Note: Descriptions are shown in the official language in which they were submitted.
This i~v~e~tion relates to a nove~ e~cipie~t com-
position useful as a base for a dermatological cream, ~hich
contains microfibres of plastics material and advantageously
has non-drying and hydrating properties~
In the formulation o~ dermatolo~ical creams~ both
for cosmetic and medical use, it is known that the excipient
is the vehicle into which the active principles and the other
ingredients of the cream are incorporated, the excipient being
intended to impart to the cream the required body.
However, the excipient is not used only for that
purpose.Indeed,it may also be used for encouraging slowing or ~- -
preventing the effects of the active fraction. The excipient
, may even exhibit an activity of its own.
In the cream formulation, it is also known that
; whatis called the base of the cream is the product which pro-
duces the basic effects of hydration and so~te~ing.
The softening action is c~enerally obtained by the
greases that are spread onto the skin. The greases imbibe ~-
more or less deeply, the cutaneous layers, they are easily
admixed with the normal sebaceous secretions of the skin or
are emulged therewith so as to afford plumpness to the skin
tissues.
As a resulta cream which is composed of greases only
can be totally absorbed by the skin and can even leave, in
certain cases, a dry skin. Indeed, the skin necessitates water
in an absolute sense to retain its elasticity.
The horny surface layer of the skin is composed by
flattened cells which have lost their nuclei and-thus have
` become keratinized. Until such a layer of dead cells remains
soft and flexible, it can protect the underlying skin from
;~` desiccation. ~hen, in contrast, this layer becomes dehydrated~
fissures can be formed thereon and therefore deeper and more
~ $~.~t~
vital portion~ of the skin m~y become exposed to air.
As a result~ the base of the cre~m contain~ in
distilled water or hydroiates and wetting agents, such as
glycerol or other polyh~droxylated alcohols, addition to the
greases.
The wetting agents added to the creams have the
principal task of slowing down the loss of moisture and pre~
venting the quick drying of the product itself either in its
jars when left open or on the skin itself.
They, however, do not succeed in establishing a
reversible equilibrium between the atmospherical relative
humidity and the humidity of the cream. Thus they are unable
to prevent the possibility of drying of the products. Actually~
they are merely capable of delaying same.
It has now been found that the addition of from 0~6%
to about 15% by weight(preferably from l~ to 10%) of microfibers
of thermoplastics material having a high surface area, such
as those obtained according to the methods described in the
Canadian Patent Specifications 1.068.861 and l~011.900, to a
cream base of the conventional type containing waterr grease,
wetting agents and others additives, substantiall~ protects
the cream from drying-up without mcdifying its other basic
functional properties.
The invention will be better understood with refer-
`~ ence to the following non-restrictive examples of formulations
for some base compositions of dermatological creams and th~r
relative behaviours (loss of moisture in time), as given in
the following patterns nl and 2 and table.
In the T~BLE, there is reported, for each formulation~
the loss of weight of layers of base compositions, after a
certain period of time the weiyht per unit surfa~e being re-
ported at the foot of the T~BLE.
. ~
.
This T~BLE clearly sho~s that the formulations
which eontain microfibres exhibit a ~ateX loss ~hich is
considerably lower even if the elapsed time is long, in spite
of the fact that they contain lesser amounts of wett.ing agents~
It has been ascertained, and this is another aspeet
of the present invention, that the ineorporation, by deposit
or absorption or appropriate admixture of aeti~e prineiples,
possibly having a medicinal acti.on, in the mierofibres, the
latter being obtained aecording to the methods disclosed in
the above mentioned Canadian patents, imparts to the creams
- in whieh sueh mierofibres have been ineorporated, a ~edici~al
or a protective action which is both longlasting and eonstant
as the time goes by.
/
.
_
W
~ ore exactly, the ~ctive principles occ~uded in
the microfibres are released by the cream composition in a
manner which is both controlled and regular, so that an action
of the cream on the skin which is constant in time is made
possible, the advantages of such a feature bein.g consp~cuous
under all respects, both in the case of a medicinal or a
cosmetic cream.
