U.S. patent application number 15/816594 was filed with the patent office on 2018-04-05 for topical anti-inflammatory pharmaceutical composition with zileuton cream formulation.
The applicant listed for this patent is Qurient Co., Ltd.. Invention is credited to Ji Ye Ahn, Chunwon Jung, Hwan Kyu Kang, Hana Kim, Jaeseung Kim, Jeong Jun Kim, Sae Yeon Lee, Ki Yean NAM.
Application Number | 20180092877 15/816594 |
Document ID | / |
Family ID | 57222217 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180092877 |
Kind Code |
A1 |
NAM; Ki Yean ; et
al. |
April 5, 2018 |
TOPICAL ANTI-INFLAMMATORY PHARMACEUTICAL COMPOSITION WITH ZILEUTON
CREAM FORMULATION
Abstract
Provided herein is a zileuton cream type topical
anti-inflammatory pharmaceutical composition, and more
particularly, a zileuton cream type topical anti-inflammatory
pharmaceutical composition capable of retaining stability at room
temperature and of being applied topically to maximize medical
effects while minimizing absorption to an entirety of body, thereby
minimizing toxicity caused by the compound so as to be suitable to
topical treatment of skin diseases caused by leukotriene.
Inventors: |
NAM; Ki Yean; (Seongnam-si,
KR) ; Kim; Jeong Jun; (Seoul, KR) ; Lee; Sae
Yeon; (Yongin-si, KR) ; Ahn; Ji Ye;
(Seongnam-si, KR) ; Jung; Chunwon; (Yongin-si,
KR) ; Kim; Jaeseung; (Seoul, KR) ; Kang; Hwan
Kyu; (Ansan-si, KR) ; Kim; Hana; (Suwon-si,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Qurient Co., Ltd. |
Seongnam-si |
|
KR |
|
|
Family ID: |
57222217 |
Appl. No.: |
15/816594 |
Filed: |
November 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15215909 |
Jul 21, 2016 |
9855243 |
|
|
15816594 |
|
|
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|
14777183 |
Sep 15, 2015 |
9655841 |
|
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PCT/KR2014/007525 |
Aug 13, 2014 |
|
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|
15215909 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/24 20130101;
A61K 47/10 20130101; A61K 31/381 20130101; A61K 9/06 20130101; A61K
47/44 20130101; A61K 9/0014 20130101; A61K 47/06 20130101 |
International
Class: |
A61K 31/381 20060101
A61K031/381; A61K 47/44 20060101 A61K047/44; A61K 47/24 20060101
A61K047/24; A61K 9/06 20060101 A61K009/06; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00; A61K 47/06 20060101
A61K047/06 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 30, 2013 |
KR |
1020130130165 |
Claims
1. A cream type topical anti-inflammatory pharmaceutical
composition, comprising zileuton, an aqueous solvent, an organic
solvent, a thickening agent, and an emulsifier.
2. The composition according to claim 1, wherein the aqueous
solvent is water or a pH buffer solution.
3. The composition according to claim 2, wherein the aqueous
solution is a pH buffer solution having a pH of about 4 to about
5.
4. The composition according to claim 3, wherein the pH buffer
solution is citrate buffer, acetate buffer or phthalate buffer.
5. The composition according to claim 1, wherein the organic
solvent is at least one selected from the group consisting of
ethanol, polyethylene glycol, hexylene glycol, propylene glycol
monocaprylate, benzyl alcohol, N-methyl pyrrolidone, triacetin,
isopropyl myristate, propylene glycol dicaprylocaprate, medium
chain triglycerides, castor oil, olive oil, safflower oil, light
mineral oil, squalane, dimethicone, cyclomethicone, polyglyceryl-6
dioleate, polyglyceryl-10 monooleate, polyglyceryl-10 dioleate,
polyoxyl 40 hydrogenated castor oil, caprylocaproyl polyoxyl-8
glycerides, polyoxyethylene (20) sorbitan monolaurate, diethylene
glycol monoethyl ether, and dimethyl sulfoxide.
6. The composition according to claim 5, wherein the organic
solvent is propylene glycol.
7. The composition according to claim 1, wherein the thickening
agent comprises at least one of white petrolatum and white wax.
8. The composition according to claim 1, wherein the emulsifier is
at least one of phospholipid, stearyl alcohol and propylene glycol
stearate.
9. The composition according to claim 1, wherein the composition
further comprises an emulsifier.
10. The composition according to claim 9, wherein the emulsifier
comprises hydrogenated lecithin.
11. The composition according to claim 1, wherein the composition
further comprises a preservative.
12. The composition according to claim 11, wherein the preservative
is at least one selected from a group consisting of methylparaben,
ethylparaben, propylparaben, isobutylparaben, butyl paraben,
2-phenoxy ethanol, and 4-hydroxybenzoic acid.
13. The composition according to claim 11, wherein the composition
comprises zileuton of about 0.05 to about 2 weight %; water or pH
buffer solution of about 30 to about 34 weight %; white petrolatum
of about 36 to about 40 weight %; white wax of about 4 to about 8
weight %; propylene glycol of about 16 to about 22 weight %;
phospholipid of about 2 to about 6 weight %; and preservative of
about 0.005 to about 0.04 weight.
14. The composition according to claim 11, wherein the composition
comprises zileuton of about 0.1 to about 1 weight %; water or pH
buffer solution of about 31 to about 33 weight %; white petrolatum
of about 37 to about 39 weight %; white wax of about 5 to about 7
weight %; propylene glycol of about 18 to about 20 weight %;
phospholipid of about 3 to about 5 weight %; and preservative of
about 0.01 to about 0.03 weight %.
15. The composition according to claim 1, wherein the composition
is formulated for topical application to human skin.
16. The composition according to claim 1, wherein zileuton is
racemic zileuton.
17. A method for relieving or treating atopic dermatitis, acne,
urticaria, psoriasis, eczema, a bullous skin disease, collagenoses,
Sjogren-Larsson syndrome, or acne in skin lesions of mastocytosis,
wherein said method comprises administering, to a subject in need
of such relief or treatment, a composition of claim 1.
18. The method according to 17, wherein the composition is applied
topically to human skin.
19. A method for preparing a cream type topical anti-inflammatory
pharmaceutical composition, comprising: mixing zileuton, an aqueous
solvent, an organic solvent, a thickening agent, and an emulsifier
under a mixing condition of a temperature of about 30 to about
80.degree. C. and about 600 to about 1200 rpm.
20. The method according to claim 19, wherein the aqueous solvent
is a water or a pH buffer solution having a pH of about 4 to about
5.
21. The method according to claim 19, wherein, in the mixing, a
preservative is further mixed.
