PHARMACEUTICAL METHODS AND TOPICAL COMPOSITIONS
CONTAINING ACITRETIN
BACKGROUND
1. Field
The present invention is directed to methods and compositions for topical
administration of acitretin. More specifically, the present invention is related
to methods and compositions for the treatment or prevention or reduction of
symptoms or signs of dermatological conditions using acitretin in a topical
administration. More specifically, the present invention is related to methods
and compositions containing acitretin which are effective for the treatment or
prevention or reduction of symptoms or signs of keratoses, in particular
actinic keratosis.
2. Description of the Related Art
a. Acitretin
Acitretin ((2£,4£ ',6£',8£)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-
dimethylnona-2,4,6,8-tetraenoic acid) is a synthetic aromatic analogue of
retinoic acid (Vitamin A derivative) indicated for the treatment of severe
psoriasis, disorders of keratinisation and other dermatoses responsive to
etretinate. Acitretin is an active metabolite of etretinate. Acitretin is
available as oral capsules and tablets for systemic treatment. Acitretin is a
known cause of birth defects when absorbed systemically. Acitretin was first
developed in the 70's by Hoffmann LaRoche Inc.
U.S. Pat. No. 4,105,681 describes a synthesis of acitretin.
b. Actinic keratosis
Actinic keratosis (also called "solar keratosis" and "senile keratosis") is a
premalignant condition of thick, scaly, or crusty patches of skin. Actinic
keratosis requires treatment, as in some cases it will progress to squamous
cell carcinoma. Actinic keratosis is particularly suitable for topical treatment,
as the lesions are usually relatively localized. Disadvantages with topical
treatment may include skin irritation and low efficacy.
Existing topical treatments for actinic keratosis include imiquimod
(marketed under the brand names Aldara and Zyclara), diclofenac (marketed
as Solaraze) and 5-fluorouracil (Efudix).
c. Formulations
Current dosage forms of acitretin include oral tablets and capsules. The
known oral dosage forms of acitretin result in the drug being absorbed
systemically - that is, throughout the whole body. Systemic drug therapy
has the disadvantage that the drug is distributed throughout the body's
systems, not only where it is actually required. This may result in
undesirable side effects in systems of the body other than those requiring
treatment. For example, acitretin is known to cause birth defects in cases of
in utero exposure.
It would therefore be advantageous, when using acitretin for the treatment or
reduction of symptoms of dermatological conditions, to as far as possible
confine the distribution of the drug to the skin - more particularly, to the area
of skin requiring treatment, and to reduce or eliminate systemic absorption.
"Topical administration" refers to a drug or medication which is applied to a
specific area of the skin of a subject and affects only or substantially only the
area to which it is applied.
Topical use of acitretin has been suggested by Hsia et al. in "Effects of
topically applied acitretin in reconstructed human epidermis and the rhino
mouse", J . Invest. Dermatol. 2008, Jan; 128(l):125-30. However, no
commercial product has been released.
For a topical medicament to be effective it must be readily released from the
vehicle matrix and interact intimately with the skin to be treated. In order to
be effective, it is desirable for actives in topical compositions to be either
fully dissolved or nano-sized, so as to achieve the necessary degree of
penetration. However, this has proved difficult to achieve in the case of
acitretin, in particular because the solubility characteristics of acitretin differ
from other retinoids.
Typical solvents for use in creams would include alcohol or water.
However, acitretin is in general very poorly soluble in water, so that an
aqueous formulation is unlikely to be clinically efficacious. Acitretin is also
quite poorly soluble in suitable alcohols. Also, it is undesirable to use large
amounts of alcohol as a solvent in topical formulations, as the high levels of
alcohol tend to irritate the skin of the user.
For example, U.S. Pat. No. 5,721,275 discloses topical compositions of
retinoids in large concentrations of alcohol.
WO 2006/053006 proposes compositions comprising a retinoid, an
anhydrous alcohol and an ester such as alkyl benzoate, isopropyl palmitate,
diisopropyl adipate, or isopropyl myristate.
WO90/14833 describes aqueous gel vehicles for the topical application to the
skin of irritating active ingredients such as retinoids, particularly tretinoin.
The compositions include an aqueous medium, a gelling agent and an anti
oxidant. However, the amount of water in this formulation means it would be
unsuitable for use with acitretin, which would be likely to crystallize. Also,
the described formulations contain significant amounts of ethanol or
isopropyl alcohol.
U.S. Pat. No. 4,034,1 14 describes a treatment to alleviate symptoms of
keratosis consisting of topical compositions containing retinal. The
compositions described contain significant amounts of alcoholic solvent
and/or rely on solvents in which acitretin is much less soluble than is retinal.
U.S. Pat. No. 3,906,108 discloses a tretinoin cream emulsion for topical
application which is stabilized by inclusion of xanthan gum. These
formulations are ineffective in achieving and maintaining solubilization of
acitretin.
It is therefore difficult to formulate a pharmaceutically acceptable topical
cream containing acitretin. In particular, there is a strong tendency for
acitretin to crystallize rather than remaining in solution in prior art
formulations.
There remains a need for a topical acitretin composition with acceptable
levels of efficacy and low irritancy.
SUMMARY
The present invention is directed to improved topical compositions of
acitretin for reducing at least one symptom of at least one dermatological
condition, and to methods of manufacture and use of such compositions, in
which acitretin is in the form of a nanosuspension.
In certain aspects, the compositions may be used to treat a subject, which
may be a human subject or a mammal subject, diagnosed with a
dermatological condition responsive to acitretin or etretinate or a symptom or
symptoms of a dermatological condition responsive to acitretin or etretinate.
In certain aspects, the compositions may be used to treat a subject, which
may be a human subject or a mammal subject, diagnosed with a
keratinisation disorder, in particular actinic keratosis or with a symptom or
symptoms of actinic keratosis.
In certain aspects the compositions are pharmaceutically acceptable
formulations. In particular aspects, the compositions are gels. In certain
particular aspects, the compositions may comprise a solid dispersion of
acitretin in a copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in a ratio
of 3:2 by mass (copovidone). A suitable copovidone copolymer is marketed
under the trade mark Plasdone-S630.
The present invention is further directed to a topical medicament for
reducing at least one symptom of at least one dermatological condition, and
to methods of manufacture and use of such compositions, which comprises
not less than 0.25% w/w acitretin, or at least about 0.5% w/w acitretin, and
which shows a release rate of not less than 0.01 mg/cm2 per min as
measured using a Franz diffusion cell in vitro release testing system utilizing
the following conditions: receptor medium comprising 1% DMSO in (35%
ethanol:65% phosphate buffer pH 8.0), speed 700 rpm, membrane
polysulfone 0.45mp , dosage 300 ± 30mg, temperature 32.5 ± 0.5°C.
