
a valuable tool in categorizing and selecting surfactants in the preparation
of
formulations. Surfactants used may be classified into different classes based
on the nature of the hydrophilic group into: nonionic, aniv, iic, cationic,
zwitterionic and amphoteric (Rieger, in "Pharmaceutical Dosage Forms,"
Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 285).
[0049] Common nonionic surfactants are polyoxyethylene ester and ether
surfactants, a specific example of which is Tween 60. Other suitable nonionic
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surfactants are described in McCutcheons "Detergents and emulsifiers", North
American edition (1986), published by Allured Publishing Corporation, the
contents of which are specifically incorporated herein by reference. Examples
of common nonionic surfactants can be derived from condensation reactions
between long chain alcohols (C8-C30) with sugar or starch polymers. Other
useful nonionic surfactants are the condensation products of alkylene oxides
with fatty acids (alkylene oxide esters of fatty acids, or alkylene oxide
diesters
of fatty acids), or the condensation products of alkylene oxides and fatty
alcohols (alkylene ethers of fatty alcohols).
[0050] Other useful nonionic emulsifying agents include sugar esters, poly
esters, alkoxylated sugar esters and polyesters, C1-C30 fatty acid esters of
C1-30 fatty alcohols, alkoxylated derivatives of C1-C30 fatty acid esters of
Cl-
30 fatty alcohols, alkoxylated ethers of C1-30 fatty alcohols, polyglyceryl
esters of C1-C30 fatty acids, C1-C30 esters or ethers of polyols, alkyl
phosphate, polyoxyalkylene fatty ether phosphates, fatty acid amides, acyl
lactylates and mixtures thereof.
[0051] Exemplary cationic emulsifying agents are those disclosed in
McCutheon's, Detergents and Emulsifiers, North American Edition (1986), the
contents of which are hereby incorporated by reference in their entirety.
Useful cationic surfactants include cationic ammonium salts such as
quaternary ammonium salts and amino-amides.
[0052] Useful anionic emulsifying agents include alkoxyl isethionates, alkyl
and alkyl ether sulfates and salts thereof, alky and alkyl ether phosphates
and
salts thereof, alkyl methyl taurates and soaps of fatty acids.
[0053] An ionic polyamide polymer containing acrylamidopropanesulfonic
acid (AMPS) and/or its salts as a comonomer may be used as an ionic
polymeric stabilizing agent. These polymers can be formed from a variety of
monomers including acrylamide and methacrylamide, which may be
unsubstituted or substituted with one or two alkyl groups (preferably Cl to
C5), or N-vinyl pyrrolidone. In one emuodiment the acrylate amide and
methacrylate amide are monomers in which the amide nitrogen is
unsubstituted, or substituted with one or two Cl to C5 alkyl groups
(preferably
methyl, ethyl, or propyl), for example, acrylamide, methacrylamide, N-
methacrylamide, N-methylmethacrylamide, N,N-dimethylmethacrylamide, N-
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isoproprylacrylamide, N-isopropylemthacrylamide, and N,N-
dimethylacrylamide. In another embodiment the polyacrylarnide-AMPS
copolymer is the product given the CTFA designation polyacrylamide (and)
isoparrafin (and) Iaureth-7, available under the Trade name Sepigel 305 from
Seppic Corporation (Fairfield, N.J.). In another embodiment a copolymer of
ammonium AMPS and N-vinylpyrrolidone, commercially under the trade name
Aristoflex , can be used. In a particular embodiment a mixture containing
sodium AMPS (also known as acryloyid imethyltau rate) copolymer,
isohexadecane, and polysorbate 80, commercially available under the trade
name Simulgel 600 is used. Mixtures of two or more ionic polymeric
stabilizing agents may also be used.
[0054] The ionic stabilizing agents of the present invention are included in
an amount sufficient to prevent visible separation of the composition. The
stabilizers are generally present in a concentration of about 0.1 to about 10%
by weight. One of skill in the art will also recognize that the amount of
ionic
polymeric stabilizing agent necessary will deperid upon the hydrophobic and
hydrophilic phases, intended use, intended storage, and use conditions, and
other optional ingredients which maybe used within the composition as well as
the mixing conditions and mixing apparatus used to prepare the emulsion or
dispersion.
[0055] The ionic polymeric stabilizing agents of the present invention allow
for the formation of a stable composition at lower concentrations of alcohol
than compositions without these ionic stabilizing agents. In one embodiment,
the ionic polymeric stabilizing agent is present from between about 1 and
about 10 percent, for example, from about 2 to about 8 percent by weight of
the composition.
[0056] Antioxidants are also commonly added to emulsion formulations to
prevent deterioration of the formulation. Antioxidants used may be free
radical
scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole,
butylated hydroxytoluene, or reducing agents such as ascorbic acid aiid
sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric
acid, and lecithin.
[0057] The compositions of the present invention may additionally contain
other adjunct components conventionally found in pharmaceutical
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compositions, at their art-established usage levels. Thus, for example, the
compositions may contain additional, compatible, pharmaceutically-active
materials such as, for example, antipruritics, astringents, steroids, local
anesthetics or anti-inflammatory agents, skin conditioning agents such as oils
and vitamins or may contain additional materials useful in physically
formulating various dosage forms of the composition of present invention,
such as dyes, flavoring agents, preservatives, antioxidants, opacifiers,
thickening agents and stabilizers.
