Note: Descriptions are shown in the official language in which they were submitted.
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Method of Controlled release of a drug through skin
The present invention pertains to the field of drug formulation for topical
administration.
Background:
The poor penetration of drugs into the skin (and, partially, the
permeation across the Stratum corneum) often limits the efficacy of topical
formulations. Basically, skin penetration can be enhanced by the following
strategies: (i) increasing drug diffusivity in the skin; (ii) increasing drug
solubility
in the skin, and/or (iii) increasing the degree of saturation of the drug in
the
formulation. However supersaturated formulations, in which the degree of
saturation of the drug is increased compared to conventional formulations, are
often unstable, mainly because of crystallisation of the drug.
Summary of the invention:
The invention provides a method for the controlled release of a drug
through skin, which method comprises topically administering a composition
that comprises at least one solubilized drug, a film-forming silicone, and at
least
one volatile solvent.
More particularly the invention provides a method wherein the drug
penetrates the upper layers of the skin that serves as a reservoir wherein the
drug concentrates before being released to dermis.
For instance the drug may be vitamin D or a vitamin D analogue, such
as calcitriol, or a corticosteroid, such as clobetasol or clobetasol-17-
propionate,
alone or in combination.
Legends to the figure:
The figure shows the results of a blanching test, presented as mean
values of visual core across time after topical application of Dermoval ,
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Daivobet , Diprolene creams, or a silicone ointment, as described in Example
2.
General description of the invention:
The inventors have found out that topical compositions that comprise at
least one solubilized drug, a film-forming silicone, and at least one volatile
solvent allow for the controlled release of the drug through skin, while
showing a
good stability. The release of the drug is slow and sustained, which makes it
possible to lower the dosage. The drug can thus be administered at a dosage
that is lower than the dosage used for compositions comprising the same drug,
but free of the film-forming silicone and the volatile solvent.
The drug penetrates into the skin according to a specific zero-order
kinetic, which means that the drug concentration exhibits a linear variation
vs
time, and that the penetration is constant and sustained. The drug is first
maintained within the upper layers of the skin, that is to say the layers
consisting of :
- Stratum comeum,
- Stratum lucidum,
- Stratum granulosum, and
- Stratum germinativum (including Stratum spinosum and Stratum
basale).
The release of the drug into the lower layers (i.e. dermis and
hypodermis) is controlled by the in situ supersaturation of the drug.
Supersaturation is achieved when the solvent evaporates after the composition
is applied onto skin. This evaporation concentrates the drug in solution,
which
favors its penetration in the upper layers of the skin and creates a reservoir
effect. In parallel, the silicone allows the control of the evaporation
kinetic of the
solvent and the control of the crystallisation of the drug, which also favors
its
penetration.
The composition described herein comprises at least one drug, i.e. a
pharmaceutically active ingredient. In particular it may comprise two drugs.
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Examples of drugs of interest are vitamin D or a vitamin D analogue.
The term "vitamin D" means the various forms of vitamin D such as
vitamin DI, D2, D3 or vitamin D4.
The term "vitamin D analogue" means the compounds that exhibit
analogous biological properties compared to vitamin D, in particular with
regard
to the transactivation of the response elements of vitamin D (VDRE), such as
an
agonist or antagonist activity towards the vitamin D receptors. These
compounds preferably are synthetic compounds that comprise the squeleton of
vitamin D with modifications of lateral chains and/or that also comprise
modifications within this squeleton. The analogues may comprise structural
analogues, in particular biaromatic compounds.
Preferably the vitamin D analogue is selected from the group consisting
of calcitriol, calcipotriol, doxercalciferol, secalcitol, maxacalcitol,
seocalcitol,
tacalcitol, paricalcitol, falecalcitriole, 1 a,24S-dihydroxy-vitamine D2,
1(S),3(R)-
dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-seco-
pregna-(Z),7(E),10(19)-triene and mixture thereof. Most preferably, it is
calcitriol.
