Note: Descriptions are shown in the official language in which they were submitted.
276
.
~RIN ~YD NAIL COMPO~ITION GONTAINING
PHOSPHATIDE-TRIALK~NOL~TINE COMPLEX
_
This invention relates to a preparation for the
treatment of skin and nails, referred to herein as a "skin
preparation". More partieularly, this invention relates to
a skin preparation having prolonged moisturizing action.
Furthermore, this invention relates to a skin preparation
which is effective for ~ long period of time in dispersing
and retaining drugs for topical delivery to a patient in a
uniform manner in the topical zones of skin.
This invsntion is based upon t~e discovery that a
complex of a phosphatide and an alkanolamine is particularly
suited for keeping skin moist, and that the skin preparation
of this invention, when applied to topically deliver drugs
to a patient, disperses and retains the drugs in the topical
zones of skin in a uniform manner for a longer period of
time to render the drugs more effective.
Although the exace theory of the invention has not
been conclusively established, it is believed that a comple~
of a phosphatide with an alkanolamine is formed, which has
hydrophilic and hydrophobic end groups. W~en applied to
skin, it interacts with a lipid and/or a phosph~tide in a
double layer o~ lipids of the skin cells to be retained at
the skin surface for a long period of time.
In addition, it is believed that each molecule of
the complex closely binds 10 to 12 molecules of water, to
the extent that the nature of the water molecule is
sufficiently altered so that the water does not freeze
(decreasing the transpiration of water from the skin). The
comolex oi the phosphatide with the alkanolamine is believed
to combine non-covalently with many drugs to dispers6 and
retain them in the skin in a stable manner thereby
permitting those drugs to e~ert their action effectively for
a long period of time.
. ~ . .
~, . . . ~, . .
-2- ~3~
It has been found that thin deformable films of
appro~imately 2 to 50 micrometers thickness will form on the
topical application of the skin preparation of this
invention. The resultant film is permeable to atmospheric
gas exchange and able to reduce the evaporative loss of
water from the tissue surfaces. As described before, the
skin preparation of this invention keeps skin moist.
Accordingly, the use of the skin preparation is
particularly suited for the prevention o~ pathologically dry
skin. In addition, this moisturizing action is believed to
stren~then the action of topical drug delivery due to an
effect similar to that of occlusive dressing technique.
The phosphatides which can be used in the skin
preparation of this invention include phosphatidyl choline
(lecithin), phosphatidyl ethanolamine (cephalin),
phosphatidyl serine, phosphatidyl inositol and phosphatidic
acid. A mi~ture of the above phosphatides can also be
used. Optimally the phosphatide should contain 10 to ~0%
lecithin.
It is advanta~eous to use a commercially available
lecithin containing a phosphatide mixture and especially soy
phoSphRtide (30y lecithin) and egg phosphatide (egg
lecithin) as the mi~ture of the phosphatides. Such
commercially available phosphatides contain various
phosphatides and other components.
The amount of the phosphatides which are used in
the skin preparation of this invention varies with the
condition or symptom to be treated, the formulation, and the
kind and amount of the topically delivered drugs contained
in the skin preparation. ~owever, the amount of the
phosphatides is normally in the range of 1 to 8~ by weight,
and preferably 3 to ~ by weight. If the phosphatide is
used in too small amounts, the beneficial effects of this
invention will be insufficient. The effect of the skin
preparation attained when the phosphatide is used in an
e~cessive amount is not proportional to the ~mount of the
phosphatide to be used, because the skin cannot ~bsorb the
e~cessive amount of the phosphatide. In addition, the use
of the e~cessive phosphatides causes stickiness. Therefore,
~-3~ 276
in general, a not more than 5~O composition will be
satisfactory. The skin preparation of this invention, when
applied to nail, may contain 15 to 30% by weight of
phosphatides, because the nail can absorb more phosphatides,
an optional preparation containing about 20% by weight. The
alkanolamine which can be used in the skin preparation of
this invention includes mono-, di-, and trialkanolamines~
Among these alkanolamines, substituted and
hindered lower trialkanolamines are preferred.
Triethanolamine and triisopropanolamine are most preferred,
because their safety for the human body has been proved.
Also useful are such isomers and homolo~s as
tripropanolamine, tributanolanine and the like. The amount
of the alkanolamine to be used is dependent upon the amount
of the phosphatide to be used. If the al~anolamine is used
in a smaller, less than equimolar amount, the phosphatide
and the alkanolamine do not form the complex with each other
to R sufficient e~tent. On the other hand, if the
alkanolamine is used in an unnecessarily larger amount, the
advantageous effect obtained does not correspond to the
amount of the alkanolamine. The alkanolamine can be used in
an amount of 0.2 to 25 moles per mole of the phosphatide,
preferably 1 to 10 moles, and more preferably 1.~ to 5 moles
are used.