In specific embodiments, the compositions of the invention may comprise
acitretin which is in the form of a stable nanosuspension (as defined herein).
The invention provides a topical medicament for reducing at least one
symptom of at least one dermatological condition comprising acitretin
particles as a nanosuspension, wherein at least 90%, by volume, of the
acitretin particles suspended are 1 micron or less in size, and wherein at least
98%, by volume, of the acitretin particles suspended are 1 micron or less in
size. The invention further provides the topical medicament wherein at least
99%, by volume, of the acitretin particles suspended are 1 micron or less in
size. The invention further provides a topical medicament in gel form.
The invention further provides a topical medicament wherein the acitretin is
a solid dispersion of acitretin with a copolymer. The invention further
provides a topical medicament wherein acitretin is present at about 0.25 - 0.5
% w/w. The invention further provides a topical medicament, wherein the
copolymer is copovidone.
The invention further provides a topical medicament further comprising a
dispersing agent, and further wherein the dispersing agent is a polysorbate,
and further wherein the dispersing agent is polysorbate 20 present in an
amount of less than about 0.3% w/w.
The invention further provides a topical medicament further comprising a
chelating agent further wherein the chelating agent is EDTA. The invention
further provides a topical medicament, wherein the composition comprises
less than about 0.3% w/w polysorbate 20, and no EDTA. The invention
further provides a topical medicament further comprising EDTA in the
absence of polysorbate 20. The invention further provides a topical
medicament further comprising EDTA in the presence of less than about
0.1% w/w polysorbate 20.
The invention further provides a topical medicament comprising residual
solvent, further wherein the residual solvent is THF, and further wherein it is
present in a concentration of at least about 0.4% w/w. The invention further
provides a topical medicament, further comprising at least one preservative,
further wherein the preservative is selected from the group consisting of a
sodium paraben, sodium methylparaben, sodium propylparaben, potassium
sorbate, phenoxyethanol, and combinations thereof.
The invention further provides a topical medicament further comprising
propylene glycol of about 2.5% to about 5% w/w. The invention further
provides a topical medicament wherein the composition comprises carbomer,
further wherein acitretin is present at about 0.25 - 0.5 w/w, and the carbomer
is between 0.4 % and 0.6 %.
The invention further provides a topical medicament wherein the
medicament shows a release rate of not less than 0.01 mg/cm2 per min½ as
measured using a Franz diffusion cell in vitro release testing system utilizing
the following conditions: receptor medium comprising 1% DMSO in (35%
ethanol: 65% phosphate buffer pH 8.0), speed 700 rpm, membrane
polysulfone 0.45mp , dosage 300 ± 30mg, temperature 32.5 ± 0.5°C.
The invention provides a method of manufacture of the topical medicament
which comprises forming a solid dispersion of acitretin particles and a
copolymer of vinylpyrrolidone and vinyl acetate by spray drying predissolved
acitretin with a copolymer, and combining the solid dispersion
with an aqueous gel base, further, wherein at least 90%, by volume, of the
acitretin particles formed are 1 micron or less in size, further wherein at
least 98%, by volume, of the acitretin particles formed are 1 micron or less in
size, further wherein at least 99%, by volume, of the acitretin particles
formed are 1 micron or less in size. The invention further provides the
method wherein acitretin is present at about 0.25 - 0.5 % w/w. The invention
further provides the method wherein the copolymer is copovidone.
The invention further provides the method wherein the topical medicament
further comprises a dispersing agent, wherein the dispersing agent is a
polysorbate, further wherein the dispersing agent is polysorbate 20 present in
an amount of less than about 0.3% w/w.
The invention further provides the method wherein the topical medicament
further comprises a chelating agent, wherein the chelating agent is EDTA.
The invention further provides the method, wherein the composition
comprises less than about 0.3% w/w polysorbate 20, and no EDTA. The
invention further provides the method, further comprising EDTA in the
absence of polysorbate 20. The invention further provides the method,
further comprising EDTA in the presence of less than about 0.1% w/w
polysorbate 20.
The invention further provides the method wherein the topical medicament
comprises residual solvent, further wherein the residual solvent is THF, and
further wherein it is present in a concentration of at least about 0.4% w/w.
The invention provides the method wherein the topical medicament further
comprises at least one preservative, further wherein the preservative is
selected from the group consisting of a sodium paraben, sodium
methylparaben, sodium propylparaben, potassium sorbate, phenoxyethanol,
and combinations thereof.
The invention provides the method wherein the topical medicament further
comprises propylene glycol of about 2.5% to about 5% w/w. The invention
further provides the method, wherein the topical medicament further
comprises carbomer. The invention further provides the method wherein the
topical medicament comprises acitretin at about 0.25 - 0.5 % w/w, and the
carbomer is between 0.4 % and 0.6 %.
The invention provides the method wherein the topical medicament shows a
release rate of not less than 0.01 mg/cm2 per min½ as measured using a
Franz diffusion cell in vitro release testing system utilizing the following
conditions: receptor medium comprising 1% D SO in (35% ethanol: 65%
phosphate buffer pH 8.0), speed 700 rp , membrane polysulfone 0.45mhi,
dosage 300 ± 30mg, temperature 32.5 ± 0.5°C.
The foregoing and other objects, features and advantages of the present
invention will become more readily apparent from the following detailed
description of exemplary embodiments as disclosed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
The following figures form part of the present specification and are included
to further demonstrate certain aspects of the present invention. The
invention may be better understood by reference to one or more of the
figures in combination with the detailed description of specific embodiments
presented herein.
In the descriptions herein: "Triton X-100" is a trade mark for a product, the
generic name for which is poly(oxy-l,2-ethanediyl), -hydroxy; "Tween 20": is a trade mark for a
product, the generic term for which is polysorbate 20; and "Tween 80" is a
trade mark for a product, the generic name for which is polysorbate 80.
Embodiments of the present invention are described, by way of example
only, with reference to the attached figures, wherein:
FIG. A illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder comprising 5% acitretin dispersed in
95% Plasdone -S630™ dispersed in water with 0.7% Triton X-100™.
FIG. IB illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder comprising 5% acitretin dispersed in
95% Plasdone -S630™, dispersed in water with 2% Tween 20™ .
FIG. 1C illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder comprising 5% acitretin dispersed in
95% Plasdone -S630™, dispersed in water with 2% Tween 80 ™
FIG. D illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder comprising 3% acitretin dispersed in
97% Plasdone -S630™, dispersed in water with 0.7% Triton X-100 ™.
FIG. IE illustrates laser diffraction particle size distribution data for a sample
of acitretin spray dried powder comprising 7.5% acitretin dispersed in
92.5% Plasdone -S630™, dispersed in water with 0.7% Triton X-100™.
FIG. IF illustrates laser diffraction particle size distribution data for a sample
of acitretin spray dried powder comprising 10% acitretin dispersed in 90%
Plasdone -S630™, dispersed in water with 0.7% Triton X-100™.