Further examples of vitamin D analogues include those described in
documents WO 02/34235, WO 00/64450, EP1124779, EP1235824,
EP1235777, WO 02/94754, WO 03/050067 et WO 00/26167. The compounds
described in WO 00/26167 relate to structural analogues of vitamin D that show
a selective activity on cell proliferation and differentiation without showing
hypercalcemic activity.
Advantageously, the quantity of vitamin D or vitamin D analogue
solubilized in the composition is from 0.00001 to 5 % w/w, preferably from
0.0001 to 3 % w/w and more preferably from 0.0003 to 1% w/w.
Another drug of interest, alone or in combination with vitamin D or the
vitamin D analogue, is a corticosteroid.
The term "corticosteroid" means a topical steroid of group I, II, III or IV
(strong or weak).
More particularly, it may be selected from the group consisting of
betamethasone, clobetasol, clobetasone, desoximethasone, diflucortolon,
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diflorasone, fluocinonide, flumethasone, fluocinolon, fluticasone,
fluprednidene,
halcinonide, hydrocortisone, momethasone, triamcinolon, pharmaceutically
acceptable esters or acetonides thereof, and mixtures thereof.
Examples of esters or acetonides include 17-valerate, 17-propionate,
17,21-dipropionate, acetonide, acetonide-21-N-benzoyl-2-methyl-R-alaninate,
acetonide-21-(3,3-dimethylbutyrate) and 17-butyrate.
Most preferably, the corticosteroid is clobetasol or clobetasol-17-
propionate.
Advantageously, the quantity of corticosteroid in a solubilized form in
the composition is from 0.0001 to 1 % w/w, more preferably from 0.0005 to 3 %
w/w, and more preferably from 0.001 to 0.1 % w/w.
In a preferred embodiment, the active ingredients are solubilized in the
same solvent or in several solvents.
The solvent is selected among pharmaceutically acceptable
compounds, i.e. compounds that are suitable for a topical application.
Preferred volatile solvents include alkanols, alkylglycols, alkylketones
and/or alkyl esters wherein the alkyl moieties contain from 1 to 6 carbon
atoms,
preferably from 1 to 4 carbon atoms, such as ethanol, isopropanol, n-butanol,
ethyl acetate, acetone, and mixtures thereof.
Preferably the volatile solvent is ethanol, especially when the drugs are
calcitriol and clobetasol-17-propionate.
Advantageously, the quantity of solvent within a composition is from 1
to 50 % w/w (based on the total weight of the composition), preferably from 2
to
40 % w/w and more preferably from 5 to 20 % w/w.
The film-forming silicone used in the invention preferably comprises at
least one polyorganosiloxane elastomer.
The term "polyorganosiloxane elastomer" hereby refers to any siloxane
polymer, which is chemically cross-linked and which exhibits viscoelastic
properties.
Examples of suitable polyorganosiloxane elastomers according to the
invention are those described in patents US 4,980,167 and US 4,742,142. The
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used polyorganosiloxanes may especially be addition products (adducts)
resulting from hydrosylation, and/or polymeric products deriving from the
addition of (i) a polyorganosiloxane having unsaturated groups, such as vinyl
or
allyl groups, for example linked to at least an atome, and (ii) another
silicone
product able to be involved in the addition reaction, such as an
organohydrogenopolysiloxane.
According to a specific embodiment, the polyorganosiloxane elastomer
is present in a least one volatile silicone oil that is a linear or cyclic
polyorganosiloxane oil having 2 to 10 silicium atoms.
The terms "polyorganosiloxane oils" hereby refers to any silicone oil
able to evaporate in contact of skin, mucosa or keratinic fibers preferably
with
an evaporation duration of less than 1 hour, at ambient temperature and water
atmospheric pressure.