By happily combining this action with the con~
; stant hydration action, the advantages can be ~ull~ appreciated~
To illustrate this aspect of the ~nvention but
without limiting it thereby, a series of test will ~ow be
descri.bed, which have been performed with creams as prepared
with an excipient which contains the microfibres indicated
above, in which hydrocortisone has been occluded, as compared
~ with fibres of the identical composition but in which hydro-
: cortisone has not been occluded by the fibres /PATT~RN 3).
.. ~,1, -
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. 5.
PATTERN l
.
Formulation A Form~lat on A'
Carboxyl~ethylcellulose ~ 85 95
Glycerol , 50 55
- 5 Dist. water 'l 76~5 8So
Microfibres " 100
Formulation B Yormulation B'
carboxymethylcellulose g 20 22
-~; Polyvinyl alcohol '' 40 44
Vaseline ll 3oo 334
Dist. wa~er ~' 540 600
Microfibres " 100
.
Formulation C Formulation C'
Carboxymethylcellulose g 10 12
Poly~inyl alcohol " 40 42
Glycerol D 45~ ~3
Dist. water ~ 450 473
Micro*ibres ~' 50
Formulation D Formulation D~ Formulation D"
_ ~
~- 20 Carboxymethyl-
~-~ cellulose g23 22 25
Glycerol ~184 180 200
Dist. water!1 713 698 775
Microfibres " 80 100
, :
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PATTERN 2
Eo ~lulation E Formulation E'
~ Carboxymethylcellulose g 48 5~
; Glycerol " 190 200
Dist. water ~ 71~ 748
Microfibres ls 50
~ Formulation F'
Carboxymethylcellulose g 76 79
Glycerol ~' 194 200
Dist. water ~ 710 '~21
Microfibres ll 20
F ~llation G Formulation G'
Polyacrylic acid g 9.9 10
` Ethanol ~'149~0 ~50
Glycerol "198.0 200
Triethanolamine "19.8 20
Dist. water "617.3 620
Microfibres ~' 60
o~ml31ation H Formulation H'
~` 20 Polypropyleneglycol
stea~ate g 178 180
paraffin oil " 78 80
Sodium methyl-p.benzoate
~`~ D~. w~er ll733 739
Miorofibr~s " 10
Formu t on I Formulation I
Fatty alcohols g 148 1$0
Glyc~rol ~ 198 200
Dist. water n 644 650
Microfibres ~ 10
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The tests which have been carried out to evaluate
the release of the medicinal substance in the creams have
been tests of two kinds, that is, in vivo, by evaluation of
the vessel-constricting effect of hydrocortisone, which gives
as a conspicuous effect a decrease of the skin temperature,
and in vitro by measuring the diffusion of the active prin-
ciple from the composition immersed in a solvent medium, by
measuring the active principle which is present in the solvent
at regular intervals.
The microfibre employed for the formulation
of the creams had been obtained, respectively, from high-den-
sity polyethylenes (PA 1/1), from modified high-density poly-
ethylene, that is a hydroxyl group containing polyethylene
(P~ 1/2) and from low-density polyethylene (PA 1/4).
The creams which have been used have been
prepared in the form of gels or ointments. In the case of
the gels, the excipient base had the following composition :
Polyacrylic acid [Carbopol 934 (trademark)
for pharmaceutical use~ 10 g
Ethanol 150 g
Glycerol 200 g
Water ~20 g
Triethanolamine a quantity sufficient to
ad~ust the pH to the de-
sired value
The gel has been prepared according to the
conventional procedures, viz.: dispersion of the Carbopol
in the mixture of alcohol and glycerol with stirring. Upon
obtaining a homogeneous mixture, water has eventually been
added by gently stirring to prevent the incorporation of
too much air.
8 --
~ .
.
The gel has been allowed to st~nd for about 48
hrs. whereafter the active principl~ has been incorpo~ated,
alone or occluded in the microfibres, by admixture in a mortar
or in a slowly moving planetaxy mixer.