FIG. 1G illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder 12.5% acitretin dispersed in 87.5%
Plasdone -S630™, dispersed in water with 0.7% Triton X-100™
FIG. 1H illustrates laser diffraction particle size distribution data for a
sample of acitretin spray dried powder comprising 15% acitretin dispersed in
85% Plasdone -S630™, dispersed in water with 0.7% Triton X-100™.
FIG. II illustrates laser diffraction particle size distribution data for a sample
of acitretin spray dried powder comprising 25% acitretin dispersed in 75%
Plasdone -S630™, dispersed in water with 0.7% Triton X-100™.
FIG. 2A illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 2 herein.
FIG. 2B illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 3 herein.
FIG. 2C illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 4 herein.
FIG. 2D illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 5 herein.
FIG. 2E illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 6 herein.
FIG. 2F illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 7 herein.
FIG. 2G illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 8 herein.
FIG. 2H illustrates the drug release profile, obtained by in vitro release
testing using a Franz diffusion cell system as further described herein, for an
acitretin gel formulation according to Example 9 herein.
FIG. 21 is a bar chart presentation of the average release rate of acitretin gel
formulations according to Examples 2-9 herein.
FIG. 3A shows an optical microscopic image of spray dried acitretin solid
dispersion (5% acitretin dispersed in 95% Plasdone -S630™) at 400x
magnification.
FIG. 3B shows an optical microscopic image of a sample of a gel preparation
containing spray dried acitretin solid dispersion, the solid dispersion
comprising 5% w/w acitretin dispersed in 95% Plasdone -S630™ shortly
after the time of preparation, at lOOOx magnification.
FIG. 3C shows an optical microscopic image of the sample in FIG 3B after
14 days storage at 40°C/75%RH, at lOOOx magnification.
DETAILED DESCRIPTION
It will be appreciated that for simplicity and clarity of illustration, where
considered appropriate, reference numerals may be repeated among the
figures to indicate corresponding or analogous elements. In addition,
numerous specific details are set forth in order to provide a thorough
understanding of the example embodiments described herein. However, it
will be understood by those of ordinary skill in the art that the example
embodiments described herein may be practiced without these specific
details. In other instances, methods, procedures and components have not
been described in detail so as not to obscure the embodiments described
herein.
The present invention is directed to systems, methods and compositions for
the topical administration of acitretin.
In exemplary embodiments, a subject in need of treatment for one or more
dermatological conditions or signs or symptoms of one or more
dermatological conditions, such as a mammal, and in specific embodiments a
human, is administered acitretin topically. In such embodiments, the one or
more dermatological conditions may include actinic keratosis.
In specific embodiments, the subject in need of treatment is a subject
exhibiting one or more signs or symptoms of actinic keratosis. In such
embodiments, signs or symptoms may include one or more of the following:
precancerous or premalignant flat or thickened, scaly, warty or horny, skin
coloured or reddened lesions.
In specific embodiments, the compositions of the invention may be
pharmaceutical compositions in which acitretin is in the form of a stable
nanosuspension. By "stable" is meant at least 90% of potency of the drug
substance is preserved during at least 3 months storage at 40°C/75%RH
without significant change in the rate and extent to which the drug product is
released from the product matrix. In certain particularly preferred
embodiments longer stability may be observed, for example at least 90% of
potency of the drug substance may be preserved during at least 6 months
storage at 40°C/75%RH and/or at least 9 months or at least 12 months
storage at 25°C/60%RH without significant change in the rate and extent to
which the drug product is released from the product matrix. By "significant
change" is meant more than about 10-15% change.
The amount of acitretin in the present compositions will depend on the
particular application. Generally topical acitretin compositions in
accordance with this invention may contain, for example, from 0.01 to 1%
w/w acitretin. In specific embodiments compositions in accordance with this
invention may, for example, contain 0.03%, 0.05%, 0.1%, 0.15%, 0.2%,
0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.6% or 0.75% acitretin on a
weight basis. The precise amount of acitretin may in part be chosen to
optimize the desired release rate.
Gels
In specific embodiments, the compositions of the invention may be
formulated as a gel. By a "gel" is meant a pharmaceutical preparation
comprising a colloid in which a solid dispersed phase forms a network in
combination with a fluid continuous phase, resulting in a viscous semirigid
solid.
In specific embodiments, the present invention discloses gels in which
acitretin is present as a substantially stable nanosuspension. By
"nanosuspension" is meant a preparation in which nano sized solid acitretin
is dispersed in a liquid phase. The acitretin may be amorphous.
In specific embodiments, the gels of the invention may further comprise
copovidone. Copovidone is a copolymer of l-vinyl-2-pyrrolidone and vinyl
acetate.
In specific embodiments, the present invention discloses a method of
manufacture of a stable nanosuspension of acitretin, which comprises
forming a solid dispersion of acitretin with a copolymer, preferably by spray
drying pre-dissolved acitretin with copovidone (a copolymer of l-vinyl-2-
pyrrolidone and vinyl acetate), and combining the resulting powder with an
aqueous gel base. By a "solid dispersion" is meant a solid material in which
the active is dispersed in an amorphous state. This may result for example
from the active being fully solubilized in a solvent, such as tetrahydrofuran
(THF), before being spray dried with the copolymer. Fig 4A shows an
optical microscopic image of such a solid dispersion.
When mixed with the aqueous gel base, the spray dried powder particles are
seen microscopically as homogeneous spheres of approximately 5 to 50
microns in diameter comprising acitretin dispersed in copovidone. Fig. 4B
shows such a gel preparation immediately after addition of the spray dried
solid dispersion. It has been surprisingly observed that over the course of
less than around 24 hours, in certain preferred embodiments less than 1 hour,
the spheres dissolve resulting in a gel matrix containing very small (submicron)
precipitated particles of acitretin with a relatively uniform particle
size distribution within the gel matrix. The particle size distribution
determined by laser diffraction indicates that the majority of the acitretin
particles are less than 1 micron in size. In some instances, although the
particle size is small, some agglomeration of the particles may initially
occur. A brief application of sonication, for example a 30 second internal
pulse of sonication, may be required to disperse such agglomerates and allow
the true particle size to be determined. By optical microscopy, as shown by
Fig. 4C, the precipitated acitretin particles can be seen to be surprisingly
homogeneous in size and shape. A particle size distribution where the
majority of the particles are less than 1 micron in size can improve the
topical absorption of insoluble drug substances such as acitretin.
For example, in particular embodiments, at least 90% or at least 98%, or at
least 99% of the acitretin particles suspended in the gel (on a volume basis)
are 1 micron or less in size (i.e., D(v,0.90)NMT 1 micron). It has been found
that acitretin spray dried powder exhibiting a particle size value d90>l
micron when dispersed in 0.7% Triton-X, does not effectively form a
nanosuspension within the topical gel composition of the invention.