Polyorganosiloxane oils useful in the invention are, for example, linear
or cyclic polyorganosiloxanes having 2 to 10 silicium atoms, optionally
comprising alkyl or alkoxy groups having 1 to 22 carbon atoms. Silicone oils
used in the invention advantageously exhibit a viscosity of at most 6.10-6
m2/s (6
centistokes).
Suitable volatile silicone oils especially include cyclomethicones and/or
dimethicones of low molecular weight. In this scope, cyclic
polyorganosiloxanes,
especially cyclic methoxylated organospolysiloxane, with a 4-membered to 12-
membered siloxane ring such as octamethylcyclotetrasiloxane and
decamethylcyclopentasiloxane, may be used. Other suitable volatile silocne
oils
are dodecamethylcyclohexasiloxane, heptamethylhexyltrisiloxane,
heptamethyloctyltrisiloxane, hexamethyldisiloxane, octamethyltrisiloxane,
decamethyltetrasiloxane, dodecamethylpentasiloxane, and mixtures thereof.
A particularly suitable film-forming silicone according to the invention
comprises a polyorganosiloxane elastomer in decamethyltetrasiloxane. In this
scope, a preferred silicone product is the so-called "ST Elastomer 10,E" of
DOW
CORNING, which is formulated in the form of a viscous and translucid gel.
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According to a specific embodiment, the film-forming silicone used in
the method of the invention is a silicone product obtained by a cross-linking
of :
(A) a polysiloxane having =SiH groups ;
(B) an alpha, omega-diene ;
(C) a polysiloxane having a low molecular weight,
in the presence of a catalyst.
In this scope, polysiloxane (A) advantageously comprises one or more
compounds having one of the following formulae (A'), (A2-1 ) and (A2_2) :
R314SiO(R152SiO)a(R16HSiO)b SiR314 (A)
HR214SiO(R152SiO)a(R16HSiO)b SiR214H (A2-1),
HR214SiO(R152SiO)cSiR214 H (A2_2)
wherein :
- R14, R15 et R's are similar or different, and each represents an alkyl
group with 1 to 6 carbon atoms ;
- a is an integer having a value of 0 to 250,
- b is an integer having a value of 1 to 250 ; and
- c is an integer having a value of 0 to 250.
- Preferably, polysiloxane (A) contains compounds of above formulae
(AZ"') and/or (A2"2), preferably together with compounds of formula
(A), , with a molar ratio (A2-' + A2"2) :(A) preferably between 0 to
20, especially from 0 to 5.
Alpha, omega - diene (B) is a compound of formula
CH2=CH(CH2)dCH=CH2, wherein d is an integer having a value of 1 to 20.
Representative examples of suitable alpha, omega - diene are
especially 1,4-pentadiene, 1,5-hexadiene, 1,6-heptadiene, 1,7-octadiene, 1,8-
nonadiene, 1,9-decadiene, 1,11-dodecadiene, 1,13-tetradecadiene, et 1,19-
eicosadiene.
Polysiloxane (C) may especially include, alone or in combination :
(C1) linear, branched, or cyclic volatile methylsiloxanes, for example :
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- volatile methoxysiloxanes selected from hexamethyldisiloxane,
octamethyltrisiloxane, decamethyltetrasiloxane,
dodecamethylpentasiloxane, tetradecamethylhexasiloxane, and/or
hexadecamethylheptasiloxane ;
- cyclic volatiles methylsiloxanes such as hexamethylcyclotrisiloxane,
octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and/or
dodecamethylcyclohexasiloxane.