In the case of ointments, the followin~ compositions
have been used:
A - Polypropyleneglycol stearate l~ ~
Liquid~paraffin oil 8 y
Sodium methyl-parahydroxybenzoate 0.1 g
Water 100 mls
B - Admixture of ~atty alcohol with
polyhydroxyethylene alcohol 15 g
Glycerol 20 g
Water lO0 g
Upon melting the fatty excipients to give a homo-
geneous mixture, water has been added by increments unti~ -
it was totally incorporated and the mixture allowed to cool
at 20C. After a stay of about 12 hrs, followed by ho~
mogeneization, the active principle has been incorporated,
either alone or occluded in the microfibres, in a planetary
mixer having a slow motion.~ For the addition of the hydro-
cortisone to the microfibres, a hydrocortisone solution has
; been prepared, in which the microfibres have been dispersed
by stirring in an Ultra-Turrax turbodispersing apparatus.
Upon filtration under atmospherical pressures, the mixture
has been allowed to dry, a mass of microfibres having thus
-- been obtained, which were loaded with the active principle.
The absorption of hydrocortisone from its solution was ~irtu-
; ally complete. In the experimental
.. ~
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,' ~ . .
. .
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formula-tions~ there have been added o.6 g of hydro-
cor-tisone per 0.4 of microfibres and the addition of
the thu31y loaded microfibres to the creams has been
carried out in such ratios as to obtain a final con-
tents of 1% hydrocortisone.
The in vivo tests have been carried out both on
Guinea pigs and menO To this purpose~ the gel or cint-
ment has been applied to skin areas with an occlusive
bandage and the decrease OI the sl~in -temperature has
been measuring by telemetering the temperature.
On account of the impossibiL:ity of maintaining
the bandage on the experimental animals for a long time~
no long-range evaluations have been carried out on
Guinea pigs for days, but~ rather~ for hours The in
vitro tests have been carried ouJ; in Paulson cells~
according to the diagram of FIGURE 19 in which 1 is the
stirrer (30 rpm), 2 is the thermostatic ba~h at 37~C~
~ is the solvent liquor ~in this case it was isopropyl
myristate, about 200 mls), and 4 is a Petri capsule
containing the preparatio-sl in gel form.
The Petri capsule~ containing 20 g of preparation
has been dipped in the solvent~ whereafter stirring
has been started and sampling ~f 1 ml each of 301ven-t
has been started, a-t intervals of one hour and during
~5 7 hours On the samples portions, the diffused hydro-
cortisone has been tested colorimetrically on tetra-
zole biue in methanol medium. The optical densities
have been read out in a spectrophotometer at 325 mane-
metres and there has been evaluated the quantity of
diffused product by comparison with a calibration curYe.
- The results of each test series are repor-ted in TABLES
1, 2~ 3 and 4 and in FIGURES 2, 3 and 4~ respectively.
~' .
TABLE 1 - Variation of temperati~re of the skin
-
after administration of ointlllent w.ith
hydrocortisone (wit,h microfibres and
~ithout same)
Timc e~apse~ as from
administra~ion~hours 2 4 6
_ _
~ Temperature ~ riations
C C ~ C
Control ~uinea O O
lQ pig (no treat-
ment whatsoever)
~ 1 tl
i Microfi.bre~free ~ 1 - 3 -5
gel - 1 - 2 -3
. 15 - 1 _3
Microfihre loaded --- 0.5 - 2
gel - 1.5 ~ 1.5 -1 :
~ 0.5 -2.5
,; Ointment A wit,hout - 1 0.5 -1
:` 20 microfihres ..
Ointment A with O - 1 -1oS
- r.licrofibres O 5 - 1.5 ~-5
~ . .
Ointment B wi-thout - 2 - 2 -1.5
microfibres - 2 - 2 ~3
~ 25 Ointment B with 0.5 - ~ -2
.- . microfibres
- 1 - 2 -3
' - - - - -- ---- _ _
,~ . , ' .
:: .
'- ,
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, .
. .
'
.
It is apparent, even though the results are not
completely uniform, presumably due to dif~iculties in main-
taining the bandage on the test animals, that the ointments
which contain microfibres have an activity which is slightly
delayed as compared with that of the ointment which has not
been micro-fibre-loaded.
