CA1113005A - Excipient composition for creams - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:
The delayed release of an active principle incor-porated in a cream for dermatological or medical use is considerably improved by admixing to the cream base an amount of from 0.6% to 15% on a weight base of microfibres having an extremely high surface for weight unit of fibres. The active principle can also be occluded in the microfibres prior to their admixture with the cream base.

Description

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.

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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.

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~ 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).

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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"
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~- 20 Carboxymethyl-~-~ cellulose g23 22 25 Glycerol ~184 180 200 Dist. water!1 713 698 775 Microfibres " 80 100 , :

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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.

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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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~ o -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.

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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 ' - - - - -- ---- _ _ ,~ . , ' .

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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 ., .

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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

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~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.

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Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A base composition for dermatological cream, said composition having a high hydrating power and comprising at least one dermatologically acceptable mixture of grease and water in association with a wetting agent mixture characterized in that said composition further comprises from 0.6% to 15%
by weight of thermoplastic microfibres having a high specific surface.

2. A base composition according to claim 1, comprising from 1% to 10% of thermoplastic microfibres on a weight basis.

3. A base composition according to claim 1 or 2, wherein the thermoplastic microfibres contain active principles occluded in their structure.

4. A base composition according to claim 1 or 2, wherein thermoplastic microfibres are made of high density polyethylene.

5. A base composition according to claim 1 or 2, wherein the thermoplastic microfibres are made of high density polyethylene containing a hydroxyl group.

6. A base composition according to claim 1 or 2, wherein the thermoplastic microfibres are made of low density polyethylene.