- branched volatile methylsiloxanes, such as heptamethyl-3-
[(trimethylsilyl)oxy]-trisi loxane, hexamethyl-3, 3, bis[(trimethylsilyl)oxy]-
trisiloxane, and/or pentamethyl[(trimethylsilyl)oxy]-cyclotrisiloxane ;
(C2) alkyl- and/or aryl- siloxanes, which are linear, or cyclic, and which are
volatile or non-volatile,
especially low molecular weight, non-volatile, compounds having a viscosity
of about 100 to 1000 mm2/s (centistokes), especially those depicted by the
following formula :
R R ,7 R ,7
R"Si O-Si-R"
R R,s e R,7
wherein :
- e has a value preferably of 80 to 375,
- R" et R18 are alkyl radical having 1 to 20 carbon atoms, or an aryl
group such as a phenyle,
for example polydimethylsiloxanes, polydiethylsiloxanes, polymethyl-
ethylsiloxanes, polymethylphenyisiloxanes and/or polydiphenylsiloxanes ;
(C3) functionalized siloxanes, which are linear, or cyclic, especially fluid
siloxanes, for example functionalized with groups selected from acrylamides,
acrylates, amides, amino, carbinol, carboxy, chloroalkyles, epoxy, glycol,
cetal,
mercapto, methylester, perfluoro and silanol.
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Preferably, Polysiloxane (C) is a low molecular weight silicone oil
selected from volatile methylsiloxanes, of low molecular weight, which are
linear
or cyclic.
Other polysiloxanes suitable for an use as film-forming silicones
according to the invention are silicone polymers with an average molecular
weight of at least 10 000 (e.g. from 10 000 to 10 000 000). Examples of such
polysiloxanes include copolymers of crosslinked siloxanes, especially
copolymers of dimethicone or dimethicone derivatives, for example siloxane
stearyl methyl-dimethyl copolymers (such as Gransil SR-CYC of Grant
Industries), copolymers of the type of the Polysilicone-11 (crosslinked
elastomer silicone formed by reaction of a vinyl-terminated silicone with
methylhydrodimethylsiloxane in the presence de cyclomethicone), crosslinked
cetearyl dimethicone/vinyl dimethicone copolymers (namely copolymers of
cetearyl dimethicone crosslinked with a vinyl dimethyl polysiloxane),
crosslinked
dimethicone/phenyl vinyl dimethicone copolymers (namely dimethylpolysiloxane
copolymers crosslinked with phenyl vinyl dimethylsiloxane), and crosslinked
dimethicone/vinyl dimethicone copolymers (namely dimethylpolysiloxane
copolymers crooslinked with vinyl dimethylsiloxane).
Silicones formulated as a gel may be obtained especially from the
Grant Industries. Examples of such gels especially include :
- mixtures of cyclomethicone and polysilicone-1 1, such as commercial
product Gransil GCM5 ,
- mixtures of cyclotetrasiloxane and polysilicone-1 1, such as
commercial product Gransil PS-4 ,
- mixtures of cyclopentasiloxane and polysilicone-1 1 such as
commercial product Gransil PS-5 ,
- mixtures of cyclopentasiloxane, dimethicone and polysilicone-1 1,
such as commercial product Gransil DMCM-5 ,
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- mixtures of cyclotetrasiloxane, dimethicone and polysilicone-1 1, such
as commercial product Gransil DMCM-4 >>,
- mixtures of polysilicone-1 1 and isododecane such as commercial
product Gransil IDS , and
- mixtures of cyclomethicone, polysilicone-11 and phytosphingosine,
such as commercial product Gransil SPH >>.
Other examples are gels of crosslinked polymers of cyclopentasiloxane
and dimethicone/vinyl dimethicone, such as SFE839 of the General Electric
Company. Yet other silicone gels are those commercialized by the Shin-Etsu
Company under references KSG-15, KSG-16 and KSG-17.
According to a specific embodiment, the composition used in the
method of the invention is advantageously free from polyorganosiloxane having
alkyl groups.
Whatever its exact nature, the film-forming silicone of the method of the
invention is advantageously present in the composition at a concentration of
20
to 90% weight based on the total weight of the composition, preferably of
between 30 and 80%.
The compositions described herein may further contain an oily additive,
such as isopropyl paimitate, dicaprilic ether, dimethicone, or mixtures
thereof.