22. The method according to claim 19, further comprising cooling a
resultant of the mixing at a temperature of about 20 to about
30.degree. C. while stirring at about 600 rpm or less.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 15/215,909, filed Jul. 21, 2016; which is a
continuation-in-part application of U.S. patent application Ser.
No. 14/777,183, filed on Sep. 15, 2015 (now U.S. Pat. No.
9,655,841); which is a National Stage Application of International
Application No. PCT/KR2014/007525, filed on Aug. 13, 2014; which
claims priority to Korean Patent Application No. 10-2013-0130165,
filed Oct. 30, 2013, all of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relate to a topical pharmaceutical
composition with zileuton cream formulation for treatment of skin
diseases caused by leukotriene.
BACKGROUND
[0003] Leukotriene is a metabolite of arachidonic acid, and is well
known as an inflammatory factor that is deeply involved in causing
inflammation, edema, and secretion of mucus and the like. A
well-known leukotriene inhibitor developed so far is zileuton
((.+-.)-1-(1-(benzo[b]thiophen-2-yl)ethyl)-1-hydroxyurea).
[0004] Zileuton is a mixture of stereoisomers:
(R)-1-(1-(benzo[b]thiopen-2-yl)ethyl)-1-hydroxyure and
(S)-1-(1-(benzo[b]thiophen-2-yl)ethyl)-1-hydroxyurea. It has been
approved as an oral drug for treatment of asthma, and is known to
be administrable twice a day. Clinical trials have shown that
zileuton exhibits an effective anti-inflammatory pharmaceutical
effect against inflammation reaction of asthma.
[0005] Clinical trials have revealed that oral administration of
zileuton alleviates atopic dermatitis symptoms. However, zileuton
is not being widely used despite its excellent anti-inflammatory
effects due to toxicity of the compound.
[0006] Zileuton has significant hepatotoxicity, and thus an oral
administration of zileuton should be accompanied by monitoring of
liver functions of the patient.
BRIEF SUMMARY
[0007] Therefore, a purpose of the present invention is to provide
a topical pharmaceutical composition with a cream formulation,
capable of applying zileuton topically to skin lesions of diseases
caused by topical skin inflammation reactions such as atopic
dermatitis, acne, various types of urticaria, psoriasis, eczema,
bullous skin diseases such as bullous pemphigoid, collagenoses,
Sjogren-Larsson syndrome, mastocytosis and the like, and maximizing
pharmaceutical effects of zileuton while minimizing absorption to
an entirety of a patient's body so as to minimize toxicity of the
compound.
[0008] Another purpose of the present invention is to provide a
cream type topical pharmaceutical composition having improved
physiochemical stability.
[0009] Further, another purpose of the present invention is to
provide a method for preparing a topical pharmaceutical composition
with zileuton cream formulation.
[0010] Further, still another purpose of the present invention is
to provide a method for relieving or treating atopic dermatitis,
acne, urticaria, psoriasis, eczema, a bullous skin disease,
collagenoses, Sjogren-Larsson syndrome, or acne in skin lesions of
mastocytosis using the pharmaceutical composition.
[0011] In order to achieve the purposes, one embodiment of the
present invention provides a cream type topical pharmaceutical
composition, comprising zileuton, an aqueous solvent, an organic
solvent, a thickening agent, and an emulsifier.
[0012] The aqueous solvent may comprise water or a pH buffer
solution, and the organic solvent may comprise, without any
limitation, at least one selected from the group consisting of
ethanol, polyethylene glycol, hexylene glycol, propylene glycol
monocaprylate, benzyl alcohol, N-methyl pyrrolidone, triacetin,
isopropyl myristate, propylene glycol dicaprylocaprate, medium
chain triglycerides, castor oil, olive oil, safflower oil, light
mineral oil, squalane, dimethicone, cyclomethicone, polyglyceryl-6
dioleate, polyglyceryl-10 monooleate, polyglyceryl-10 dioleate,
polyoxyl 40 hydrogenated castor oil, caprylocaproyl polyoxyl-8
glycerides, polyoxyethylene (20) sorbitan monolaurate, diethylene
glycol monoethyl ether, and dimethyl sulfoxide.
[0013] The aqueous solvent may be a pH buffer solution having a pH
of about 4 to about 5.
[0014] The thickening agent may comprise at least one of white
petrolatum and white wax.
[0015] The emulsifier may comprise at least one selected from a
group consisting of phospholipid, stearyl alcohol and propylene
glycol stearate. Preferably, the emulsifier may comprise
phospholipids including hydrogenated lecithin.
[0016] Furthermore, the pharmaceutical composition of the present
invention may further comprise a preservative.
[0017] The preservative may comprise at least one selected from a
group consisting of methylparaben, ethylparaben, propylparaben,
isobutylparaben, butyl paraben, 2-phenoxy ethanol, and
4-hydroxybenzoic acid.
[0018] The pharmaceutical composition of the present invention may
comprise zileuton of about 0.05 to about 2 weight % as an active
pharmaceutical ingredient; water or pH buffer solution of about 30
to about 34 weight %; white petrolatum of about 36 to about 40
weight %; white wax of about 4 to about 8 weight %; propylene
glycol of about 16 to about 22 weight %; phospholipid of about 2 to
about 6 weight %; and preservative of about 0.005 to about 0.04
weight %.
[0019] Further, the composition may comprise zileuton of about 0.1
to about 1 weight %; water or pH buffer solution of about 31 to
about 33 weight %; white petrolatum of about 37 to about 39 weight
%; white wax of about 5 to about 7 weight %; propylene glycol of
about 18 to about 20 weight %; phospholipid of about 3 to about 5
weight %; and preservative of about 0.01 to about 0.03 weight
%.
[0020] The composition may be for topical application to human
skin, and the zileuton may be racemic zileuton.
[0021] Another embodiment of the present invention provides a
method for relieving or treating atopic dermatitis, acne,
urticaria, psoriasis, eczema, a bullous skin disease, collagenoses,
Sjogren-Larsson syndrome, or acne in skin lesions of mastocytosis,
comprising administering, to a subject in need of such relief or
treatment, the composition of the present invention.
[0022] Still another embodiment of the present invention provides a
method for preparing a cream type topical anti-inflammatory
pharmaceutical composition, including mixing zileuton, an aqueous
solvent, an organic solvent, a thickening agent, an emulsifier, and
optionally a preservative under a mixing condition of a temperature
of about 30 to about 80.degree. C. and about 600 to about 1200 rpm,
for about 10 to about 60 minutes.
[0023] In the method, the aqueous solvent may be water or pH buffer
solution having a pH of about 4 to about 5.
[0024] The method may further include cooling the mixed ingredients
at a temperature of about 20 and about 30.degree. C. while stirring
at about 600 rpm or less.