Depending upon the intended use of the skin
preparation o~ this invention, other components can be
incorporated into the skin preparation of this invention to
prepare the skin preparation having various rheological
properties.
For such formulations there can be used an aqueous
mixture such as a solution, colloidal solution, emulsified
lotion, oil-in-water cream (hydrophilic cream) and aqueous
~el wherein the aqueous phase is the continuous one.
For such formulations, there can also be used an
oily mixture such as a solution, ointment, water-in-oil
cream, gel base (e.~. Plastibase, a polyethylene and liquid
petrolatum base), absorption base and hydrophilic ointment
wherein the oil phase is the continuous one and a non-
aqueous ~ater-soluble base such as a mi~ture of polyethylene
. . ~
,,, .,:
~3~76
_4_
glycol. ~uch water-in-oil formulations are expecially
useful in preventing transdermal water loss and serve as
effective carriers for transdermal drug delivery.
A suspension base such as a shaking lotion, in
which a solid dispersin~ agent is added, ean also be
prepared. Oily components, emulsifiers, dispersing agents,
gelatinizers and solid materials which can be used to
prepare such formulations are well known, as those used are
in the preparation of cosmetics and topical products.
The oily components include hydrocarbons such as
liquid paraffin, petrolatum, solid paraffin,
microcrystalline wax and the li~e; higher aliphatic alcohols
such as cetyl alcohol, hexadecyl alcohol, stearyl alcohol,
oleyl alcohol and the like, esters of higher aliphatic
alcohols such as bees wax, spermaceti and the like; esters
of higher aliphatic acids with lower alcohols such as
isopropyl myristate, isopropyl palmitate and the like,
vegetable oils, modified vegetable oils, anhydrous lanolin
and its derivative, squalene, squalane and the like. Higher
aliphatic acids such as palmitic acid, stearic acid and the
like can also be used. However, they should be used in a
smaller arnount, since they form a soap with an al~anolamine.
Useful emulsifiers and dispersing agents inelude
nnionic, cationic and nonionic surfactants. Nonionic
surfactants are preferred because of their low level of
irritation to skin. Typical of nonionic surfactants are
monoglycerides such as glyceryl monostearate and the like;
sorbitan aliphatic esters such as sorbitan monolaurate and
the like; sucrose aliphatic esters; polyo~yethylene
aliphatic esters such as polyoxyethylene stearate; and
polyoxyethylene higher alcohol ethers such as
polyo~yethylene cetyl ether, polyoxyethylene oleyl ether,
polyoxyethylene fatty ethers and the like.
Gelatinizers include carboxymethylcellulose,
cellulose gel, carbopol (carboxypolymethylene), polyvinyl
al~ohol, polyethylene glycol and various gums.
The`se oily components, emulsifiers, dispersing
agents and gelatinizers can be used alone or in combination
with each other.
,
-_5_ ~3~7~
The incorporation into the skin preparation of
this invention of propylene glycol~ glycerine, sorbitol or
the like which have moisturizing action is preferred,
because it enhances moisturizing action of the skin
preparation of this invention.
Ethanol may be provided as a component of the skin
composition, ethanol having bacteriostatic action and
providing a cooling effect upon application to the skin.
In order to increase the stability of the skin
preparation of this invention and/or the drugs contained
therein, it is preferred to add antioxidants, chelating
agents, antiseptics and the like, if necessary. The
antioxidants include butylated hydroxytoluene, butylated
hydroxyanisole, tocopherol, sodium pyrosulfite, acetone
sodiurn bisulfate and the like. The chelating agents include
ethylenedi~ninetetraacetic acid, thioglycolic acid,
thiolactic acid, thioglycerol and the like.
The suitable antiseptics include methyl, ethyl,
propyl and butyl esters of p-hydroxybenzoic acid, o-
phenylphenol, dehydroacetic acid and the salts thereof, p-
chloro-m-cresol, p-chloro-m-xylenol and the like.
In addition, it is preferred to adjust the pH of
the skin preparation of this in~ention by adding citric
acid, lactic acid, tartaric acid or the like. The pH value
which should be adjusted to is dependent upon the stability
of the skin preparation. In general~ it is preferred that
the skin preparation be slightly acidic to slightly
alkaline.
A fragrance may be added in a slight arnount, if
desired.
~ hen the skin preparation of this invention is
used for the delivery of drugs,the action of the drugs is
strengthened, because the dispersion and retention in the
skin of the drugs are enhanced to a considerable extent and
pressure of the drugs maintained for a long period of
time. Thus in the case of rnany steroids there appears to
occur a complexing with the phosphatide causing uniform
distribution~and release over the skin surface.
: ~
.~ : ', '- : ;
: , ~
,, - , , : : :
-6- ~ ~3~27~
Any drugs which are applicable to the skin can be
used in the skin preparlqtion of this invention. Examples of
such drugs are topical steroid hormones such as
hydrocortisone, prednisolone, methylprednisolone,
dexamethasone, triarncinolone, triamcinolone aceton;de,
flumethasone, fluocinonide, beclomethasone, betamethasone,
fluocinolone, fluorometholone, fludoxycortid, clometasone,
clobetazol and their esters.