The compositions described herein may also contain flavour-enhancing
agents, preservatives such as para-hydroxybenzoic acid esters, stabilizing
agents, moisture regulators, pH regulators, osmotic pressure modifiers,
emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as
a-tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide
dismutase, ubiquinol, or certain chelating agents.
Preferably, the composition is in form of a cream, a gel, an ointment or
a pomade.
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Preferably, the composition is substantially free of water, i.e. it contains
less than 5 % w/w of water, preferably less than 3 %, most preferably 0 % of
water.
Preferred compositions comprise :
- isopropyl palmitate
- cyclopentasiloxane
- cyclomethicone 5/dimethicone crosspolymer
- calcitriol
- clobetasol-1 7- proprionate
- ethanol.
In a preferred embodiment, the composition comprises :
- isopropyl palmitate 0.5-2%
- cyclopentasiloxane 10-20%
- cyclomethicone 5/dimethicone crosspolymer 70-80%
- calcitriol 0.0001-0.0005%
- clobetasol-17-proprionate 0.01-0.05%
- ethanol 5-10%.
Examples:
Example 1: Preparation of a controlled-release formulation
The process described below is a general manufacture process of a
silicone ointment that comprises a vitamin D analogue and a corticosteroid.
The process is performed at room temperature, between 20 C and 25 C.
First step : preparation of the phase that comprises the silicone
(phase I) :
The ingredients of phase I ("Elastomer ST 10 ", silicone oil and oily
additive) are weighed in a vessel. The mixture is homogenised until
obtention of a homogenous gel.
Second step : preparation of the phase that comprises the active
ingredients (phase II)
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A parent solution is prepared, that comprises a vitamin D analogue
in an appropriate solvent, and an anti-oxidant. The solution is stirred until
solubilization of the active ingredient.
The corticosteroid is weighed and put in the solvent. The solution is
stirred until solubilization of the active ingredient.
The two active phases are incorporated in phase I under stirring.
The mixture is homogenised.
When the solvent is the same for the two active ingredients, the
corticosteroid is added to the parent solution of vitamin D analogue.
Table 1 :
Composition
Ingredients Quantities in % (w/w)
PHASE I : 1
ISOPROPYL PALMITATE'
(oily additive)
CYCLOPENTASILOXANE 16
(solvent)
CYCLOMETHICONE 5 / DIMETHICONE
CROSSPOLYMER 74.95
(silicone a ent3
PHASE II : 0.04
BUTYLHYDROXYTOLUENE
(anti-oxidant)
CALCITRIOL 0.0003
(active in redient
CLOBETASOL PROPIONATE 0.025
(active in redient
ABSOLUTE ETHANOL 8
(solvent)
1 Crodamol IPP
2 Mirasil CM5
3 Elastomer ST 10
Example 2: Sustained-release of the drug
The objective of this study was to compare a fixed-combination of
calcitriol 3 pg/g and clobetasol propionate 250 pg/g (composition of example
1)
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by evaluation of its blanching capacity to three marketed corticosteroids
formulations:
- Dermoval (Temovate )) cream (clobetasol propionate 500pg/g)
- Diprolene cream (betamethasone dipropionate 500pg/g)
- Daivobet ointment (fixed-combination containing calcipotriol 50 pg/g
and betamethasone dipropionate 500 pg/g).
The creams of reference (Dermoval , Diprolene , Daivobet ) above do
not contain a combination of silicone and volatile solvent.
Methodology :
This study was conducted as a single center, investigator masked,
active controlled, intra-individual comparison.
The tested products were randomly allocated to pre-marked 2.2 cm
diameter sites on forearms. Applications were performed by a trained research
assistant out of the sight of the blanching evaluators. The study products
were
administrated as six hours non occlusive application.