[0025] As aforementioned, the present invention provide a cream
type topical pharmaceutical composition that comprises zileuton as
an active pharmaceutical ingredient and exhibits treatment effects
to diseases caused by topical skin inflammation reactions such as
atopic dermatitis, acne, various types of urticaria, psoriasis,
eczema, bullous skin diseases such as bullous pemphigoid,
collagenoses, Sjogren-Larsson syndrome, skin lesions of
mastocytosis, and the like.
[0026] Furthermore, the cream type pharmaceutical composition
according to the present invention has a pharmacokinetic profile
that enables zileuton that is a leukotriene inhibitor to be
absorbed to skin effectively but minimizing the amount of
absorption to an entirety of a patient's body, and a physiochemical
stability.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a graph showing the pH changes of the
pharmaceutical compositions with or without a pH buffer solution at
40.degree. C. over 4 weeks.
[0028] FIG. 2 is a schematic diagram illustrating results of a test
conducted to verify medical effects of the pharmaceutical
composition according to the present invention by applying the same
to an atopic mouse model;
[0029] FIG. 3 is a graph showing thicknesses of a mouse's ear
measured after topically applying the pharmaceutical composition
according to the present invention to an atopic mouse model;
and
[0030] FIGS. 4 and 5 show research results of the pharmacokinetic
profile of the pharmaceutical composition according to the present
invention in a minipig.
DETAILED DESCRIPTION
[0031] The present invention now will be described more fully
hereinafter in the following detailed description of the invention,
in which some, but not all embodiments of the invention are
described. Indeed, the present invention may be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein; rather, these embodiments are
provided so that this disclosure will satisfy applicable legal
requirements.
[0032] The following detailed description is provided to assist the
reader in gaining a comprehensive understanding of the compositions
and methods described herein. Accordingly, various changes,
modifications, and equivalents of the compositions and/or methods
described herein will be suggested to those of ordinary skill in
the art. Also, descriptions of well-known functions and
constructions may be omitted for increased clarity and
conciseness.
[0033] Furthermore, a singular form may include a plural from as
long as it is not specifically mentioned in a sentence.
Furthermore, "comprise/includes" or "comprising/including" used in
the specification represents that one or more components, steps,
operations, and elements exist or are added.
[0034] Furthermore, unless defined otherwise, all the terms used in
this specification including technical and scientific terms have
the same meanings as would be generally understood by those skilled
in the related art. The terms defined in generally used
dictionaries should be construed as having the same meanings as
would be construed in the context of the related art, and unless
clearly defined otherwise in this specification, should not be
construed as having idealistic or overly formal meanings.
[0035] Herein below, explanation will be made on a pharmaceutical
composition according to the present invention, a method for
preparing the same, and a use thereof.
[0036] In order to provide a cream type topical formulation
comprising zileuton as an active pharmaceutical ingredient, which
exhibits effective treatment effects to atopic dermatitis and acne
and the like, the inventors of the present invention sought for
ingredients that can be applied with zileuton among the ingredients
being used in cream type formulations, and sought for amount ratio
of the ingredients for preparing a cream formulation comprising
them, and then defined optimal concentration of the zileuton and
stabilization conditions for realizing physiochemical stability,
and thereby completed the present invention.
[0037] Therefore, the present invention provides a cream type
topical pharmaceutical composition comprising zileuton, an aqueous
solvent, an organic solvent, a thickening agent and an
emulsifier.
[0038] Herein, zileuton is a mixture of stereoisomer:
(R)-1-(1-(benzo[b]thiopen-2-yl)ethyl)-1-hydroxyure and
(S)-1-(1-(benzo[b]thiophen-2-yl)ethyl)-1-hydroxyurea, in a white
powder form, and may be racemic zileuton. That is, the present
invention provides a cream type composition optimized to racemic
zileuton as an active pharmaceutical ingredient.
##STR00001##
[0039] The zileuton may be synthesized chemically, or is available
commercially (Cornerstone Therapeutics Inc., product name: ZYFLO,
ZYFLO CR etc.) The aqueous solvent used in the pharmaceutical
composition of the present invention may comprise water or a pH
buffer solution.
[0040] In a preferred embodiment of the present invention, the
aqueous solvent is a pH buffer solution. In a more preferred
embodiment, the aqueous solvent may be a pH buffer solution having
a pH of about 4 to about 5. For example, the pH buffer solution may
be, but not limited to, citrate buffer (citric acid with sodium
citrate), acetate buffer (acetic acid with sodium acetate) or
phthalate buffer (potassium hydrogen phthalate with sodium
hydroxide or formaldehyde).
[0041] In case of using such pH buffer solution as an aqueous
solution, the pharmaceutical composition of the present invention
may exhibit more improved chemical stability. This is because the
pH buffer solution controls the pH change of the composition so
that any possible hydrolysis of zileuton to produce hydrolytic
degradants which are undesirable impurities in the composition can
be prevented, and thereby the chemical stability of the composition
can be improved.
[0042] In a preferred embodiment of the present invention, the
production of hydrolytic degradants of zileuton can be minimized by
stabilizing the pH of the composition by using a pH buffer
solution, and thereby the chemical stability of the composition may
be improved.
[0043] The organic solvent used in the pharmaceutical composition
of the present invention may comprise, but not limited to, at least
one selected from the group consisting of ethanol, polyethylene
glycol, hexylene glycol, propylene glycol monocaprylate, benzyl
alcohol, N-methyl pyrrolidone, triacetin, isopropyl myristate,
propylene glycol dicaprylocaprate, medium chain triglycerides,
castor oil, olive oil, safflower oil, light mineral oil, squalane,
dimethicone, cyclomethicone, polyglyceryl-6 dioleate,
polyglyceryl-10 monooleate, polyglyceryl-10 dioleate, polyoxyl 40
hydrogenated castor oil, caprylocaproyl polyoxyl-8 glycerides,
polyoxyethylene (20) sorbitan monolaurate, diethylene glycol
monoethyl ether, and dimethyl sulfoxide.
[0044] In a preferred embodiment of the present invention, the
organic solvent is propylene glycol.
[0045] The thickening agent used in the pharmaceutical composition
of the present invention may comprise, but not limited to, at least
one of white petrolatum and white wax.
[0046] The emulsifier may be, but not limited to, at least one
selected from a group consisting of hydrogenated lecithin, stearyl
alcohol and propylene glycol stearate. Preferably, the emulsifier
may comprise phospholipids including hydrogenated lecithin. For
example, the emulsifier is commercially available as a product name
of Phospholipon 90H.
[0047] The pharmaceutical composition of the present invention may
further comprise a preservative.