Other drugs which can be applied to the skin
preparation of this invention include topical antibiotics
such as kanamycin, erythromycin, tetracycline, ~entamycin,
fradiomycin, chloramphenicol and their salts; anti-mucotic
agents such as griseofulvin, siccanin, trichomycin,
nystatin, silver sulfadiazine, and the like; topical sulfa
drugs such as sulfiso~azole and the like; topical
antihistamines such as diphenhydramine, chlorphenilamine and
the like; local anesthetics such as lidocaine, dibucaine,
cyproheptazine and cocaine; non-steroidal antiinflammatory
agents such as indomethacin, diflumidone, bufe~amac and the
like; anticoagulants such as heparin sodiurn; skin
keratolytic agents such as urea, salicylic acid, resorcinol,
coal tar, anthralin and the like; agents affecting
pigmentation such as methozalen and the likes; vitamins such
as vitamin A, vitamin E and the like; sex hormones such as
ethinyl estradiol, testosterone, progesterone and the like;
antianginal drugs such as isosorbide dinitrate,
nitroglycerin, verapamil, prenilarnine and the like; beta-
blocking agents such as propanolol, pindolol, alprenolol and
the like; antihypertensive agents such as hydralazine,
reserpine, clonidine and the like and bronchodilators such
as isoproterenol, meta-proterenol and the like; antiallergic
agents such as cromolyn sodium and the like and
antiserotonergic agents such as cyproheptazine.
The topical steroid hormone can be applied in
combination with one or more drugs of topical antibiotics,
antihistaminics and antimycotie agents.
Anticancer drugs such as tetrahydro~luorouracil,
flourouracil, bleomycin, mitomycin and the like can also be
applied to the skin preparation of this invention.
,. . ;
', ~
_7_ ~3~7~
The amount of the drugs to be added to the skin
preparation should be determined on the basis of the
activity of the drugs. When a larger amount of the drug is
used, it is preferred to increase the amounts of the
phosphatide and the alkanolamine to be used.
A drug can be added to the skin preparation either
in the form of a solution in the oily eomponents, water,
propylene glycol, polyethylene glycol or ethanol, or in the
form of a solid as it is or as pulverized powder.
The symptoms of patients with a dry skin condition
disappear or are alleviated by applica~ion of the skin
preparation of this invention.
The skin preparation of this invention may also be
used to treat burn victims to protect fro~ fluid loss. It
has been found that thin deformable layers of approximately
to 50 micrometers thickness will form upon the topical
application of the skin preparation of this invention to a
subject, which provides a strong flexible film. The
resultant film is both permeable to atmospheric gas exchange
and able to reduce the evaporative loss of water from the
tissue surfaces. Silver sulfadiazine can be included in the
skin preparation to avoid wound infection.
The skin preparation of this invention containing
a topical steroid hormone can be used to treat eczema,
ichthyosis, lichen psoriasis and the like to attain the
disappearance or alleviation of the sympton. ~s described
above, the sk;n preparation of this invention has the action
of moisturizing and tenderizing skin and nail. In addition,
the skin preparation of the invention, when used for the
delivery of drugs, disperses and retains the drugs in the
skin in a uniform manner. Therefore, the skin preparation
of this invention is very useful for moisturizing skin,
preventing keratinization, tenderizing nail and treating
skin diseases.
8eyond the general description of this invention,
a more complete understanding can be obtained by ex~nples
~hich are provided herein for purposes of illustration only
and are not intended to be limiting in any manner.
,", : , ....
:
: - :.. ' :., : . , :: '~
7~
A. OLEAGINOUS OINTMENT
(A-l) Ointments prepared from petrolat~m
White petrolatum was melted on a water bath and
warmed to about 70C. The other ingredients were
dispersed in the liquid paraffin and warmed to 70C
and then added to the petrolatum and was stirred
until it congealed.
(A-2) Ointments ere~ared from Plastibase
All of the components are combined and stirred to
obtain a uniform mixture.
B. POLYETHYLENE GLYCOL OINTM~NT
Polyethylene glycol 400 was heated on a water bath
at 60 to 70C. Polyethylene glycol 400 and the
other ingredients, previously dispersed in the
liquid paraffin, wera added to this melt with
stirring. Stirring was continued until the
solidification takes place.
C. ~BSORPTION OINTMENT
Cetyl alcohol and white petrolatum were melted on a
water bath, then the other ingredients were added
to this melt and the mixture was heated to about
75C with stirring. Next, the deionized water was
heated to the same temperature and added. The
mixture was stirred until it congealed.