[0058] Suitable steroids can include a co-active ingredient such as a
corticosteroid. Examples of some suitable corticosteroids include: clobetasol
propionate, betamethasone dipropionate, betamethasone valerate,
diflucortolone valerate, fluticasone valerate, hydrocortisone 17-butyrate,
mometasone furoate, methylprednisolone aceponate, aclometasone
dipropionate, clobetasone butyrate, fluocinolone acetonide, triamcinolone
acetonide, hydrocortisone and other useful cotricosteroids and their analogs
including salts. Other co-active ingredients useful in treating skin disorders
can also be used with the macrolide and can include anti-inflammatories, non-
steroidal anti-inflammatories, antifungals, antibiotics, anti-infectives, and
skin
protectants such as sunscreen components. However, such materials, when
added, should not unduly interfere with the biological activities of the
components of the compositions of the present invention. The formulations
can be sterilized and, if desired, mixed with auxiliary agents, e.q.,
lubricants,
preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure, buffers, colorings flavorings and/or aromatic substances
and the like.
[0059] The effects of the topical compositions according to the invention are
further illustrated by way of the following representative examples which in
no
way are intended to limit the scope of the invention.
EXAMPLES
Example 1-3:
[0060] These Examples compare the percutaneous absorption through
human cadaver skin of FK506 from alcoholic formulations containing 0.5 wt.%
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FK506, and either 0, 5%, or 10% of SEPA 0009 (2-n-nonyl-1,3 dioxalane)
with the remainder comprising 200 proof ethanol.
[0061] The tests are run in standard static cells with phosphate buffered
saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin
temperature = 32 C ). The following table 1 indicates the formulations used
in Examples 1-3. Each test was run for 24 hours under non-occluded
conditions with a finite dose of the test formulation.
TABLE 1
Example 1 Example 2 Example 3
wt.% FK 506 0.5 0.5 0.5
wt.% SEPA0009 0 5 10
Ethanol (200 Proof) 99.5 94.5 89.5
[0062] The results obtained are reported in Table 2 as cumulative % of
dose delivered for the three formulations. The values reported represent
average values for 24samples with the exception of the 4 hr values which
represent averages of 16 samples. The cumulative % dose delivered was
significantly higher at each time point for each formulation containing the
1,3
dioxolane.
TABLE 2
TIME (hr.) EXAMPLE 1 EXAMPLE 2 EXAMPLE 3
0 0.000 0.000 0.000
4 0.320 0.584 0.466
8 0.695 1.471 1.600
24 1.970 4.888 5.420
Examples 4-5 and Comparative Examples A-C
[0063] These Examples compare the percutaneous absorption through
human cadaver skin of FK506 from alcoholic formulations containing 0.5 wt.%
FK506, and either 0, 5%, 10% of SEPA 0009 (2-n-nonyl-1,3 dioxalane), or
17
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5% or 10% dimethyl sulfoxide (DMSO) with the remainder comprising 200
proof ethanol.
TAB LE 3
Ex. A Ex. 4 Ex. 5 Comp. Ex. Comp. Ex. C
B
wt.% FK 506 0.5 0.5 0.5 0.5 0.5
wt.% SEPA0009 0 5 10 0 0
wt.% DMSO 0 0 0 5.0 10.0
Ethanol (200 99.5 94.5 89.5 94.5 89.5
Proof)
[0064] The tests are run in standard static cells with phosphate buffered
saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin
temperature = 32 C ). Table 3 indicates the formulations used in Examples
4-5 and Comparative Examples A-C. Each test was run for 24 hours under
non-occluded conditions with a finite dose of the test formulation.
[0065] The results obtained are reported in Tables 4 and 5 as Flux and as
cumulative % of dose delivered for the five formulations. The values reported
represent average values for 12 samples. The flux and cumulative % dose
delivered was significantly higher at each time point for each formulation
containing the 1,3 dioxolane.
TABLE 4 - Flux (mg/sq.cm/hr)
Time Comp. Ex. Comp Ex.
hr Comp. Ex. A Example 4 Example 5 B C
0 0 0 0 0 0
4 0.002 0.061 0.088 0.006 0.007
16 0.002 0.067 0.130 0.000 0.001
TABLE 4 - Cumulative Amt. (% of applied dose)
Comp. Ex. Comp. Ex. Comp Ex.
Time hr A Example 4 Example 5 B C
0 0 0 0 0 0
8 0.032 0.949 1.420 0.097 0.112
24 0.072 2.180 4.822 0.097 0.129
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Comparative Examples D-G:
[0066] These Examples compare the percutaneous absorption through
human cadaver skin of Cyclosporine A from alcoholic formulations containing
4.0 wt% of Cyclosporine A, and either 0, 5%, or 10% of DMSO or 10% of
SEPA 0009 (2-n-nonyl-1,3 dioxalane) with the remainder comprising 200
proof ethanol.
[0067] The tests are run in standard static cells with phosphate buffered
saline (PBS) solution as the receptor fluid (surface area =0.635 cm2, skin
temperature = 32 C ). The following table 6 indicates the formulations used
in Comparative Examples D-G. Each test was run for 24 hours under non-
occluded conditions with a finite dose of the test formulation.
TABLE 6
Comp. Ex. Comp. Ex. E Comp. Ex. F Comp. Ex.
D G
wt.% Cyclosporine 4.0 4.0 4.0 4.0
wt.% DMSO 0 5 10 0
wt. % SEPA0009 0.0 0.0 0.0 10.0
wt. % Ethanol (200 96.0 91.0 86.0 86.0
Proof)
[0068] The results obtained are reported in Table 7 as cumulative % of
dose delivered for the four formulations. The values reported represent
average values for 12 samples. From the tables it is clear that none of the
formulations appears to deliver measurable amounts of Cyclosporine A.
TABLE 7
TIME (hr.) Comp. Ex. Comp. Ex. E Comp. Ex. F Comp. Ex.
D G
0 0.000 0.000 0.000 0.000
4 0.000 0.000 0.000 0.000
8 0.000 0.000 0.000 0.000
24 0.000 0.000 0.000 0.000
19