[0048] The preservative may be, but not limited to, at least one
selected from a group consisting of methylparaben, ethylparaben,
propylparaben, isobutylparaben, butyl paraben, 2-phenoxy ethanol,
and 4-hydroxybenzoic acid.
[0049] The pH buffer solution, organic solvent, thickening agent
such as white petrolatum and white wax, emulsifier, and
preservative to be used in the pharmaceutical composition of the
present invention are available commercially.
[0050] In one exemplary embodiment, the cream type pharmaceutical
composition of the present invention may comprise zileuton of about
0.05 to about 2 weight % as an active pharmaceutical ingredient;
water or pH buffer solution of about 30 to about 34 weight %; white
petrolatum of about 36 to about 40 weight %; white wax of about 4
to about 8 weight %; propylene glycol of about 16 to about 22
weight %; phospholipid of about 2 to about 6 weight %; and
preservative of about 0.005 to about 0.04 weight %.
[0051] In another exemplary embodiment, the cream type
pharmaceutical composition of the present invention may comprise
zileuton of about 0.1 to about 1 weight %; water or pH buffer
solution of about 31 to about 33 weight %; white petrolatum of
about 37 to about 39 weight %; white wax of about 5 to about 7
weight %; propylene glycol of about 18 to about 20 weight %;
phospholipid of about 3 to about 5 weight %; and preservative of
about 0.01 to about 0.03 weight %.
[0052] The cream type topical pharmaceutical composition of the
present invention may retain its physical and chemical stability
for about 4 weeks or more under the temperature condition of about
25 to about 40.degree. C.
[0053] The present invention also provides a method for relieving
or treating atopic dermatitis, acne, urticaria, psoriasis, eczema,
a bullous skin disease, collagenoses, Sjogren-Larsson syndrome, or
acne in skin lesions of mastocytosis, wherein said method comprises
administering, to a subject in need of such relief or treatment, a
composition of the present invention.
[0054] In the method for relieving or treating any of the
aforementioned diseases according to the present invention, the
composition may be applied topically to human skin.
[0055] According to an embodiment of the present invention, the
medical effect of the cream type topical pharmaceutical composition
has been verified in a Delayed Type Hypersensitivity Reaction in
mouse induced by DNFB. The test article was applied to a mouse's
skin 3 times a day, and then the medical effect was measured.
Furthermore, an excess amount of the zileuton was injected using a
non-optimized test vehicle, acetone. Test results showed that an
increase of thickness of the mouse's ear caused by inflammation and
edema in the mouse model administered with the cream type
pharmaceutical composition of the present invention was effectively
inhibited, proving that the composition has an effective
anti-inflammation function.
[0056] In order to determine whether or not a medical effect caused
by absorption to an entirety of body is included, absorption to
skin and body absorption pattern were evaluated. For this purpose,
a skin PK was examined from a minipig having a skin structure most
similar to human. Test results showed effective skin absorption
patterns, but showed no systemic exposure pattern. That is, it was
identified that a cream type topical pharmaceutical composition
according to the present invention effectively induces skin
absorption, and minimizes body absorption, proving that the
composition according to the present invention is suitable
formulation for administration to human skin.
[0057] Therefore, a cream type topical pharmaceutical composition
according to the present invention exhibits an anti-inflammatory
effect by inhibiting formation of leukotriene, and thus is
effective in relieving or treating diseases caused by topical skin
inflammation reaction such as atopic dermatitis, acne, various
types of urticaria, psoriasis, eczema, bullous skin diseases such
as bullous pemphigoid, collagenoses, Sjogren-Larsson syndrome, skin
lesions of mastocytosis, and the like.
[0058] The acne may be an inflammatory acne selected from a group
consisting of acne papulosa, acne pustulosa, acne papulopustolosa,
and severe inflammatory acne.
[0059] The cream type pharmaceutical composition may be for topical
application to human skin. More specifically, it may be applied
topically once to four times a day.
[0060] Further, the present invention also provides a preparation
method for a cream type topical pharmaceutical composition, the
method comprising mixing zileuton, an aqueous solvent, an organic
solvent, a thickening agent, and emulsifier under a mixing
condition of a temperature of 30 and 80.degree. C. and 600 to 1200
rpm.
[0061] The mixing may be performed for 10 to 60 minutes.
[0062] The aqueous solvent used in the method may comprise a pH
buffer solution. In a preferred embodiment, the aqueous solvent may
be, a pH buffer solution having a pH of about 4 to about 5. For
example, the pH buffer solution may be, but not limited to, citrate
buffer (citric acid with sodium citrate), acetate buffer (acetic
acid with sodium acetate) or phthalate buffer (potassium hydrogen
phthalate with sodium hydroxide or formaldehyde).
[0063] In the mixing step, a preservative may be further mixed.
[0064] In one exemplary embodiment, the preparation method for a
cream type topical pharmaceutical composition of the present
invention may comprise mixing zileuton of about 0.05 to about 2
weight %; water or pH buffer solution of about 30 to about 34
weight %; white petrolatum of about 36 to about 40 weight %; white
wax of about 4 to about 8 weight %; propylene glycol of about 16 to
about 22 weight %; phospholipid of about 2 to about 6 weight %; and
preservative of about 0.005 to about 0.04 weight %.
[0065] In another exemplary embodiment, the preparation method for
a cream type topical pharmaceutical composition of the present
invention may comprise mixing zileuton of about 0.1 to about 1
weight %; water or pH buffer solution of about 31 to about 33
weight %; white petrolatum of about 37 to about 39 weight %; white
wax of about 5 to about 7 weight %; propylene glycol of about 18 to
about 20 weight %; phospholipid of about 3 to about 5 weight %; and
preservative of about 0.01 to about 0.03 weight %.
[0066] The preparation method for a cream type topical
pharmaceutical composition may further comprise cooling the
resultant from the mixing under the condition of a temperature of
about 20 and about 30.degree. C. while stirring at about 600 rpm or
less.
[0067] The cream type topical pharmaceutical composition prepared
through the aforementioned method may retain its stability for
about 4 weeks or more at a temperature of about 25 to about
40.degree. C., and may thus be suitable to topical application.
[0068] Hereinafter, examples of a cream type topical pharmaceutical
composition of the present invention will be explained. However,
the examples are intended for just illustrating, but not limiting
the scope of the present invention thereto.
Example 1--Preparing Zileuton Cream Type Composition
1. Screening Test for Suitability of the Cream Type Composition
[0069] Suitability of components generally used in cream
formulation with respect to zieluton was screened, prior to
preparing a zieluton cream formulation. For this purpose, 5 mg of
zileuton was dissolved in 5 mg of excipient, and then changes of
TRS % (Total Related Substances) were observed for up to 4 weeks
under a 50.degree. C. condition. That is, the stability of
excipient at 50.degree. C. was tested.