D. OIL-IN-WAT~R CRE~M (HYDROPHILIC OINTMENT)
Stearyl alcohol, cetyl alcohol, polyoxyethylene 45
monostearate and white petrolatum were melted on a
water bath, then the other ingredients were added
to this melt and the mi~ture was heated to about
75C with stirring. Next, the deionized water was
heated to the same temperature and added. The
mi~ture was stirred until it congealed.
:
,.~ ~. . , ;
9 ~34276
E~ample 1 Oil-In-Water Cream
The following skin preparation was made:
White petrolatum g.9% by weight
liquid paraffin 12.9
stearyl alcohol 5.0
Cetyl alcohol 2.1
SLP-~.~ite (powdery soy 4.0
lecithin having a phos-
phatide content of 95~)
Triethanolamine 0.8
Citric acid monohydrate 0.35
Dibutyl hydroxytoluene 0.025
Polyo~yethylene 1000
cetyl ether 4.0
p-Chloro-m-cresol 0.2
~eionized water remainder
1 00~6
The above skin preparation has been tested on the skin and
found to provide a good moisturizing effect. The moisture
barrier provided by the relatively large molecular complex
(esch mols of lecithin capable of complexing tightly with 10
to 12 molecules of water) and the lecithin staying near the
surface due to the positively and negatively charged
portions of the molecule, the skin preparation of the
present invention provides relatively long protection for
the skin against drying. Varying the ratio of
triethanolamino to a phosphatide, tests have been made.
~lost advantageous effects have been found for 1 to 4 moles
of triethanolamine per mole of a phosphatide.
. , ,: ,.
- .......................... ..... .
, :: :, ::: .,
~ 3~76
Eg~LES 2 to 5
The following skin preparations were made:
Polyethylene
o/w Oleaginous Glycol Absor?tion
cream Ointment Ointment Ointment
_
EX~MPLE
No.
Composition _ 2 3 _ 4 5
SLP^~Yhite
(Soybean lecithin) 4.0 4.0 4.0 4.0
Triisopropanolamine 1.0 1.0 1.0 1.0
Lactic Acid 0.58 0-.58 0.58 0.58
Butylated
hydroxytoluene 0.025 0.025 0.025 0,025
tVhite petrolatum 9.9 ~ - 10.0 40.0
liquid paraffin 12.9 - - -
Plastibase 50 W
(polyethylene and
llquid petrolatum base) = ~ 94.395 ~ -
Stearyl alcohol ~ 5.0
Cetyl alcohol 2.1 - - 18.0
Polyethylene glycol
4000 - - ~1.395
Sorbitan Sesquioleate - - - 5,0
Polyoxyethylene 45
Monostearate 4.0
Polyoxyethylene lauryl
ether
p-Chloro-m-cresol 0.2 - ~ 0.2
Deionized water 60.745 - -- 30.695
Total (~ by weight) 100.0 100.0 100.0 100.0
- : ', ..
. ~
- ~ . : : ,.
:: ' , : ?
' . :' :
: ' ' -~, , ": ' ''
: ' '. . ;' '
3~ 6
Using these skin preparations, transepidermal water loss
e~periments were made.
I. Skin samples are obtained from fresh cadavers. All skin
samples are from the abdominal area. Epidermis is
separated from dermis by the procedure of Baumberger (J.
of Natl. Cancer Inst. (US) 2, 413, 1941). Epidermal
samples are wrapped in aluminum foil and are maintained
at -20 until used.
II. ~Apparatus for transepidermal water loss is all glass
with ground glass joints to secure the epidermis. The
opening in the apparatus over which the epidermis is
placed occupied 2 cm2. All of the apparatus is placed
inside an analytical balanee. The balance chamber
contains a humidity controller. Weight measurements are
made as a function of time. Epidermal samples, about 2
cm on a side, are placed onto the WAter reservoir
portion of th-e TWL apparatus. The open cover of the
apparatus is clipped into place with the epidermis
clamped between the ground glass surfaces. The
apparatus containing the epidermal sample and water is
weighed. Thirty minutes are allowed for evaporation of
surface water before measurements begin. ~ravimetric
measurements allow for determinations of water loss to
be made. 2-4 hours are required for s-teady state to be
achieved. ~easurements continue for several hours after
steady state has been achieved. The steady state rate
at the 15th hour from the start of the measurement is
used as the transdermal water loss rate.
- ,
: . ,;
- . .. ~
- - . : :. . : -
. . ~.~ .
-12- ~3~6
The following skin preparations were used as references:
Cream Oleaginous Ointment
. . . _ _ . . .. .. . . ... ..
Comparative Skin Preparation
A B C
Composition
_ _ _
~ite petrolatum 9.9--~ - 100
Liquid paraffin 1~.9
Plastibase 50W - 100
Stearyl alcohol 5.0
Cetyl alcohol 2.1
Polyoxyethylene
cetyl ether 1.7 - -
P-Chloro-M-Cresol 0.1
Deionized water 68.3
Total (% by weight) 100.0 100.0 100.0
.