TABLE 2 - Average variation of the temperature o the skin
of patients subjected to administration of hydro-
cortisone gel with and without microfibres - pH
6.8
Average drop of skin After After After After
temperature5 hrs 24 hrs 48 h~s 72 hrs
:,. C C C C
: Wit~lout
-1.5 -1.7 -1.3 -0.75
: microfibres
With
~-~ microfibres
PA 1/1 -2 -1.25 -1.25 -0
PA 1/2 -1.5 -1~75 -1.25 -1.5
PA 1/4 -O~S -1 -2 -1.25
., .
. ~ .
.~
. .
'';,',
.
.- - 12 -
, ' ' '
13.
TABLE_ 3 ~ Average variation of the skin temperature
of patients subjected to administration
of hydrocortisone gel w:;th and ~ithout
/~icrofibres - pH 4.~
Ave.skin After A:~ter After After
temperature S hrs 24 hrs 48 hrs 72 hrs
- drop
C '` C
. Without microfibres -1.25 -1 -1.5 Cl.3
, ~ , ,,,,, , _ ,
With microfibres
PA 1/.~ ` -2 -1.75 -1~5 -0
P~ 1/2 -0.5 -0.5 -1.75 -1
PA 1/4 -1 -1.5 -1O5 -1.5
.
_
TABLE 4 - Average variation of the ski~ temperature of patients: -
treated by administration of hydrocortiso-
;ne gel with and without microfibres - pH 708
, . . _ . . . .. ..
Ave.tempera- After Afte:r A~ter After
ture drop 5 hrs 24 hrs 48 hrs 72 hrs
......... ___'' '' '------F' o C C ----'-'C- ----
No microfibres -1.25 -1c7 -~1.5 -1.35
;
With microfibres
PA 1/1 ~ .5 -~ -1 5 `:
: PA 1/2 -2
PA 1/4 -1 -~05 -1.75 ~2
,, .
.
.. ..
.
.
,;, : `
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The in vivo tests on humans have shown a
regular delay effect, that is a time shift of the vessel-
constriction effect of hydrocortisone for the creams which
contained microfibres of the type PA 1/4, that is those
based on low-density polyethylene under all the pH conditions
which have been tested. Also in the cases in which the
hydrocortisone had been absorbed on other microfibres, the
delaying effects become nonetheless conspicuous.
Fig. 1 is a diagrammatical cross-sectional
view of a Paulson cell for carrying out in vitro tests.
Figs.2, 3 and 4 are plots which show on
the abscissae the time in hours and on the ordinates the
quantity of released hydrocortisone during progress of the
_ vivo tests: more particularly r the tests plotted in Fig. 2
refer to an environmental pH of 4,2, the pH being 7.8 for
the tests plotted in Fig. 3 and was 7.8 for the tests plotted
in Fig. 4.
From a scrutiny of the plots reported in
FIGU~ES 2, 3 and 4 of the accompanying drawings, which show
the diffusion of the hydrocortisone in a solvent medium star-
ting from the preparations which contain it in the free state
and occluded in the fibres of the types considered hereinabove
~ at different values of the pH, it is apparent that a delayed
; release of hydrocortisone is experienced from those creams
which contain that active principle occluded in the microfibres.
The diffusion values plotted in FIGURES 2,
;~ 3 and 4 relate -to gels having the respective pH values of 4.2,
6.8 and 7.8. In all three FIGURES 2, 3 and 4, the plots mar-
ked by a circle ~ refer to gels having 1~ hydrocortisone
without microfibres added, whereas those marked with a barred X
- 14 -
~"
:,, . -
;. :
~3
; ' . ,
X ) refer to gels containing 1% h~drocortisone with mi-
crofibres of the type PA 1~4 and those marked by --o--to
gels with l~ hydrocortisone with fibres of the kind PA 1j2
and lastly, those marked with --O-- to geIs having l~ hydro-
cortisone and fibres of the kind PA l/l, as defined herein-
before. ~
In all three FIGURES, an initial flattening
of the curves relative to the diffusion of hydrocortisone
from-gels which contain microfibres is apparent, that which
indicates a marked delay in the release o.f the active principle.
''''i ~ '
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