[0070] As a result, as illustrated in Table 1 shown below, stearyl
alcohol, phospholipon 90H, white wax, titanium dioxide, HPMC F4M,
carbomer (carbopol 940), propylene glycol stearate, and aluminum
starch octenylsuccinate were found to be suitable, whereas
Ceteareth-20 was found to be unsuitable.
TABLE-US-00001 TABLE I API: Day 0 2 weeks, 50.degree. C. 4 weeks,
50.degree. C. Excipient Appear- Recovery TRS. Appear- Recovery TRS.
Appear- Recovery TRS. No. Excipient ratio ance % % ance % % ance %
% 1 Zileuton API -- -- 2.378 White 101.47 3.311 White 99.12 2.711
powder 101.30 3.006 powder 98.23 2.493 2 Stearyl 1:1 White 98.71
3.311 White 101.69 2.935 White 102.91 2.512 alcohol powder powder
101.28 2.796 powder 98.77 2.567 3 Ceteareth- 1:1 White 100.34 2.394
White 99.99 3.454 White 97.59 3.632 20 powder powder 100.36 3.362
semi- 96.39 3.549 solid 4 Phospholipon 1:1 White 100.61 2.400 White
101.50 2.820 White 97.26 2.557 90 H powder powder 102.21 2.846
powder 103.30 2.429 5 White 1:1 White 99.46 2.372 White 100.07
2.863 White 98.77 2.459 wax powder powder 102.20 2.843 powder 97.31
2.381 6 Titanium 1:1 White 100.59 2.344 White 102.52 2.803 White
99.14 2.507 dioxide powder powder 102.86 2.839 powder 99.17 2.504 7
Hypromellose 1:1 White 103.72 2.610 White 102.67 2.864 White 98.86
2.555 powder powder 102.97 2.949 powder 100.86 2.580 8 Carbomer 1:1
White 99.34 3.326 White 102.45 2.385 White 99.63 2.330 powder
powder 103.39 3.067 powder 97.65 2.403
[0071] In the solution stability test, suitability with solvents
for solubilizing zileuton (ethanol, PEG400, propylene glycol,
hexylene glycol, capryol 90, benzyl alcohol, water) was screened.
For this purpose, 10 mg of zileuton was dissolved in a 2 mL vehicle
(solvent), and then changes of TRS % were observed in conditions of
25.degree. C., 40.degree. C., and 70.degree. C., respectively.
[0072] As a result, as illustrated in Tables 2 and 3 below, most of
the solvents were suitable to zileuton under the 25.degree. C.
condition, but were unstable under the condition of 40.degree. C.
or 70.degree. C. Table 2 shows the result of stability test of the
solution at 25.degree. C., and Table 3 shows the result of
stability test of the solution at 40.degree. C. or 70.degree.
C.
TABLE-US-00002 TABLE 2 TRS TRS (%) increase Solvents Temp. Day 0
Day 1 Day 3 Day 8 rate % Ethanol 25.degree. C. 1.255 1.014 1.951
2.137 0.882 Polyethylene 25.degree. C. 1.427 1.491 2.897 4.065
2.638 glycol (PEG-400) Propylene glycol 25.degree. C. 1.457 1.624
1.478 2.132 0.675 Hexylene glycol 25.degree. C. 1.505 1.448 1.583
1.980 0.475 Capryol 90 25.degree. C. 1.623 1.444 1.478 2.201 0.578
Benzyl alcohol 25.degree. C. 1.642 0.869 1.806 2.023 0.381 Water
25.degree. C. 1.424 1.879 1.816 1.965 0.541
TABLE-US-00003 TABLE 3 TRS TRS (%) increase Solvents Temp. Day 0
Day 1 Day 3 Day 8 rate % Ethanol 40.degree. C. 1.255 1.778 2.375
4.704 3.449 Polyethylene 70.degree. C. 1.427 43.725 94.366 97.142
95.715 glycol (PEG-400) Propylene glycol 70.degree. C. 1.457 26.382
82.228 96.325 94.868 Hexylene glycol 70.degree. C. 1.505 8.061
29.999 60.352 58.847 Capryol 90 70.degree. C. 1.623 10.312 39.603
76.445 74.822 Benzyl alcohol 70.degree. C. 1.642 11.350 20.397
24.250 22.608 Water 70.degree. C. 1.424 35.171 80.268 91.994
90.570
[0073] Furthermore, the suitability of other various solvents for
solubilizing zileuton was screened. For this purpose, solubility of
zileuton in each solvent was observed in condition of 25.degree. C.
(RT), respectively.
[0074] As a result, as illustrated in Table 4 below, all of the
solvents listed in Table 4 can be used for solubilize zileuton in
manufacturing a zileuton cream formulation. Especially,
hydrophilics solvents such as alcohols may be preferably used.
TABLE-US-00004 TABLE 4 Zileuton Solubility Solvent at RT (% w/w)
Triacetin 0.50-0.72 Isopropyl Myristate <0.20 Propylene Glycol
Dicaprylocaprate <0.20 Medium Chain Triglycerides <0.21
Castor Oil <0.16 Olive Oil <0.07 Safflower Oil <0.07 Light
Mineral Oil <0.04 Squalane <0.04 Dimethicone <0.06
Cyclomethicone <0.06 Polyglyceryl-6 Dioleate <0.06
Polyglyceryl-10 Mono/Dioleate/Caprol PGE-860 <0.16 Polyoxyl 40
Hydrogenated Castor Oil/Kolliphor <0.37 RH40 Caprylocaproyl
Polyoxyl-8 Glycerides/Labrasol 10.81-11.42 Polyoxyethylene (20)
Sorbitan 8.42-9.24 Monolaurate/Tween 20 Diethylene Glycol Monoethyl
Ether/Transcutol P 17.11-17.62
2. Composition Optimization Test
[0075] The components determined as being suitable in the
aforementioned suitability screen test were combined, and amount
ratios of solvents and ingredients stable under an acceleration
condition (30.degree. C., 40.degree. C.) were screened.
[0076] For this purpose, by mixing the ingredients other than
solvents such as propylene glycol and water and the like under
70.degree. C. according to the amount ratios disclosed in Table 5,
and then adding and mixing the remaining solvents while stirring
for 30 minutes under a condition of 70.degree. C. and 800 rpm or
less. The mixed composition was stirred at 100 rpm or less, and
cooled to room temperature. That is, Table 5 below shows results of
the test regarding optimized ingredient ratios.