Visual and chromametric evaluations of vasoconstriction were made
within 30 minutes before product application, and 10 minutes, 2 hours, 4
hours,
6 hours, 18 hours and 22 hours after removal of the excess (removal took place
6 hours after study products application). Assessment of blanching visual
scores (primary pharmacodynamics variable) was performed by two
independent trained evaluators, using a 5-point scale (0: no blanching to 4:
maximal blanching). Chromametric evaluation (secondary pharmacodynamics
variable) was based on chromametric parameters (a* and L* value), using a
ChromaMeter Minolta CR 300.
Safety assessment was conducted for all subjects at every visit after
enrolment in the study. The primary parameter for the safety measurement was
the record of adverse events.
Visual scoring was to be made independently by two experienced
evaluators using the following 5 point-scale:
0 No change in skin color
1 Slight (barely visible) blanching
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2 Obvious blanching
3 Intense blanching
4 Maximal blanching considered being
For visual scores, the analyzed variable was the mean of the two
evaluators' scores on each site. The area under the curve was calculated by
subject and by treatment from TO (before application) up to T28h (22 hours
after
product removal). The chromametric variables a* and L* were adjusted
according to their baseline value before application=0a* and AL*. The area
under the curve was calculated by subject and by treatment from TO (before
application up to T28h (22 hours after product removal). The areas under the
curve were submitted, by parameter, to analyses of variance including subject,
zone and treatment as factors in the model.
The treatments were compared and classified using a Tukey multiple
comparison test, which was performed at the 5% two sided significance level.
Results:
Twenty-four (2 male and 22 female healthy subjects aged 20.4 to 42.3
years) were enrolled in the study. Twenty-four subjects completed the study
according to the protocol. None of them was excluded from the analysis.
Regarding the evaluation of the blanching visual scores (based on a 5-
point scale), the analyzed variable was the area under the curve (AUC) of mean
of the two evaluators' scores on each site. This AUC was calculated by subject
and by treatment from TO (before application) up to T28h (22 hours after
product removal). These data are summarized in Table 2 below :
Daivobet Dermoval Diprolene silicone
ointment
AUC n 24 24 24 24
Mean 29.69 55.46 26.40 26.75
tSEM t2.76 t2.66 t2.73 t2.47
Median 30.84 58.51 25.54 27.93
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(Min, (0.48, (32.25, (6.23, (6.00,
Max) 53.06) 76.25) 48.79) 56.88)
Based on the visual scores of blanching (primary pharmacodynamics
variable), investigational products were classified in two separate groups
with a
significantly different vasoconstriction activity, as follows:
- Dermoval cream >
- silicone ointment, Daivobet ointment, Diprolene cream.
However a very specific vasoconstriction profile was observed with the
silicone
ointment demonstrating a very slow release. The maximal effect was not
reached after TO + 22 hours, that is 28 hours after product application. The
AUC
of this product is therefore not complete and cannot be appropriately compared
to the other products for which entire AUC could be calculated.
The chromametric parameters L* and a* supported the results obtained
from visual scores.
In terms of safety analysis, neither treatment-related adverse events
nor serious adverse events were reported. Only one unrelated adverse event
(common cold) was reported during the study. All tested products were
therefore considered well-tolerated.
Conclusion :
The release of clobetasol from the silicone ointment is continuously
increasing with the maximal effect of vasoconstriction not reached after 28
hours.
Example 3 : Distribution of the drug :
[Example to be completed with greater details on the protocol
and the interpretation of results]
Clobetasol-17-propionate was shown to accumulate in the Stratum
corneum 16 hours after application on a human skin (Franz' cells).
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Table 3:
% Applied Dose
Formulations Stratum Dermis Absorbed Dermal Mass
corneum / dose delivery balance
Epidermis
Temovate 5.33 0.54 2.62 0.48 0.01 8.43 0.79 98.76
Cream 0.38 2.33
Silicone 8.24 t 1.28 1.12 t 0.59 t 0.01 9.96 t 1.36 97.82 t
Ointment 0.18 3.66