The co-precipitation of polymer and active in various ratios produces solid
dispersions. In specific embodiments, the spray dried powder comprises
about 5% acitretin and about 95% copovidone (w/w). In certain
embodiments, the ratio of % acitretin to % copovidone in the spray dried
powder may be less than 50:50, in particular less than or equal to 25:75. In
certain embodiments, the ratio of % acitretin to % copovidone in the spray
dried powder may be 25:75, or 20:80, or 15:85, or 12.5:87.5, or 10:90, or
7.5:92.5, or 3:97.
In general, it has been found that acitretin spray dried powders having
between 3% and 25% acitretin can be used to formulate a topical gel
composition containing a nanosuspension of acitretin in accordance with the
invention. By contrast, gels prepared using micronized acitretin capsule fill
(not spray dried powder), do not result in nanosuspension.
In certain specific embodiments, gel formulations according to the invention
may comprise a suitable dispersing agent. For example, a suitable
dispersing agent may be a polysorbate, for example polysorbate 20, which is
sold under the brand name Tween 20™.
If Tween20 is added, then it may be necessary to avoid the use of effective
chelators, such as sodium edentate (EDTA). EDTA is commonly used as a
manufacturing and preserving agent. However, it has been found that as an
effective chelator, EDTA can promote crystallization of acitretin in the
compositions of the invention, when the acitretin is not contained within the
spray dried powder spheres.
At levels above about 0.3% w/w, it has been found that Tween 20 can
partially dissolve the acitretin nano-particles. Over time, the dissolved
portion of the acitretin is susceptible to spontaneous recrystallisation. When
this occurs it can promote further dissolution and recrystallisation of acitretin
as relatively large, typically > 1 micron, acitretin crystals. In the presence of
EDTA, the dissolved acitretin will relatively rapidly form and grow crystals.
In the absence of EDTA, the escaped acitretin resulting from inclusion of
Tween20 levels greater than 0.3% w/w will slowly grow crystals. In the
absence of Tween20, a nanodispersed acitretin gel containing EDTA exhibits
no crystal growth.
Therefore, preferred formulations according to the invention may contain
less than about 0.3% w/w Tween20, and preferably no EDTA, or may
contain EDTA in the absence of Tween20, or in the presence of only very
low levels of Tween20, for example less than about 0.1% w/w.
Figs. 1A to II show the results of particle size distribution analysis for
samples of acitretin spray dried powder (containing a range of ratios of
acitretin in copovidone) dispersed in water together with a nonionic
surfactant or dispersant, which in these examples is either 0.7% Triton X-100
or 2% Tween 20 or 80. Each of these examples shows a D(0.9) of less than
one micron.
The spray dried powder containing acitretin active typically also contains
residual solvent such as THF. It has been found that if the residual THF
content of the spray-dried powder falls below about 0.4% w/w, the ability of
the acitretin in the spray dried powder to yield nano-dispersions during gel
formulation is lost. Instead, the acitretin in the spray dried powder tends to
aggregate to form large crystals and does not form a nanosuspension when
formulated into a gel.
Therefore, it is preferred that the residual THF content of the acitretin spray
dried powder is 0.4% w/w or above. However, when determining the
acceptable residual level, it is also necessary to take into account the
intended daily dosage of the composition in use, when compared with the
permitted daily exposure limit for THF.
In certain preferred embodiments the gel formulation according to the
invention may include one or more preservatives. Suitable preservatives
include sodium parabens, such as sodium methylparaben or sodium
propylparaben, potassium sorbate, and phenoxyethanol. These ingredients
can be used either singularly or in combination of two or more compounds.
The exact levels of particular preservatives will be determined in order to
achieve desired levels of preservative efficacy in particular instances.
It has been found that interactions between preservatives in the composition
can affect the successful formation of a nanosuspension. In particular it
appears that the sodium parabens can play an additional role in generating a
nanosuspension, over and above simply raising the pH. For example, if
potassium sorbate or phenoxyethanol are present without sodium
methylparaben and sodium propylparaben also being present, the
nanosuspension tends not to form, even with the use of sodium hydroxide to
raise the pH. However, a nanosuspension will form when potassium sorbate
or phenoxyethanol are used as preservatives in combination with sodium
methylparaben or sodium propylparaben.
Other possible excipients may be utilized in the formulation. For example,
propylene glycol may help to preserve the formulation. The level of
propylene glycol used will affect the viscosity of the formulation. For
example at 10% w/w propylene glycol the gel is quite runny. A preferred
level of propylene glycol is about 2.5% to about 5%, most preferably about
5%.
In certain preferred embodiments the gel formulation according to the
invention may contain carbomer. Suitable carbomers include high molecular
weight crosslinked polymers of acrylic acid, for example Carbomer 974P.
The level of carbomer should be chosen so as to achieve a suitable viscosity
and an IVRT release rate for a 0.25 - 0.5 % w/w acitretin gel of not less than
about 0.010 mg/cm /min 1 2 . For example, for a 0.25 - 0.5 % w/w acitretin
gel a suitable level of carbomer is between 0.4 % and 0.6 %, more preferably
0.45 - 0.5 %, most preferably about 0.45 %.
According to at least one presently preferred embodiment of the invention a
stable topical gel formulation comprising 0.5% w/w acitretin as a stable
nanosuspension displaying a release rate of not less than about 0.01 mg/cm2
may comprise 2.50% acitretin spray dried powder containing 1:4
acitretinxopovidone, 0.3-0.8%, preferably 0.4-0.5%, most preferably 0.45%
carbomer 974P, 1.0-10%, preferably 2.5-7.5%, most preferably 5.0%
propylene glycol, up to 0.40%, preferably about 0.20% sodium
methylparaben, up to 0.73%, preferably about 0.40% sodium propylparaben,
about 7.50% copovidone filler, and water.
According to at least one further presently preferred embodiment of the
invention a stable topical gel formulation comprising 0.5% w/w acitretin as
a stable nanosuspension displaying a release rate of not less than about 0.01
mg/cm2 may comprise 10.00% acitretin spray dried powder containing 1:19
acitretinxopovidone, 0.3-0.8%, preferably 0.4-0.5%, most preferably 0.45%
carbomer 974P, 1.0-10%, preferably 2.5-7.5%, most preferably 5.0%
propylene glycol, up to 0.40%, preferably about 0.20% sodium
methylparaben, up to 0.73%, preferably about 0.40% sodium propylparaben,
and water.