TABLE-US-00005 TABLE 5 Ingredients (w %)/samples 2-1 2-2 2-3 2-4
2-5 2-6 2-7 2-8 2-9 2-10 2-11 2-12 Zileuton -- -- -- -- -- -- -- --
-- -- -- -- Water -- -- -- 57 16 -- -- 10~31 White petrolatum 43
38~48 24 20 43 38 18~31 White wax 6 6 6 6 5 7 7 5~9 Propylene 24
32~42 10 55 47 52 25~55 glycol (PG) Stearyl Alcohol 16 -- -- -- --
-- -- -- -- -- -- -- Propylene glycol -- -- -- -- -- -- -- -- -- --
-- -- stearate Phospholipon 90 H -- 3 3 3 4 3 3 4 4 4 4 4 Ethanol
-- -- -- -- -- -- -- -- -- -- 10.5 10.5 Aluminum 11 11 11 -- -- --
-- -- -- -- -- -- starch octenyl- succinate Appearance Little Cream
Cream Liquid Oint- Oily Very Cream Cream Cream Cream Cream dry ment
cream oily cream cream Approximate -- -- -- -- <1.3% <3% --
<0.1% <0.3% <0.7% <2.3% <2.5% solubility (%)
[0077] As shown in Table 5, it was found the composition ratios of
2-2, 2-3, 2-8, 2-9, 2-10, 2-11, and 2-12 provide suitable cream
type formulation. From the aforementioned result, it was confirmed
that the amount ratios of water, white petrolatum, white wax, and
propylene glycol have critical significance in the aforementioned
ranges.
3. Optimization Test of Cream Processing Method
[0078] A condition that satisfies the physical and chemical
stability with a target drug concentration (1%) was screened based
on the amount ratios discovered in the composition optimization
test. For this purpose, the ingredients other than the solvents
such as propylene glycol and water were mixed according to the
amount ratios disclosed in Table 6 under 70.degree. C., and then
the remaining solvents were mixed at 70.degree. C. and 800 rpm or
less. The mixed cream composition was stirred at or less than 100
rpm and cooled to room temperature.
[0079] Physical stabilities were measured by checking with the
naked eye whether or not phase separation occurred after leaving a
sample for a certain period of time at a condition of 25.degree.
C., 30.degree. C. or 40.degree. C. This is a test to discover an
optimized processing method for obtaining a cream formulation.
TABLE-US-00006 TABLE 6 Ingredients (wt %)/ samples 3-1 3-2 3-3 3-4
3-5 3-6 3-7 3-8 3-9 3-10 3-11 3-12 Zileuton -- -- -- -- -- -- -- --
-- -- -- -- Water 10~12 17~21 White 18~20 17~21 petrolatum White
wax 6 6 6 6 6 6 6 6 6 6 6 6 Propylene 51 51 53 55 55 51 54 51 48 52
54 56 glycol (PG) Phospholipon 4 4 4 4 4 5 5 4 4 4 4 4 90 H Ethanol
4.5~9 -- -- -- -- Stirring 20 20 20 20 20 20 20 20 20 20 20 20 time
(min) Shape Cream Cream Cream Cream Cream Cream Cream Cream Cream
Cream Cream Cream Approximate <2.1% <1.8% <2.7% <2.7%
<2.3% <2.1% <2.1% <2.1% <1.3% <1.5% <1.7%
<2.1% solubility (%) Physical Bad Bad Bad Bad Bad Bad Bad Bad
Good Good Good Good stability at 25.degree. C.
[0080] As disclosed in Table 6, it was found that the formulation
conditions of 3-9, 3-10, 3-11, and 3-12 provide excellent physical
stability at 25.degree. C. so as to dissolve active pharmaceutical
ingredient 1% or more. Furthermore, the aforementioned cream
formulations do not comprise ethanol, and this is because ethanol
deteriorates physical stability.
[0081] Next, as a test for optimizing the processing method for
cream type formulation, in order to find out whether the stirring
time affects the shape of the cream, stirring times of 5 minutes,
30 minutes and 60 minutes were applied and then observed. As a
result, as illustrated in Table 7 below, the stirring time of 30
minutes was confirmed as the optimized condition.
TABLE-US-00007 TABLE 7 samples Ingredients (wt %) 3-13 3-14 3-15
Zileuton -- -- -- Water 10~26 White petrolatum 17~29 White wax 6 6
6 Propylene glycol (PG) 35~56 Phospholipon 90H 4 4 4 Ethanol 6.5 --
-- Total sum of ingredients 100 100 100 Stirring time (min) 5 30 60
Appearance Liquid like Cream Cream Cream Approximate solubility (%)
-- 0.3% <1.3% Physical stability at 30.degree. C. Good
4. Optimization Test of Solvent
[0082] It was determined that using an excessive amount of
propylene glycol to adjust to 1% of drug concentration has a
negative effect on the physical stability of the composition, and
thus a composition ratio of high stability with a lower drug
concentration was sought for.
[0083] Therefore, in order to improve the physical stability of the
composition after increasing the scale of sample, a cream type
formulation with a reduced loading amount of drugs was prepared.
For this purpose, formulation 3-14 was selected, and based on this
cream type composition, the amount of drug loading was raised up to
1%, and then a solvent capable of obtaining chemical stability
while retaining physical stability was screened.
[0084] The aforementioned screening test was conducted by mixing
ingredients other than the solvents such as propylene glycol, water
and the like at 70.degree. C. in accordance with the composition
ratio disclosed in Table 8 below, and then mixing the remaining
solvents according to the composition ratio of Table 8 under a
stirring condition of 800 rpm or less for 30 minutes at 70.degree.
C. The mixed composition was stirred at or less than 100 rpm and
cooled to room temperature.
[0085] The chemical stability was evaluated by measuring changes in
TRS % through LC analysis after leaving a sample for a certain
period of time under a temperature of 25.degree. C. or 40.degree.
C.
TABLE-US-00008 TABLE 8 Ingredients N-methyl pyrrolidone (wt %)/
(NMP) Capyrol 90 Benzyl alcohol samples 4-1 4-2 4-3 4-4 4-5 4-6 4-7
4-8 4-9 4-10 Zileuton -- -- -- -- -- -- -- -- -- -- Water 24~26
20~24 37~41 White 29~33 29~33 38~42 petrolatum White wax 6 6 6
12~24 6 Propylene 24 24 24 -- -- -- -- -- -- -- glycol (PG) Stearyl
-- -- -- -- -- 4 -- -- -- -- Alcohol Propylene -- -- -- -- -- -- 4
-- -- -- glycol stearate Phospholipon 4 4 4 4 4 4 -- -- 4 4 90 H
Ethanol -- -- -- -- -- -- -- -- -- -- Aluminum -- -- -- -- -- -- --
-- -- -- starch octenyl-succinate N-methyl 10 10 8 -- -- -- -- --
-- -- pyrrolidone (NMP) Benzyl -- -- -- -- -- -- 14 14 10 10
alcohol Capyrol 90 -- -- -- 28 28 28 -- -- -- -- Dimethyl -- -- --
-- -- -- -- -- -- -- sulfoxide Stirring 30 30 30 30 30 30 30 30 30
30 time (min) Appearance Liquid Liquid Cream Cream Cream Cream
Cream Cream Cream Cream Approximate 1% 1% 0.8% 0.8% 0.8% 0.8%
solubility (%) Physical Bad stability at 30.degree. C. Physical Bad
Bad Bad Bad Bad Bad Bad stability at 40.degree. C.