The results are shown in the following table:
Rate of Epiderm~l Water Loss
(mg H2O/cm -hour)
(at the 15th hour from
Skin Preparationthe start of the experiment
Untreated epidermal sample 0.49
llpid e~tracted material 1~0
carried out wlth CHC13/MeOH
Skin Preparation A 0.44
" 8 0.065
n C
Skin Preparation 2 0.25
" 3 ~.041
rt 4 0.055
" 5 0.13
-~.
" - ,: .~: .,. , :
. . : . ,: : :
-13- ~34~76
The transepidermal water loss (~L) values represent averages of
3 sets o values carried out on 3 different samples of epidermal
skin for each condition. The data obtained with lipid extracted
material (carried out with chloroform-methanol) demons.rate that
the water loss through epidermis is substantially enhanced. This
indicates that the barrier to water loss by epidermis and by
stratum corneum is sustantially determined by lipid content. The
untreated sample drops to a half value. The rate of epidermal
water loss of the epidermal skin sample treated with the
conventional skin preparation decreases as the water content of
the skin preparation decreases. Although a decrease in the rate
of epidermal water loss of the epidermal skin sample treated
according to this invention is accompanied by a decrease in the
water content of the skin preparation, the decrease is always
smaller than that of the conventional skin preparation compared
at the same water content. This demonstrates that phosphatide
and triisopropanolamine contained in the skin preparation of this
invention suppress the water loss.
F~LES 6, 6', 6", 7, 7' and 8
Topical ~teroid hormone skin preparstions having the following
composition were prepared.
~L~3a~Llf~11~6
\
\ O U~ U~ 0
\ ~ lllo
O,
U~
~CO O C~ ~ O O U~ O O
1~ ~roOO I~ 1 1 lo
_
~ \
~ \ O O OU~OO
t~ \ ~ I I I ~ I I I U~OOL~
O,
U~ L7
~1 ~ ~ U~ O
~ 0 ~ ~ 0 0 0 0 ~ ~ ~ 0
~ ~r o' o o' o I I I ",~ O' ~; O
~ _
b u~ \ o
~ o ~ ~ ~ o ~ o ~ o
~ \ a~ I I o~o
o
O CO D O U~ O
~ ~ro'o'o' I I ~ I I I I I I I I I o
U~ ,,
o ' '
~o
o co ~o o a~ o ~ o ~ er O
...... .. . ...
~ ~r o o o ~ I I ~oo
~ I oo
~ / ~ oo ~
~ / ~ o ~
I ~ a~
/ a~ o ~ ~ ~ ~ ~ 3 ~
/ ~ J `~ ~ (O ~1 o .~ h ~ 3
/ ~O O ~ O o ~ 0 `~ ~
/ ~ ~
,1 O--~ ~ O ~ ,h
/ ~ U~ ~ ~
/ O o r` >1 ~ ~ ~ ~ 5 rC ~1 ~1 ~ a~ O O O o O a) O
, c~ ~ ~ m x ~ , ~ .
~4
. , , . ~ ..
: , .
- - ~
,. . , ... ~ . ,
... ..... .. . .
-15- ~ ~3~2~
The Toneli method was used to measure the anti-inflammatory
QCtivity of this skin preparation (Endocrinology 77 625-634
(196~)).
A ph1Ogistic solution comprising pyridine, ether and croton oil
(50:~5:5 (V/V)) is applied to the right ear of the mouse and then
the skin prepartion is applied thereon. Eive hours after the
treatment, both o~ the ears are excised at a predetermined
position and the wet weights of the ears are determined to
calculate the edema ratio according to the following equation:
Edema Ratio (~) = (Weight of Left Ear ~ 1) ~ 100
Inhibition ratio is calculated according to the following
equation:
~nhibition Ratio (~)
Edema r~tio when treated with ointment)
= (1 - '''~-'~`~--Edema ratio when untreated ---- x 100
Ten male mice weighing 20 to 25 g are used as one group. The
results are shown in the following table,
'''~~Dr~ Preparaticn '' Edemfl Ratio Inhibition Effect*
%Ratio
(?6)
_
Ex~mple 6 22.9 7T.9 +++
~eclomethasone Example 6 2~.1 -7T.7 +++
17, 21-dipropionate Comparative D32.8 68.4 ++
~ Example 7 39.1 62.3
Hydrocortisone Comparative E -lS.l 56.5
Example 8 35.7 65.5 ++
Prednisolone Comparative F40.2 61.2 ++
Untreated 10~.6 0
Score Inhibition ~atio
+++ -75-100%
++ 50-75~
+ 25-5~%
- 0-25%
., : . . .
- 1 s~ 3~7~;
As is apparent from the above table, the skin preparation of this
invention possesses higher anti~inflammatory activity as compared
with the conventional ointment bases. Judging from these
results, the pharmaceutical effects of the skin preparation of
this invention are raised by the formation of a complex in which
a phosphatide is non-convalently complexed with a steroid,
because the complex increases the compatibility and retainability
of the steroid in the skin.