According to at least one further presently preferred embodiment of the
invention a stable topical gel formulation comprising 0.25% w/w acitretin as
a stable nanosuspension may comprise 1.25% acitretin spray dried powder
containing 1:4 acitretinxopovidone, 0.3-0.8%, preferably 0.4-0.7%, most
preferably 0.50% carbomer 974P, 1.0-10%, preferably 2.5-7.5%, most
preferably 5.0% propylene glycol, up to 0.40%, preferably about 0.20%
sodium methylparaben, up to 0.73%, preferably about 0.40% sodium
propylparaben, about 8.50% copovidone filler, and water.
According to at least one further presently preferred embodiment of the
invention a stable topical gel formulation comprising 0.25% w/w acitretin as
a stable nanosuspension may comprise 5.00% acitretin spray dried powder
containing 1:19 acitretinxopovidone, 0.3-0.8%, preferably 0.4-0.7%, most
preferably 0.50% carbomer 974P, 1.0-10%, preferably 2.5-7.5%, most
preferably 5.0% propylene glycol, up to 0.40%, preferably about 0.20%
sodium methylparaben, up to 0.73%, preferably about 0.40% sodium
propylparaben, about 4.75% copovidone filler, and water.
According to at least one further presently preferred embodiment of the
invention a stable topical gel formulation comprising 0.25% w/w acitretin as
a stable nanosuspension displaying a release rate of not less than about 0.01
mg/cm2 may comprise 1.25% acitretin spray dried powder containing 1:4
acitretinxopovidone, about 0.50% carbomer 974P, 1.0-10%, preferably 2.5-
7.5%, most preferably 5.0% propylene glycol, up to 0.40%, preferably about
0.20% sodium methylparaben, up to 0.73%, preferably about 0.40% sodium
propylparaben, about 8.50% copovidone filler, and water.
Dosage
The actual dosage amount of a composition for delivery of drugs can be
determined by physical and physiological factors such as body weight,
severity of condition, the type of disease being treated, previous or
concurrent therapeutic interventions, idiopathy of the patient and on the route
of administration. The practitioner responsible for administration will, in any
event, determine the concentration of active ingredient(s) in a composition
and appropriate dose(s) for the individual subject.
An effective amount of the therapeutic composition is determined based on
the intended goal. As a topical composition, the compositions of the
invention are intended to be applied directly to the affected area or lesion, for
example with a fingertip. The quantity to be administered, both according to
number of treatments and unit dose, depends on the protection or effect
desired.
Packaging
The compositions of the invention may be packaged for use in various forms
of packaging for gels as are known in the art. For example, the gel may be
packaged in a tube, such as an aluminium barrier laminate tube, having a
relatively large diameter orifice, for example around 8mm, in which case a
relatively viscous product (for example, containing 0.6% carbomer, as in
Example 8) may be desirable to prevent leakage. Alternatively, the gel may
be packaged in a small orifice container, a pump or sachet, in which case a
less viscous (i.e. runnier) formulation may be more suitable (for example
containing 0.4% carbomer, as in Example 9) .
EXAMPLES
The following examples are included to demonstrate preferred embodiments
of the invention. It should be appreciated by those of skill in the art that the
techniques disclosed in the examples which follow represent techniques
discovered by the inventors to function well in the practice of the invention,
and thus can be considered to constitute preferred modes for its practice.
However, those of skill in the art should, in light of the present invention,
appreciate that many changes can be made in the specific embodiments
which are disclosed and still obtain a like or similar result without departing
from the spirit or scope of the invention. The following examples are offered
by way of illustration and not by way of limitation.
Example 1A: Preparation of Amorphous Acitretin 5%w/w Spray Dried
Powder
1. Dissolve the copovidone and acitretin in THF with constant stirring.
2. Spray dry the resulting solution using a co-current two fluid nozzle under an
atmosphere of nitrogen process gas with an inlet temperature of 120°C and an
5 exhaust temperature of 80°C.
Example IB : Preparation of Amorphous Acitretin 20 %w/w Spray Dried
Powder
. Dissolve the copovidone and acitretin in THF with constant stirring.
0 2. Spray dry the resulting solution using a co-current two fluid nozzle under an
atmosphere of nitrogen process gas with an inlet temperature of 120°C and an
exhaust temperature of 80°C.
Example 2: 0.5% w/w Acitretin Gel Formulation
Gel preparation
1. Stir the water with open-blade impeller overhead mixer at 1000 rpm, generating
a vortex slightly larger than the impeller diameter.
2. Slowly sprinkle the carbomer into the vortex, followed by all the other
5 excipients except the amorphous spray dried powder comprising 5%w/w
acitretin and 95% w/w copovidone.
3. Continue mixing at a reduced speed until the mixture appears homogeneous.
4. Into a 500 mL beaker weigh amorphous acitretin spray dried powder (5%
acitretin, 95% copovidone as a solid dispersion) 10.0 g
0 5. Carefully transfer the gel into the beaker containing amorphous acitretin and mix
with an overhead mixer to obtain a smooth gel.
6. Stir carefully, knocking, tapping, scraping the sides of the beaker to aid
homogenisation.
5 This example formulation was found to work well, with no crystal formation.
Example 3: 0.25% w/w Acitretin Gel Formulation
Attorney Docket No. D2026/20004
Gel Preparation
1. Stir the water (840.0 g)in a 2 L beaker with two-tier paddle on overhead mixer at
high speed, generating a strong vortex.
2. Sprinkle the carbomer into the vortex over period of 10 minutes to avoid
clumping.
3. Add the BHT and continue stirring for another 40 minutes on reduced vortex to
dissolve the carbomer.
4. Add the propylene glycol.
5. Add the Sodium methylparaben. To aid efficient mixing increase the rpm as the
gel thickens.
6. Add the Sodium propylparaben.
7. Continue mixing at high speed u til homogeneous. Spatula the sides if
necessary.
8. Split the gel into two equal amounts.
9. To one of the two parts add amorphous spray dried powder comprising 5%w/w
acitretin and 95% w/w copovidone and stir with an overhead mixer.
10. To the second portion of the gel add the copovidone and water (2.5 g) and stir
with an overhead mixer .
11. Combine and mix together the gels from Steps 9 and 10.
This example formulation was found to work well, with no crystal formation.
Example 4: 0.5% w/w Acitretin Gel Formulation with 0.3 %w/w Tween 20
Attorney Docket No. D2026/20004
Gel preparation
. Using a large overhead mixer with a three-pronged paddle, stir water (I) in a
1L beaker with an overhead mixer at high speed, generating a strong vortex.
2. Sprinkle the carbomer into the water over period of 10 minutes to avoid
clumping. Continue stirring until carbomer has fully hydrated, free from any
lumps.
3. Into a small vessel fully dissolve the parabens into water (II) with a bench
top overhead mixer.
4. Into a medium vessel dispense propylene glycol.
5. Into the propylene glycol from step 4 admix the parabens solution from step
3.
6. Into the carbomer solution from step 2 admix the glycolic parabens solution
from step 5, increasing the mixing speed as the gel cures.