[0086] As illustrated in Table 8, NMP and benzyl alcohol were
screened as solvents, but both showed bad physical stability with
phase separation. Furthermore, capryol 90 was screened as a
solvent, but all showed bad physical stability due to phase
separation.
[0087] Consequently, the processing method was changed from 3-14
condition, and an amount of drug loading was increased to 1%, and
thereby a cream type composition that satisfies both the target
drug concentration and physical stability was discovered. However,
regarding the chemical stability, a significant TRS % change was
observed after 3 weeks under a temperature condition of 40.degree.
C.
5. Test for Confirming an Improvement in Stability of the
Composition by Use of a pH Buffer Solution as Solvent
[0088] In order to confirm the effect of a pH buffer solution on
the chemical stability of the composition, the compositions were
prepared by mixing ingredients other than the solvents at
70.degree. C. in accordance with the composition ratios disclosed
in Table 9 below, and then mixing the remaining solvents according
to the composition ratios of Table 9 under a stirring condition of
800 rpm or less for 30 minutes at 70.degree. C. The mixed
compositions were stirred at or less than 100 rpm and cooled to
room temperature.
[0089] The chemical stability was evaluated by measuring changes in
pH, quantitative analysis of degradants of zileuton by HPLC, and
TRS % through LC analysis after leaving a sample for a certain
period of time under the storage condition of a room temperature of
25.degree. C. (RT) and 40.degree. C.
TABLE-US-00009 TABLE 9 samples Ingredients (wt %) 5-1 5-2 Zileuton
1.0 1.0 pH buffer solution* -- 32 Water 32 -- White petrolatum
36-40 White wax 4-8 Propylene glycol 16-22 Phospholipon 90H 2-6
Propylparaben 0.005-0.04 Total sum of ingredients 100 Appearance
Cream Cream *pH buffer solution at pH 4, 5 and 6 with various
concentration
[0090] As illustrated in FIG. 1, pH changes of the pH buffered
creams at pH 4 and pH 5 were lowered in comparison with the
non-buffered cream under accelerated condition (40.degree. C.). It
is noted that the pH buffered cream with a pH buffer solution of pH
4 can be controlled between pH 4.5 to 5 at which the generation of
hydrolytic degradants of zileuton, i.e. impurities, are mostly
suppressed, even at 40.degree. C. when 10 mM to 100 mM pH buffer
solutions were used, while the pH of the non-buffered control
sample was changed to .about.pH 7.
[0091] Furthermore, as illustrated in Table 10 below, the changes
of TRS (total related substances) of the non-buffered control
composition was increased up to 9.96% at 40.degree. C. for 2
months, while the changes of TRS of the buffered composition with
25 mM pH buffer solution of pH 4 was only increased up to 2.74% in
the same condition.
TABLE-US-00010 TABLE 10 *Initial 40.degree. C./3 Weeks 40.degree.
C./2 months non- non- pH 4 pH 4 non- pH 4 pH 4 buffered buffered 10
mM 25 mM buffered 10 mM 25 mM Total 0.23% 2.18% 1.60% 1.52% 10.19%
3.29% 2.97% related sub- stance % -- 1.95% 1.37% 1.29% 9.96% 3.06%
2.74% Change of TRS *Initial: day of formulation
6. Optimization Test of the Amount of Ingredients
[0092] Furthermore, as illustrated in Table 11 below, a test for
determining a critical amount range of ingredients was conducted
after selecting an ingredients and an approximate composition ratio
that could satisfy criteria as a topical cream.
TABLE-US-00011 TABLE 11 Ingredients samples (wt %) Criteria 6-1 6-2
Zileuton -- -- -- Water 30~40 32 32 White petrolatum 36~40 33 38
White wax 4~8 6 6 Propylene glycol 16~22 25 19 Phospholipon 90H 2~6
4 4 Appearance Cream Cream Cream Physical stability for 4 Stable
Phase separation Stable weeks under 40.degree. C. observed at the
4.sup.th week
[0093] As shown in Table 11, as in the formulation 6-1, when the
amount ratio of white petrolatum and propylene glycol are 33 and
25, respectively, it was observed by naked eyes that the physical
stability was deteriorated due to separation of oil phase and water
phase starting from the 4.sup.th week.
[0094] Table 12 below shows candidate formulations according to the
test result.
TABLE-US-00012 TABLE 12 Candidate formulations samples Ingredients
(wt %) 6-3 6-4 Zileuton 1 1 Water 32 26 White petrolatum 32 29
White wax 6 6 Propylene glycol (PG) 25 34 Phospholipon 90H 4 4
Total sum of ingredients 100 100 Stirring time (min) 30 30
Appearance Cream Cream Approximate 1% 1% solubility (%) Physical
stability Good Good at 40.degree. C. Chemical stability at 6.65% of
changes for 9.79% of changes for 40.degree. C. (TRS %) 3 weeks 3
weeks
[0095] As shown in Table 13, the formulations 6-3 and 6-4 satisfied
conditions required for development up to clinical phase 2.
Further, in order to develop the final formulation, an experiment
for developing a new composition ratio and processing method was
additionally conducted while measuring the chemical stability under
30.degree. C. acceleration condition of 062-1.
[0096] Accordingly, as shown in Table 13 below, the amount of
propylene glycol was optimized, and propylene paraben was added as
a preservative. As a result, the cream formulations 6-5 and 6-6 of
the composition ratios of Table 13 satisfied chemical/physical
stabilities under 30.degree. C. acceleration condition.
TABLE-US-00013 TABLE 13 samples Ingredients (wt %) 6-5 6-6 zileuton
0.1 1 Water 30-34 30-34 White Petrolatum 36-40 36-40 White wax 4-8
4-8 Propylene glycol 16-22 16-22 Phospholipon 90H 2-6 2-6
Preservative (Propylparaben) 0.05-0.4 0.05-0.4 Total sum of
ingredients 100 100 Stirring time (min) 30 30 Appearance Cream
Cream Physical stability Good for 4 weeks Good for 4 weeks Chemical
stability 1.4% of changes for 1.4% of changes for (TRS %) 4 weeks
at 30.degree. C. 4 weeks at 30.degree. C.