..
:.'' ' :. . ' ' :
., . "
' !
., ,'
,.. '' ' ~ ' ' ~'~ ' ,
-17- ~3~2~
EY~.~LES 9, 10 and 101
The skin preparation having the following composition are
prepared.
. _ . . ..
Oleaginous o/w cream Absorption
_ Ointment _ _ _ Ointment
Example
No. Example Compara- Example Compara- Example
tive tive
Com~osition ~9) _ (G) (10) ~H)__ _ (10')
Hydrocortisone
17-butylate 0.1 0.1 - - -
Indomethacin - - 1.0 1.0 1-.0
____________________________________________________________
SLP-White 4.0 - ~ 4.0 - 4.0
(Soy lecithin)
Triisopro-
panolamine 1.0 - 1.0 - 1.0
Lactic acid 0.58 - 0.58 - 0.58
Butylated
hydroxytoluene0.025 - 0.025 - 0.025
~ite
Petrolatum - - 9.9 9.9 40.0
Liquid
paraffin - - 12.9 12.9
Plastihase 50W94.29299.9
Stearyl alcohol - - 5.0 5.0
Cetyl alcohol - - 2.1 2.1 -18.0
Polyoxyethylene
45-monostearate - -- 4.0 4.0
p-Chloro-m-
cresol - -- 0.2 0.2 0.2
~eionized water - - qs qs 29.695
Sorbitan
sesquioleate - - - -~~ 5.0
Polyoxyethylene
lauryether - - - - o.5
_~ ,
Total (w/w~) 100.0 100.0 100.0 100.0 100.0
, ~ " . :
- , , -: ., -. . : ,
-18- ~3~7~
Anti-inflammatory activity is measured for the above skin
preparations by skin carrageenan edema inhibition test. The test
is condu~ted by the following method.
Male rats weighing 190-210 g are used in the following
test. Their side abdominal hair is removed before the start of
this test. 1~ carrageenin solution is injected intra-dermally at
a predetermined position from each side of the abdomen.
Immediately after carrageenin injection, 1 ml of 1% pontamine sky
blue saline is administered intravenously. ~urthermoe~ an
accurately determined volume of topical formulation is applied on
the surface of the abdominal skin.
Five hours after the treatment, the abdominal skin is
removed from the body and score as to the following items.
Dye lealcage at the iniection site
Calculated by measuring the ma~imum and minimum diameter of
the dye blue spot.
Edema skin weight
Calculated by measuring the weight of the perforated edema
skin (lcm ~ lcm = round shape)
_________________________________________________________________
Edema weight = Edema skin weight - Normal skin weight
Edema ratio = Edema weight / Normal skin weight
The results are shown in the following table.
- :
-19~ 6
_ . ... ... _
Hydrocortisone 17-alpha-butyrate - 0.1%
Example Comparative Untreated
(9) (G)
_ _
Edema weight -58.4 72.9- 111.7
(mg) ~47.7~) -(~-34~.7%) ( - )
Edema ratio 79.4 ~99.7 142.8
(--4~.~) (-30.2%) ( - )
~lue ~rea 6S.7 79.3 123.3
(mm ) (-44.3~) (-35-.5~) ( _ )
____________________________________________________________
Effect ++ ++
. . . _ . ~
Indomethacin 1~
E~ample Comparative Untreated
(10) (H)
_
Edema weight 51.6 62.9 - 67.6
(mg) (-23.7%) (- 7.0~) ( - )
Edema ratio -68.9 - -86.9 90.8-
(-24.1~) (- 4.3~) ( - )
Blue area 72.5 68.2 77.9-
(mm~) (- 6.9~) (-12.5%) ( - )
_________~__________________________________________________
Effect +
.. ~ . _ .
Score ~+ Inhibition ratio3~-45%
+ 15-30~
_ 0-15%
As is apparent from the above table, the skin preparation of this
invention possesses higher anti-inflammatory aetivity as compared
with the conventional topical formulations.
.,
.,
.
.
: " .
-2~-
~ .~.3~
Eg~MPLES 11 and 11'
The skin preparations having the following composition were
prepared.
o/w cre~m ~bsorption
Ointment
_
Example 11 ~xample 11'
Chlorpheniramine Maleate 1.0 % by weight1.0
White petrolatum g.9 40.0
Liquid paraffin 12.9
Stearyl alcohol 5.0
Cetyl alcohol 2.1 18.0
SLP-White
(Soy lecithin) 4.0 4.0
Triethanolamine 0.8 0.8
Citric acid
monohydrate 0.35 0.3s
Butylated
hydroxytoluene 0.025 0.025
Polyo~yethylene
45-monostearate 4.0
p-Chloro-m-cresol 0.2 0.2
~eionized water qs 30.125
Sorbitan sesquioleat - 5.0
Polyo~yethylene
laurylether - 0,5
Total (~ by weight) 100.0 100.0
The above skin preparation has been tested on the guinea-pig baak
skin and found to be more effective in preventing vascular
permeability increase caused by 0.1% histamine 0.05 ml as
compared with the conventional ointment bases.