7. While stirring at high speed with the large overhead mixer, add the
Amorphous Acitretin SDP to the cured base gel.
8. Continue mixing and observe the gel under microscope until the gel exhibits
uniform homogeneity of nanodispersions.
9. Add the Tween 20 to the gel from step 8. Mix the sample well with low
shear overhead mixer accurately for 5 minutes.
Example 5: 0.5% w/w Acitretin Gel Formulation using Acitretin 20% w/w Spray
Dried Powder
Gel preparation
. Into a 50 L medicine tank chamber, homogenize/mix water (I).
2. Sprinkle the carbomer into the water (I) over period of 10 minutes to avoid
clumping. Continue homogenizing/mixing until carbomer has fully hydrated,
free from any lumps.
3. Add the copovidone while homogenizing/mixing.
4. Add all the Amorphous Acitretin SDP while homogenizing/mixing.
5. Into a medium vessel fully dissolve the parabens in water (II) using a bench top
overhead mixer.
6. Into the parabens solution admix the propylene glycol.
7. Into the medicine tank add the glycolic parabens solution to cure the gel, mixing
with paddle mixer only.
8. Continue mixing and observe the gel under microscope until the gel exhibits
uniform homogeneity of nanosuspension.
Example 6: 0.25% w/w Acitretin Gel Formulation using Acitretin 20% w/w Spray
Dried Powder
Gel Preparation
1. Into a 50 L medicine tank chamber, homogenize/mix water (I).
2. Sprinkle the carbomer into the water (I) over period of 10 minutes to avoid
clumping. Continue homogenizing/mixing until carbomer has fully hydrated,
free from any lumps.
3. Add the copovidone while homogenizing/mixing.
4. Add Amorphous Acitretin SDP while homogenizing/mixing.
5. Into a medium vessel fully dissolve the parabens in water (II) using a bench
top overhead mixer.
6. Into the parabens solution admix the propylene glycol.
Attorney Docket No. D2026/20004
7. Into the medicine tank add the glycolic parabens solution to cure the gel,
mixing with paddle mixer only.
8. Continue mixing and observe the gel under microscope until the gel exhibits
uniform homogeneity of nanosuspension.
Example 7 : 0.5 %w/w Acitretin Gel Formulation with 0.6 % w/w Carbomer
Gel Preparation
. Stir water (I) in a 1L beaker with an overhead mixer at high speed, generating
a strong vortex.
2. Sprinkle the carbomer into the water slowly to avoid clumping. Continue
stirring until carbomer is fully hydrated.
3. While stirring to generate a vortex, add the copovidone to the hydrated
carbomer.
4. While stirring to generate a vortex, add the Acitretin SDP to the hydrated
carbomer.
5. Dissolve the sodium methylparaben and sodium propylparaben in water (II)
in a small beaker.
6. Into a small beaker containing the propylene glycol stir-in the paraben
solution.
7. Add the glycolic paraben mix to the carbomer solution while stirring,
increasing the mixing speed as the gel thickens. Continue mixing until
homogeneous.
8. Add Water (III) with stirring to achieve a net mass of 500 g.
Example 8: 0.5 % w/w Acitretin Gel Formulation with 0.4 % w/w Carbomer
Gel Preparation
. Stir water (I) in a L beaker with an overhead mixer at high speed, generating
a strong vortex.
2. Sprinkle the carbomer into the water slowly to avoid clumping. Continue
stirring until carbomer is fully hydrated.
3. While stirring to generate a vortex, add the copovidone to the hydrated
carbomer.
4. While stirring to generate a vortex, add the Acitretin SDP to the hydrated
carbomer.
5. Dissolve the sodium methylparaben and sodium propylparaben in water (II)
in a small beaker.
6. Into a small beaker containing the propylene glycol stir-in the paraben
solution.
7. Add the glycolic paraben mix to the carbomer solution while stirring,
increasing the mixing speed as the gel thickens. Continue mixing until
homogeneous.
8. Add Water (III) with stirring to achieve a net mass of 500 g.
Example 9: 0.5 % w/w Acitretin Gel Formulation with 0.45 % w/w
Carbomer
(5% acitretin,95%plasdone)
Water (II) 22.25 4.45
Total 500.0 100.0
Using the two-tier paddle stir 400 g water in a 1L beaker with an overhead
mixer at high speed, generating a strong vortex.
Sprinkle the carbomer into the vortex over period of 10 minutes to avoid
clumping. Continue stirring until mixture has thickened.
Sequentially add the other base gel excipients, increasing the mixing speed
as the gel thickens. Continue mixing until homogeneous
Increase/adjust the mixing speed to obtain and maintain a small vortex as the
Acitretin spray-dried powder is slowly spooned into the vortex. Stir carefully
tap and scrape the sides of the beaker to aid homogenisation.
Add Water (II) with stirring to achieve a net mass of 500 g.
Efficacy - In Vitro Release testing
For a topical medicament to be effective it must be readily released from the
vehicle matrix and interact intimately with the skin to be treated. On this
basis candidate formulations can be ranked based on in vitro release rates
through artificial or post mortem skin membranes. This is routinely
undertaken using the Franz Diffusion Cell methodology. The rate and extent
to which the drug substance is released from the product matrix are
particularly relevant to the prediction of relative efficacy of candidate
formulations.
In Vitro Release Testing (IVRT) is a useful test to assess product "sameness"
under certain scale and post approval changes for semisolid products. The
FDA Guidance on Scale up and Post Approval Changes for Semisolid
(SUPAC-SS) describes suitable conditions for this testing.
The apparatus used for IVRT is a Franz diffusion cell system acquired from
Hanson Research. It consists of six individual cells. Each cell has a standard
open cap ground glass surface with 5 mm diameter orifices, 7 mL volume
capacity, and total diameter of 25 mm. About 300 mg of the semisolid
preparation is placed uniformly on a synthetic membrane and kept occluded
to prevent solvent evaporation and compositional changes. Multiple
sampling times (at least 5 times) over an appropriate time period are
suggested in order to generate an adequate release profile and to determine
the drug release rate.