[0097] On the other hand, it was confirmed that the cream
formulations of the comparative examples having composition ratios
of Table 14 below do not exhibit good chemical/physical stabilities
under 30.degree. C. acceleration condition in the target drug
concentration range which can provide efficacious pharmaceutical
activity.
TABLE-US-00014 TABLE 14 samples Ingredients (wt %) 6-7 6-8 zileuton
0.7 0.7 Water 24 22 White Petrolatum 25 27 White wax 3 3 Propylene
glycol 46 46 Phospholipon 90H 1 1 Preservative (Propylparaben) 0.02
0.02 Stirring time (min) 30 30 Appearance Cream Cream Physical
stability Phase separation Phase separation observed at 30.degree.
C. observed at 30.degree. C.
Experiment 1 Evidence of Concept Research Using Formulation 089
[0098] An in vivo test was conducted to identify whether or not the
formulation 6-6 of the above example shows medical effects when
administered to skin in a generally used mouse atopic dermatitis
animal model. For this purpose, BALB/c mice were divided into 4
groups, each consisting of 10 mice. The groups were divided into a
vehicle (acetone), positive control group (dexamethasone 0.05
mg/ear; Dex), and zileuton groups (Formulation 5-6).
[0099] And the zileuton groups were divided into cases where
acetone (1 mg/ear) and the cream formulation of 6-6 (0.2 mg/ear and
0.02 mg/ear) were used, respectively. As illustrated in FIG. 2, on
day 0 and day 1, 25 .mu.l of 0.5% DNFB (dinitrofluorobenzene)
solution was applied once on ears of all groups to cause
inflammation. Then, on day 5, 20 .mu.l of 0.3% DNFB was applied
once again to cause inflammation in the ears. Then, dexamethasone
and zileuton dissolved in acetone vehicle were applied to the ears
at 1 hour, 6 hours, and 23 hours after the stimulation on day 5.
Thicknesses of the ears were measured at 24 hours after the
stimulation on day 5, and then ear tissues were taken for
histopathological observation.
[0100] As illustrated in FIG. 3, in the group where the formulation
6-6 was used, zileuton (API: Active Pharmaceutical Ingredient) was
effectively delivered to the skin, thereby effectively inhibiting
increase of ear thickness caused by inflammation and edema compared
to groups where acetone was used.
[0101] Through histopathological observation, excellent
anti-inflammation function of zileuton was observed.
TABLE-US-00015 TABLE 15 Test model BALB/c mouse, female 6~8 weeks
of age (17~20 g) Dosing Concentration Drug (mg/mL mL or API Regimen
Group (formulation) No. Route or %) mg/ear mg/ear (Time) 1 Vehicle
10 Topical N/A 0.02 mL N/A 1, 6, 23 (Acetone) 2 Dex 10 Topical 2.5
mg/mL 0.02 mL 0.05 1, 6, 23 (Acetone) 3 Zileuton 10 Topical 50
mg/mL 0.02 mL 1 1, 6, 23 (Acetone) 4 Zileuton 10 Topical 1 wt % 20
mg 0.2 1, 6, 23 (formulation 5-6) 5 zileuton 10 Topical 0.1 wt % 20
mg 0.02 1, 6, 23 (formulation 5-6 except of zileuton 0.1 wt %)
Measure * Weight * Ear thickness * Histopathological observation
(edema, inflammation, crust formation)
Experiment 2 PK Research Test Using Minipigs
[0102] It is necessary to find out from the Experiment 1 whether or
not medical effects by absorption to an entirety of body are
included. In order to identify the skin absorption and systemic
exposure level of the final formulation, minipigs having skin
structures most similar to those of humans may be used. Therefore,
skin PK was observed in minipigs having the most similar skin
structures as humans using the formulation 6-6 which is for the
clinical formulation derived in the process of developing the cream
formulation.
[0103] For this purpose, 20 mg of zileuton (API: Active
Pharmaceutical Ingredient) was applied to 100 cm.sup.2 of skin
using the formulation 6-6. After applying the formulation 6-6,
concentration of zileuton in plasma was measured 0.25, 0.5, 1, 1.5,
2, 3, 4, 6, and 8 hours afterwards. After applying the formulation
6-6, zileuton concentration in the skin was measured 1 and 8 hours
afterwards. For the measurement of zileuton concentration in the
skin, the skin was separated into surface, subcutaneous, dermas,
and epidermis layers. The subcutaneous layer was separated using
the tape stripping method, and the measurements of zileuton
concentrations were conducted for different depths of strip 1,
strip 2-5, strip 6-12, and strip 13-24. Test conditions are as
illustrated in Tables 16 and 17.
TABLE-US-00016 TABLE 16 Number Treatment of Concen- Bamma tration
pigs (mg Type of (#/ Test Dose API/g specimen Group Gender) drug
(mg/cm.sup.2) cream) Vehicle Route obtained 1 6 females Zileuton
0.2 (API) 10 6-6 Topical Plasma, (Q301) Formulation administration
skin Test article storage: Comments: Animals of body weights of
15~20 kg were used, Desiccated at 4.degree. C. and administration
area was 10 cm .times. 10 cm Overnight Fast of Animals: None
TABLE-US-00017 TABLE 17 Anticoagulant: K2-EDTA Administration
Animal Sampling and administration schedule (time) Group route ID
-0.5 0 0.25 0.5 1 1.5 2 3 4 6 8 1 Topical 1~3 P D P 0 P + S -- --
-- -- -- -- 4~6 P D -- P -- P P P P P P + S P: Collect blood and
separate plasma D: Administer drug to animals at determined time P
+ S: Collect blood and skin, and separate plasma from blood.
Extract corneum layer before obtaining skin sample. Separate dermas
and epidermis layers from skin.
[0104] As illustrated in FIGS. 4 and 5, the formulation 6-6 showed
effective skin absorption pattern, whereas it did not show any
systemic exposure pattern in the minipigs. It can be seen that the
cream formulation using propylene glycol effectively induces skin
absorption, and minimizes body absorption, and is thus suitable as
a future candidate formulation of zileuton for skin
administration.
[0105] While this invention has been described in connection with
what is presently considered to be preferable embodiments, it is to
be understood that the present invention is intended to cover
various changes, modifications and equivalent arrangements. It is
obvious that the present invention may be practiced by appropriate
modifications of the aforementioned embodiments. Therefore, the
aforementioned embodiments do not limit the scope of the present
invention which is determined by the claims.
INDUSTRIAL APPLICABILITY
[0106] The present invention is for providing a zileuton cream
formulation for topical treatment of skin disease caused by
leukotriene, and is an industrially applicable invention.
* * * * *