.; ,
,
4:;~7~
-21-
E~amples 12-27
~kin preparations are prepared having the composition shown in
the following table
E~MPLE NO.Example 12 Example 13 Example 14
_
DrugSulfiso~azole Tetracycline Chloramphenicol
Hydrochloride
5.0 3.0 2.0
SLP - White
(Soy lecithin) 4.0 4.0 4.0 4.0 4.0 4.0
Triethanolamine 0.8 0.8 0.~ 0.8 0.8 0.8
Triisopropanolamine
Lactic acid 0.62- - 0.62-- - 0.62
Citric Acid - 0.35 - 0.35 - 0.35
Butylated
hydro~ytoluene 0.025 0.025 0.025 0.025 0.025 0.025
White petrolatum40.0 9.9~~ 86.555 9.9 - - 9.9
Liquid paraffin - 12.9 5.0 1.2.9 - 1~.9
Plastibase 50W - - - - 92.55S
Stearyl alcohol - 5.0 -- 5.0 - 5.0
Cetyl alcohol 18.0 2.1 - 2.1 - 2.1
Polyethylene
Glycol 4000 - - - - - -
Polyethylene
Glycol 400
Polyo~yethylene 45
monostearate - 4.0 -~ 4.0 -~ 4.0
Sorbitan
sesquioleate 5.0 - - - - -
Polyoxyethylene
laurylether 0.5 - - - - -
p-Chloro-m-cresol 0.2 0.2-- - 0.2 - 0.2
Deionized water25-.855 55.725 - 57.725 - 58~725
_ . _
Total (~ by
eight) 100.0_ 100.0_100.0 100.0_ 100.0 100.0
Type of Absorption o/w olea- o/w olea- o/w
Formulation ointment cream ginuous cream ginuous cre~m
_ ointment __ _ ointment
. ~ ~ ' ' ,
,. : . ~' ' :''
:
--22- ~ ~3~7~
E~LE N~. Example_15 Example 16 Example 17
, . . . _ .
Drug Gentamicin Acrisorcin Ichthammol
sulfate 0.2 10.1
~LP _ t~hite
(Soy lecithin) 4.0 4.0 4.0 4.0 4.0
Triethanolamine 0.8 0.8
Triisopropanolamine - - 1.0 1.0 1.0
LRctic acid 0.62- - 0.58-- - 0.58
Citri~ Acid - 0.35 - 0.32
Butylated
hydroxytoluene 0.025 0.025 0.0250.025 0.025
~Yhite petrolatum - 9.9 - 40.0 - 9.9 -79.395
Liquid paraffin 10.0 12-.9 - 12.9 5.0
Plastibase 50W
Stearyl alcohol - 5.0 - 5,0
Cetyl alcohol - 2.1 18.0 2.1
Polyethylene
Glycol 4000 42.455
Polyethylene
Glycol 400 42.0
Polyoxyethylene 45
monostearate ~- 4.0 - 4.0
Sorbitan
sesquioleate - -- 5.0
Polyo~yethylene
laurylether - - 0.5
p-Chloro-m-cresol - 0.2 0.2 0.2
Deionized water - 60-.625 30.495 60.355
Total (% by
weight) lO0.0 100.0 100.0 100.0 100.0
_
Type of Polyethyl- o/w Absorp olw 01ea-
Formulation ene glycol cre~m tionous cream ginous
ointment ointment ointment
:. '' ' .
- .. :- ,:
,, , . , ~ .
--23~ L3'~'~76
[PLE `IY). Example 18 Example l9 Example 20
. . .. . _ . . _ .
Drug Undecylenic Nystatin Sodium
Acid ~~ 5.0 Heparin 0.4
Zinc Undecyle- (50,000 units)
nate 20.0
. . . _ . . .
SLP - IVhite
(Soy lecithin) 4.0 4.0 4.0 4.0
Triethanolamine - - 0.8 0.8
Triisopropanolamine 1.0 1.0
Lactic acid 0.58 0.58 - 0.62
Citric Acid
monohydrate - - - -- 0.3S
Butylated
hydro~ytoluene 0.025 0.025 0.025 0.025
White petrolatum - - 40,0 - 9.9
Liquid paraffin 10.0 - - 12.9
Plastibase 50W - 90.895
Stearyl alcohol - - - 5.0
Cetyl alcohol - - 18.0 2.1
Polyethylene
Glycol 4000 28.395
Polyethylene
Glycol ~00 31.0 -
Polyoxyethylene 45
monostearate - - - 4.0
Sorbitan
~esquioleate - - 5.0
Polyoxyethylene
lAuryl ether - - - 0.5
p-Chloro-m-cresol - - 0.2 0.2
Deioni~ed water - 30.455 60.325
.. . .