The conditions used for IVRT of the example formulations of the invention
are as follows:
The following table shows the results of IVRT under the above conditions
Acitretin 0.5 % w/w Gel (Example 2)-:
Example 2: Acitretin 0.5 % w/w Gel
Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 24.6 23.4 22.7 22.5 2 1.7 22.3
Release Rate 0.015 0.0130 0.014 0.0 1 0.01 3 0.013
(mg/cm2 per min1 2)
Regression (r) 0.9909 0.9857 0.9835 0.9832 0.9826 0.9819
Average total release = 22.9 %
Average release rate = 0.01 4 (RSD
Average Regression = 0.9846
The following table shows the results of IVRT under the above conditions on Acitretin 0.25
% w/w Gel (Example 3)-
Example 3 : Acitretin 0.25 % w/w Gel
Ce l Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 34.7 31.5 27.3 36.0 28.8 28.6
Release Rate 0.01 0.010 0.009 0.01 0.01 0 0.010
(mg/cm2 per min )
Regression (r) 0.9767 0.9769 0.9718 0.9797 0.9758 0.9796
Average total release ==3 1.1 %
Average release rate = 0.010 (RSD = 7.4 %)
Average Regression = 0.9763
The following table shows the results of IVRT under the above conditions on Acitretin 0.5%
w/w Gel (Example 4)
Example 4 : Acitretin 0.5% w/w GEL
Cell Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 19.0 17.6 16.5 17.6 19.6 16.3
Release Rate 0.01 2 0.01 1 0.01 0 0.01 0.01 2 0.010
(mg cm2 per min 2)
Regression (r) 0.9776 0.9773 0.9751 0.9757 0.971 9 0.9784
Average total release = 17.8 %
Average release rate = 0.01 mg/cm 2/min 1 2 (RSD
Average Regression = 0.9760
The following table shows the results of IVRT under the above conditions on Acitretin 0.5%
w/w Gel (Example 5)
Example 5 : Acitretin 0.5% w/w GEL,
Cell Cell 2 Cell 3 Cell 4 Cell 5 Ce l 6
Total Release, % 20.5 18.7 18.4 15.7 17.9 17.2
Release Rate 0.01 3 0.012 0.012 0.010 0.0 0.01 2
(mg/cm2 per min 2)
Regression (r) 0.981 0.9768 0.9723 0.9773 0.971 6 0.9698
Average total release = 8.1 %
Average release rate = 0.012 mg/cm /min 1 2 (RSD = 8.3 %)
Average Regression = 0.9748
The following table shows the results of IVRT under the above conditions on Acitretin
0.25% w/w Gel (Example 6).
Example 6: Acitretin 0.25% w/w Gel
Cell Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 23.8 25.3 23.7 22.2 2 1.8 2 1.4
Release Rate 0.008 0.008 0.007 0.007 0.007 0.007
(mg cm2 per min 2)
Regression (r) 0.9801 0.9728 0.9779 0.9796 0.9758 0.9774
Average total release = 23.0 %
Average release rate = 0.007 mg/cm /min 1 2 (RSD = 7.0 %)
Average Regression = 0.9773
The following table shows the results of IVRT under the above conditions on Acitretin 0.5%
w/w Gel (Example 7).
Example 7: Acitretin 0.5% w/w Gel
Ce l Cell 2 Cell 3 Cell 4 Cell 5 Cel 6
Total Release, % 20.0 19.8 18.8 18.1 19.6 16.8
Release Rate 0.013 0.012 0.012 0.012 0.012 0.01
(mg cm2 per min )
Regression (r) 0.9807 0.9741 0.9723 0.9772 0.9819 0.9800
Average total release = 18.9 %
Average release rate = 0.012 mg/cm /min 1 2 (RSD
Average Regression = 0.9777
The following table shows the results of IVRT under the above conditions on Acitretin 0.5%
w/w Gel (Example 8).
Example 8: Acitretin 0.5% w/w Gel
Cell 1 Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 22.2 19.4 19.8 20.2 19.2 18.7
Release Rate 0.014 0.01 3 0.012 0.013 0.01 2 0.012
(mg/cm2 per min1 2)
Regression (r) 0.9830 0.9820 0.9815 0.9806 0.9832 0.9793
Average total release = 19.9 %
Average release rate = 0.013 mg/cm /min I 2 (RSD = 6.4 %)
Average Regression = 0.973 1
The following table shows the results of IVRT under the above conditions on
Acitretin 0.5% w/w Gel (Example 9).
Example 9: Acitretin 0.5% w/w Gel
Cell l Cell 2 Cell 3 Cell 4 Cell 5 Cell 6
Total Release, % 23.9 20.8 24. 1 22.2 20.9 2 1.0
Release Rate 0.01 5 0.014 0.014 0.015 0.013 0.014
(mg/cm2 per min 2)
Regression (r) 0.9825 0.9816 0.9832 0.9810 0.9803 0.9771
Average total release = 22.1 %
Average release rate = 0.014 (RSD = 5.3 %)
Average Regression = 0.9810
These results are also illustrated in Figures 2A to 2H and summarized in
Figure 21. As can be seen, these formulations achieve an average release rate
of not less than 0.01 mg/cm 2 per min½ under these conditions, with the
exception of Example 6, where a lower release rate has been achieved with a
composition containing 0.25% w/w acitretin and 0.6% w/w carbomer. For
some purposes, it may be desired to achieve a lower rate of release of
acitretin, in association with particular selected properties of for example,
viscosity.
Various modifications to and departures from the disclosed example
embodiments will occur to those having ordinary skill in the art. The subject
matter that is intended to be within the spirit of this invention is set forth in
the claims.
CLAIMS
What is claimed is:
1. A topical medicament for reducing at least one symptom of at least one
dermatological condition comprising acitretin as a nanosuspension.
2. A topical medicament for reducing at least one symptom of at least one
dermatological condition comprising not less than 0.25% w/w acitretin,
wherein the medicament shows a release rate of not less than 0.01 mg/cm2
per min½ as measured using a Franz diffusion cell in vitro release testing
system utilizing the following conditions: receptor medium comprising 1%
DMSO in (35% ethanol: 65% phosphate buffer pH 8.0), speed 700 rpm,
membrane polysulfone 0.45m , dosage 300 ± 30mg, temperature 32.5 ±
0.5°C.
3. The medicament of claim 2, comprising a stable nanosuspension of
acitretin.
4. The medicament of claim 3, which is a gel.
5. The medicament of claim 3 in which the acitretin is substantially
amorphous.
6. The medicament of claim 3 in which at least 90% of the volume
distribution of acitretin particles according to the laser diffraction technique
are 1 micron or less in diameter.
7. The medicament of claim 3 in which at least 98% of the acitretin particles
are 1 micron or less in diameter.
8. The medicament of claim 3 in which at least 99% of the acitretin particles
are 1 micron or less in diameter.
9. The medicament of claim 3 comprising a copolymer of vinylpyrrolidone
and vinyl acetate.
10. The medicament of claim 3 comprising a spray dried powder comprising
a solid dispersion of acitretin in a copolymer of vinylpyrrolidone and vinyl
acetate.
11. The medicament of claim 10 wherein the spray dried powder contains
from 3% to 25% w/w acitretin.
12. The medicament of claim 10 wherein the w/w % ratio of acitretin to
copolymer in the spray dried powder is 5:95 or 25:75, or 20:80, or 15:85, or
12.5:87.5, or 10:90, or 7.5:92.5, or 3:97.
13. The medicament of claim 4 comprising a gelling agent.
14. The medicament of claim 4 comprising a dispersing agent.
15. The medicament of claim 14 where said dispersing agent is a
polysorbate.