Total (% by
weight) 100.0 100.0 lOQ.0 100.0
Type of Polyethylene Oleaginous Absorp- o/w
Formulation glycol ointment tion crearn
ointment ointment
': ' ' , ' ' - '
. .
~,
-24-
~:~3~7~
EX~MPLE NO. E~ample 21 Example 22 Example 23
. _ _ , . . _ . .
Drug Urea 10.0 ~ 5-Fluoro- Bleomycin
uracil sulf~te
_ 5. Q 0.5
SLP - ~hite
(Soy lecithin) 4.0 4.0 4.0 4.0 4-0
Triethanolamine - - - - -
Triisopropanolamine 1.0 I.O 1.0 1.0 1.0
L~ctic acid 0.58 0.58 0.580.58
Citr~c Acid ~ 0.32
Butylated
hydroxytoluene 0.025 0.025 0.0250.025 0.025
White petrolatum79.555 - 9.9 - 9.9
Liquid paraffin 5.0 ~ - 12.9 10.0 12.9
Plastibase 50W - 89.555
Stearyl alcohol - 5.0 5.0 ~ - 5.0
Cetyl alcohol - - 2.1 - 2.1
Polyethylene
Glycol 4000 - - -- 42.055
Polyethylene
Glycol 400 ~ - - - ~2.0
Polyoxyethylene 45 -~~
monostearate - -` 4.0 - 4.0
Sorbitan
sesquioleate - - - - -
Polyoxyethylene
lauryl ether
p-Chloro-m-cresol - - 0.2 ~~ - 0.2
Deionized water - - 55.295~-~ 80.055
Total (% by
wei~ht) 100.0 100.0 ldO.O 100.0 100.0
Type of Oleaginous Olea- o/w Poly- o/w
~ormulation ointment ginous cream glycol craam
_ _ ointment _ ointment
: , , ,. . - .
,: ' ~ - :
- , :. .
.. . ... . .
: - : ~ .
_~5_ ~3~Z76
. _ _ _ .. . . .
E~PLE NO. Example 24 Example 25 Example 26
. _ . . _ _ . . _ _ . . .
Dru~ Lidocaine Ethiny- Testosterone
3.0 lestoradiol 1.0
. _ _ _ . ~ . _ _ _ ... . .
SLP - ~ite
(Soy lecithin) 4.0 4~0 4.0 4.0 4.0 4.0
Triethanolamine 0.8 0.8 0.8 0.8 0.8 0.8
Triisopropanolamine - - - - - -
Lactic acid 0.62 ~ 0.62 - 0.62
Citric Acid - 0.35 - 0.35 :` 0.35
Butylated
hydro~ytoluene 0.025 0.025 0.025 0.025 0.025 0.025
Nhite petrolatum -86.555 9.9 89.545 9.9 - - 9.9
Liquid paraffin 5.0 12.9 5.0 12.9 10.0 12.9
Plastibase 50W
Stearyl alcohol - 5.0 - 5.0 - s.0
Cetyl al~ohol - 2.1 - 2.1 - 2.1
Polyethylene
Glycol ~000 ~ 41-.555
Polyethylene
Glycol 400 - - - - - 42.0
Polyo~yethylene 45
monostearate : 4.0 -- 4.0 - 4.0
Sorbitan
se~quioleate
Polyoxyethylene
lauryl ether - - - - - -
p-Chloro-m-cresol - 0.2 - 0.2 -~ - 0.2
~eionized water - 5T.725 - 60.715 - 59.725
, .
Total (~ by
weight) 100.0 100.0 100.0 100.0 100.0 100.0
... . . . _
Type of oleaginou3 oJw olea- o/~ olea- o/w
Formulation ointment cream ginous cream ginous cream
ointment ointment
,
--26~ Z76
F.YAMPLE NO~ Ex~mple 27
Drug Nitroglycerin
2.0
.. . . . _ _ .
SLP - White
(Soy lecithin) ~.0 4.0
Triethanolamine 0.8 0.8
Triisopropanolamine
Lactic acid 0.62
Citric Acid - 0.35
Butylated
hydroxytoluene 0.025 0.025
White petrolatum 87.555 9.9
Liquid paraffin 5.0 12.9
Plastibase 50W - -
Stearyl alcohol - 5.0
Cetyl alcohol - 2.1
Polyethylene
Glycol ~000
Polyethylene
Glycol 400
Polyoxyethylene 45
monostearate - 4.0
Sorbitan
sesquioleate
Polyoxyethylene
lauryl ether
p-Chloro-m-cresol - 0.2
Deioni2ed water - 58.725
Total (% by
weight) 100.0 100.0
Type of O!eaginous o/w
Formulation ointment cream
.
- --.' ~- . -
.. . .,: . ; :, :
,: . . ..