16. The medicament of claim 14 where the dispersing agent is present at a
level of not more than about 0.3 % w/w of the medicament.
17. A method of manufacture of the medicament of claim 4 comprising
forming a solid dispersion of acitretin and a copolymer of vinylpyrrolidone
and vinyl acetate and combining the solid dispersion with an aqueous gel
base.
18. The method of Claim 17 wherein the gel base comprises water and a
gelling agent.
19. The method of claim 17 wherein the solid dispersion of acitretin and
copolymer is a powder formed by spray-drying.
20. The use of a medicament according to claim 1 for treatment of actinic
keratosis.
21. A topical medicament for reducing at least one symptom of at least one
dermatological condition comprising at least about 0.5% w/w acitretin,
wherein the medicament shows a release rate of not less than 0.01 mg/cm2
per min½ as measured using a Franz diffusion cell in vitro release testing
system utilizing the following conditions: receptor medium comprising 1%
DMSO in (35% ethanol: 65% phosphate buffer pH 8.0), speed 700 rpm,
membrane polysulfone 0.45mp , dosage 300 ± 30mg, temperature 32.5 ±
0.5°C.
22. A topical medicament for reducing at least one symptom of at least one
dermatological condition comprising acitretin particles as a nanosuspension,
wherein at least 90%, by volume, of the acitretin particles suspended are 1
micron or less in size.
23 The topical medicament of claim 22, wherein at least 98%, by volume, of
the acitretin particles suspended are 1 micron or less in size.
24. The topical medicament of claim 22, wherein at least 99%, by volume, of
the acitretin particles suspended are 1 micron or less in size.
25. The topical medicament of claim 22, wherein the topical medicament is
in gel form.
26. The topical medicament of claim 22, wherein the acitretin is a solid
dispersion of acitretin with a copolymer.
27. The topical medicament of claim 22, wherein acitretin is present at about
0.25 - 0.5 % w/w.
28. The topical medicament of claim 22, wherein the copolymer is
copovidone.
29. The topical medicament of claim 22, further comprising a dispersing
agent.
30. The topical medicament of claim 29, wherein the dispersing agent is a
polysorbate.
31. The topical medicament of claim 30,wherein the dispersing agent is
polysorbate 20 present in an amount of less than about 0.3% w/w.
32. The topical medicament of claim 22, further comprising a chelating
agent.
33. The topical medicament of claim 32, wherein the chelating agent is
EDTA.
34. The topical medicament of claim 32, wherein the composition comprises
less than about 0.3% w/w polysorbate 20, and no EDTA.
35. The topical medicament of claim 32, further comprising EDTA in the
absence of polysorbate 20.
36. The topical medicament of claim 32, further comprising EDTA in the
presence of less than about 0.1% w/w polysorbate 20.
37. The topical medicament of claim 22, further comprising residual solvent.
38. The topical medicament of claim 37,wherein the residual solvent is THF,
and is present in a concentration of at least about 0.4% w/w.
39. The topical medicament of claim 22, further comprising at least one
preservative.
40. The topical medicament of claim 39, wherein the preservative is selected
from the group consisting of a sodium paraben, sodium methylparaben,
sodium propylparaben, potassium sorbate, phenoxyethanol, and
combinations thereof.
41. The topical medicament of claim 22, further comprising propylene glycol
of about 2.5% to about 5% w/w.
42. The topical medicament of claim 22, wherein the composition comprises
carbomer.
43. The topical medicament of claim 22, wherein acitretin is present at about
0.25 - 0.5 w/w, and the carbomer is between 0.4 % and 0.6 .
44. The topical medicament of claim 22, wherein the medicament shows a
release rate of not less than 0.01 mg/cm2 per min½ as measured using a Franz
diffusion cell in vitro release testing system utilizing the following
conditions: receptor medium comprising 1% DMSO in (35% ethanol: 65%
phosphate buffer pH 8.0), speed 700 rpm, membrane polysulfone 0.45m i,
dosage 300 ± 30mg, temperature 32.5 ± 0.5°C.
45. A method of manufacture of the topical medicament of claim 22 which
comprises forming a solid dispersion of acitretin particles and a copolymer
of vinylpyrrolidone and vinyl acetate by spray drying pre-dissolved acitretin
with a copolymer, and combining the solid dispersion with an aqueous gel
base.
46. The method of claim 45, wherein at least 90%, by volume, of the
acitretin particles formed are 1 micron or less in size.
47. The method of claim 45, wherein at least 98%, by volume, of the
acitretin particles formed are 1 micron or less in size.
48. The method of claim 45, wherein at least 99%, by volume, of the
acitretin particles formed are 1 micron or less in size.
49. The method of claim 45, wherein acitretin is present at about 0.25 - 0.5
% w/w.
50. The method of claim 45, wherein the copolymer is copovidone.
51. The method of claim 45, wherein the topical medicament further
comprises a dispersing agent.
52. The method of claim 51, wherein the dispersing agent is a polysorbate.
53. The method of claim 52,wherein the dispersing agent is polysorbate 20
present in an amount of less than about 0.3% w/w.
54. The method of claim 45, wherein the topical medicament further
comprises a chelating agent.
55. The method of claim 54, wherein the chelating agent is EDTA.
56. The method of claim 45, wherein the composition comprises less than
about 0.3% w/w polysorbate 20, and no EDTA.
57. The method of claim 45, further comprising EDTA in the absence of
polysorbate 20,
58. The method of claim 45, further comprising EDTA in the presence of
less than about 0.1% w/w polysorbate 20.
59. The method of claim 45, wherein the topical medicament further
comprises residual solvent.
60. The method of claim 59, wherein the residual solvent is THF, and is
present in a concentration of at least about 0.4% w/w.
61. The method of claim 45, wherein the topical medicament further
comprises at least one preservative.
62. The method of claim 61, wherein the preservative is selected from the
group consisting of a sodium paraben, sodium methylparaben, sodium
propylparaben, potassium sorbate, phenoxyethanol, and combinations
thereof.
63. The method of claim 45, wherein the topical medicament further
comprises propylene glycol of about 2.5% to about 5% w/w.
64. The method of claim 45, wherein the topical medicament further
comprises carbomer.
65. The method of claim 45, wherein the topical medicament comprises
acitretin at about 0.25 - 0.5 % w/w, and the carbomer is between 0.4 % and
0.6 %.
66. The method of claim 45, wherein the topical medicament shows a release
rate of not less than 0.01 mg/cm2 per min½ as measured using a Franz
diffusion cell in vitro release testing system utilizing the following
conditions: receptor medium comprising 1% DMSO in (35% ethanol: 65%
phosphate buffer pH 8.0), speed 700 rpm, membrane polysulfone 0.45mh ,
dosage 300 ± 30mg, temperature 32.5 ± 0.5°C.